Neurobiology of Aging - Articles in Press

Acute moderate exercise enhances compensatory brain activation in older adults - Corrected Proof

2012-02-03

Abstract: A growing number of reports state that regular exercise enhances brain function in older adults. Recently a functional near-infrared spectroscopy (fNIRS) study revealed that an acute bout of moderate exercise enhanced activation of the left dorsolateral prefrontal cortex (L-DLPFC) associated with Stroop interference in young adults. Whether this acute effect is also applicable to older adults was examined. Sixteen older adults performed a color-word matching Stroop task before and after 10 minutes of exercise on a cycle ergometer at a moderate intensity. Cortical hemodynamics of the prefrontal area was monitored with a fNIRS during the Stroop task. We analyzed Stroop interference (incongruent-neutral) as Stroop performance. Though activation for Stroop interference was found in the bilateral prefrontal area before the acute bout of exercise, activation of the right frontopolar area (R-FPA) was enhanced after exercise. In the majority of participants, this coincided with improved performance reflected in Stroop interference results. Thus, an acute bout of moderate exercise improved Stroop performance in older adults, and this was associated with contralateral compensatory activation.

Expression pattern of oxidative stress and antioxidant defense-related genes in the aging Fischer 344/NHsd rat cochlea - Corrected Proof

2012-02-03

Abstract: The biological mechanisms that give rise to age-related hearing loss (ARHL) are still poorly understood. However, there is growing recognition that oxidative stress may be an important factor. To address this issue, we measured the changes in the expression of cochlear oxidative stress and antioxidant defense-related genes in young (2 months old), middle-aged (12 months old), and old (21–25 months old) Fischer 344/NHsd (F344/NHsd) rats and compared gene expression changes with ARHL. A quantitative real-time reverse transcription polymerase chain reaction array revealed a significant age-related downregulation of only 1 gene, stearoyl-coenzyme A desaturase 1, and upregulation of 12 genes: 24-dehydrocholesterol reductase; aminoadipate-semialdehyde synthase; cytoglobin; dual oxidase 2; glutathione peroxidase 3; glutathione peroxidase 6; glutathione S-transferase, kappa 1; glutathione reductase; nicotinamide adenine dinucleotide phosphate (NAD(P)H) dehydrogenase, quinone 1; solute carrier Family 38, Member 5; thioredoxin interacting protein; and vimentin. Statistical analyses revealed significant correlations between gene expression and auditory function in 8 genes. Our results identified specific subsets of oxidative stress genes that appear to play an important role in ARHL in the Fischer 344/NHsd rat.

Alzheimer's disease and age-related macular degeneration have different genetic models for complement gene variation - Corrected Proof

2012-02-03

Abstract: Alzheimer's disease (AD) and age-related macular degeneration (AMD) are both neurodegenerative disorders which share common pathological and biochemical features of the complement pathway. The aim of this study was to investigate whether there is an association between well replicated AMD genetic risk factors and AD. A large cohort of AD (n = 3898) patients and controls were genotyped for single nucleotide polymorphisms (SNPs) in the complement factor H (CFH), the Age-related maculopathy susceptibility protein 2 (ARMS2) the complement component 2 (C2), the complement factor B (CFB), and the complement component 3 (C3) genes. While significant but modest associations were identified between the complement factor H, the age-related maculopathy susceptibility protein 2, and the complement component 3 single nucleotide polymorphisms and AD, these were different in direction or genetic model to that observed in AMD. In addition the multilocus genetic model that predicts around a half of the sibling risk for AMD does not predict risk for AD. Our study provides further support to the hypothesis that while activation of the alternative complement pathway is central to AMD pathogenesis, it is less involved in AD.

ATP13A2 mutations impair mitochondrial function in fibroblasts from patients with Kufor-Rakeb syndrome - Corrected Proof

2012-02-02

Abstract: Mutations in ATP13A2 cause autosomal-recessive parkinsonism (Kufor-Rakeb syndrome; KRS). Because several other parkinsonism-associated proteins have been connected to mitochondrial function and mitophagy, we studied the impact of endogenous mutations in ATPase type 13A2 (ATP13A2) on mitochondria in fibroblasts from KRS patients compared with controls. In patients, we detected decreased adenosine triphosphate (ATP) synthesis rates, increased mitochondrial DNA levels, a higher frequency of mitochondrial DNA lesions, increased oxygen consumption rates, and increased fragmentation of the mitochondrial network. Importantly, overexpression of wild-type ATP13A2 rescued the respiration phenotype. These findings collectively suggest that ATP13A2 contributes to the maintenance of a healthy mitochondrial pool, supporting the hypothesis that impaired mitochondrial clearance represents an important pathogenic mechanism underlying KRS.

Behavioral decay in aging male C. elegans correlates with increased cell excitability - Corrected Proof

Xiaoyan Guo, Andrew Navetta, Daisy G. Gualberto, L. Rene García — 2012-01-30

Abstract: Deteriorative changes in behavioral functions are natural processes that accompany aging. In advanced aged C. elegans nematodes, gross decline in general behaviors, such as locomotion and feeding, is correlated with degeneration of muscle structure and contractile function. In this study, we characterized the age-related changes in C. elegans male mating behavior to determine possible causes that ultimately lead to age-related muscle frailty. Unlike the kinetics of general behavioral decline, we found that mating behavior deteriorates early in adulthood, with no obvious muscle fiber disorganization or sperm dysfunction. Through direct mating behavior observations, Ca2+ imaging, and pharmacological tests, we found that the muscular components used for mating become more excitable as the males age. Interestingly, manipulating either the expression of acetylcholine receptor (AChR) genes or dietary-mediated ether-a-go-go family K+ channel function can reduce the muscle excitability of older males and concurrently improve mating behavior, suggesting a correlation between these biological processes.

Effect of plasma lipids, hypertension and APOE genotype on cognitive decline - Corrected Proof

2012-01-30

Abstract: We examined the combined effect of plasma lipids/hypertension and apolipoprotein E (APOE) genotype on cognitive function in elderly individuals. Plasma concentrations of high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglyceride (TG), total cholesterol (TC), APOE, and history of hypertension were evaluated in 622 community-dwelling individuals aged 65 years and older. We investigated the associations between plasma lipids/hypertension and cognitive function in apolipoprotein E4 allele (APOE4) carrier (E4+) and APOE4 noncarrier (E4–) groups using 3-year longitudinal data. At baseline and 3 years later, cognitive scores were correlated with plasma APOE levels in both E4– and E4+, and HDL level in E4–. The combination of hypertension and E4+, but not E4–, was associated with a significant deterioration in cognitive function during the 3-year follow-up. Our findings suggest that an interaction between APOE and HDL is facilitated by APOE4, and is possibly linked with a protective effect on cognitive decline in later life. The findings also indicate a synergistic effect of an APOE4 allele and hypertension on the acceleration of cognitive decline.

Influence of functional connectivity and structural MRI measures on episodic memory - Corrected Proof

2012-01-30

Abstract: Age-related memory decline is the consequence of multiple biological factors that lead to brain structural and functional change, including gray matter atrophy, white matter injury, and loss of functional coordination between regions. However, the independent roles that each of these brain changes play in mediating memory decline is not clear. Therefore, we used magnetic resonance imaging (MRI) to measure gray matter (GM) volume, white matter hyperintensity (WMH) volumes, and blood oxygen level-dependent (BOLD) functional magnetic resonance imaging-based functional connectivity among default mode network nodes in 76 cognitive normal older adults. We found that GM, WMH, and connectivity between left inferior parietal and medial prefrontal cortex (MPF_LIP) were independently associated with episodic memory performance. Within the group with GM volumes below the median, greater MPF_LIP connectivity was associated with better memory performance, whereas this association was not present for individuals with GM volume above the median. These findings confirm the heterogeneous nature of brain-behavior relationships in cognitive aging. In addition, the relationship between resting state functional connectivity and memory performance, particularly amongst those individuals with more brain atrophy, strongly suggests compensation against the effects of neuronal injury.

Hormetic effect of amyloid-beta peptide in synaptic plasticity and memory - Corrected Proof

Daniela Puzzo, Lucia Privitera, Agostino Palmeri — 2012-01-27

Abstract: One of the hot topics in Alzheimer's disease research field is the “amyloid hypothesis” postulating that the increase and deposition of beta-amyloid peptides (Aβ) is the main pathogenetic factor. However, antiamyloid-based therapies have so far been a failure and, most importantly, growing evidences suggest that Aβ has important physiologic functions. Based on our previous findings demonstrating that low concentrations of Aβ enhanced both synaptic plasticity and memory, whereas high concentrations induced the well-known impairment of cognition, here we show that Aβ acts on hippocampal long-term potentiation and reference memory drawing biphasic dose-response curves. This phenomenon, characterized by low-dose stimulation and high-dose inhibition and represented by a U-shaped or inverted-U-shaped curve, resembles the characteristics of hormesis. The Aβ double role raises important issues on the use of Aβ level reducing agents in Alzheimer's disease.

A simultaneous ERP/fMRI investigation of the P300 aging effect - Corrected Proof

2012-01-27

Abstract: One of the most reliable psychophysiological markers of aging is a linear decrease in the amplitude of the P300 potential, accompanied by a more frontal topographical orientation, but the precise neural origins of these differences have yet to be explored. We acquired simultaneous electroencephalogram (EEG)/functional magnetic resonance imaging (fMRI) recordings from 14 older and 15 younger adults who performed a 3-stimulus visual oddball task designed to elicit P3a and P3b components. As in previous reports, older adults had significantly reduced P3a/P3b amplitudes over parietal electrodes but larger amplitudes over frontal scalp with no between-group differences in accuracy or reaction time. Electroencephalogram/functional magnetic resonance imaging fusion revealed that the P3a age effects were driven by increased activation of left inferior frontal and cingulate cortex and decreased activation of inferior parietal cortex in the older group. P3b differences were driven by increased activation of left temporal regions, right hippocampus, and right dorsolateral prefrontal cortex in the older group. Our results support the proposal that the age-related P300 anterior shift arises from an increased reliance on prefrontal structures to support target and distractor processing.

Multiple inflammatory pathways are involved in the development and progression of cognitive deficits in APPswe/PS1dE9 mice - Corrected Proof

2012-01-27

Abstract: Increased accumulation of amyloid-beta peptide (Aβ) and neuroinflammation is known to exist within the Alzheimer's disease (AD) brain. However, it remains unclear which form of Aβ pathologies triggers neuroinflammation and whether increased neuroinflammation contributes to cognitive deficits in AD. In the present study we found that increased inflammatory responses might occur early in preplaque APPswe/PS1dE9 mice, and were significantly enhanced in both early- and late-plaque APPswe/PS1dE9 mice. Correlational analysis revealed that multiple inflammatory indexes significantly correlated with soluble Aβ level, rather than amyloid plaque burden or insoluble Aβ level, in APPswe/PS1dE9 mice. Moreover, multiple inflammatory indexes highly correlated with the impaired spatial learning and memory in APPswe/PS1dE9 mice. Collectively, these results provide evidence that inflammatory responses might be likely triggered by soluble toxic Aβ species. Importantly, we demonstrate for the first time that multiple inflammatory pathways might be involved in the development and progression of cognitive deficits in APPswe/PS1dE9 mice, suggesting that a pharmacological approach targeting multiple inflammatory pathways may be a novel promising strategy to prevent or delay AD.

PET imaging with [18F]AV-45 in an APP/PS1-21 murine model of amyloid plaque deposition - Corrected Proof

2012-01-27

Abstract: Alzheimer's disease (AD), the most common age-related neurodegenerative disorder, is characterized by the accumulation of β-amyloid peptide. In man, [18F]AV-45 with positron emission tomography (PET) is currently studied and used to track in vivo amyloid accumulation. Here, [18F]-AV45-PET was used to visualize amyloid deposition in a transgenic murine model of amyloidosis (APP/PS1-21). Studies were performed ex vivo by autoradiography and in vivo by microPET. Autoradiograms of the brain sections highlighted an increased uptake of [18F]AV-45 in APP/PS1-21 mice compared with age-matched control mice. From 8 months, an intense labeling was observed in cortex, hippocampus, and striatum. The marked accumulation of radiotracer was found in close association with thioflavin S-positive amyloid plaques. The longitudinal microPET assessment, performed from 3 to 12 months of age, demonstrated an increased [18F]AV-45 uptake in APP/PS1-21 compared with control mice. The elevated tracer uptake was increased in association with age. This study opens the possibility of [18F]AV-45, coupled with microPET, to visualize and quantitatively measure amyloid deposits in the brains of living APP/PS1 mice.

Ventral and dorsal visual streams in posterior cortical atrophy: A DT MRI study - Corrected Proof

2012-01-27

Abstract: Using diffusion tensor magnetic resonance imaging tractography, ventral (inferior longitudinal fasciculus) and fronto-occipital (inferior fronto-occipital fasciculus) and dorsal (fronto-parietal superior longitudinal fasciculus) visual pathways were assessed in 7 patients with posterior cortical atrophy (PCA), showing either predominantly ventral or additional dorsal cognitive deficits. Corpus callosum and corticospinal tracts were also studied. Gray and white matter atrophy was assessed using voxel-based morphometry. In all PCA patients, abnormal diffusivity indexes were found in bilateral inferior longitudinal fasciculus and inferior fronto-occipital fasciculus, with a left-side predominance. Patients also had mild microstructural damage to the corpus callosum. The 2 patients with more dorsal symptoms also showed right fronto-parietal superior longitudinal fasciculus abnormalities. Corticospinal tracts were normal, bilaterally. When studied separately, patients with ventral clinical impairment showed a pattern of atrophy mainly located in the ventral occipitotemporal regions, bilaterally; patients with both ventral and dorsal clinical deficits showed additional atrophy of the bilateral inferior parietal lobe. Magnetic resonance imaging patterns of abnormalities mirror closely the clinical phenotypes and could provide reliable ante mortem markers of tissue damage in PCA.

Alterations in the histaminergic system in Alzheimer's disease: a postmortem study - Corrected Proof

Ling Shan, Koen Bossers, Unga Unmehopa, Ai-Min Bao, Dick F. Swaab — 2012-01-27

Abstract: Histamine is produced by the hypothalamic tuberomamillary nucleus (TMN). We studied its involvement in Alzheimer's disease (AD) by in situ hybridization of histidine decarboxylase (HDC), the key enzyme of histamine production, in 9 AD patients and 9 controls. Additionally, messenger (m) RNA levels of the 4 histamine receptors (H1–4R) and of the enzyme involved in histamine metabolism, histamine methyltransferase (HMT), were determined by quantitative polymerase chain reaction (qPCR) in the prefrontal cortex (PFC) in the course of AD (n = 49). Moreover, alterations in glia markers were studied. HDC-mRNA levels in the TMN were unchanged in AD, despite of the reduced number of Nissl-stained neurons (p = 0.001). However, a decrease in HDC-mRNA was observed in its medial part (mTMN; p = 0.047). In the course of AD only females had increased prefrontal cortex expression of histamine receptor-3 (H3R) (p = 0.007) and histamine methyltransferase-mRNA (p = 0.011) and of the glia markers, glial fibrillary acidic protein-mRNA, vimentin-mRNA and proteolipid protein-mRNA. These findings indicate the presence of regional changes in the TMN that are at least partly gender-dependent.

Age-related changes to Na+ channel gating contribute to modified intrinsic neuronal excitability - Corrected Proof

Andrew D. Randall, Clair Booth, Jon T. Brown — 2012-01-27

Abstract: Cognitive decline occurs during normal aging and is likely to be reflected in the neurophysiological properties of neural circuits with key roles in cognition, for example those of the limbic system. To identify candidate neurophysiological changes we used patch clamp methods to compare the intrinsic excitability properties of hippocampal CA1 pyramidal neurons of mature adult (8–10 month) and aged (22–24 month) mice. Resting potential, input resistance, and the “sag” observed on injection of hyperpolarizing current were not age-dependent. In contrast, the patterns of spike firing observed with depolarizing current injections demonstrated the presence of an age-related hypoexcitability. Action potential waveform analysis revealed that spike thresholds were approximately 3 mV more depolarized in aged animals. In line with this, voltage clamp recordings of Na+ currents from nucleated macropatches exhibited an approximate 3 mV depolarizing shift in the voltage-dependence of activation gating. Inactivation curves, in contrast, were not different. These data indicate alterations in Na+ channel activation gating contribute to neuronal hypoexcitability in aging, and therefore may be a factor in age-related cognitive decline.

Test sequence of CSF and MRI biomarkers for prediction of AD in subjects with MCI - Corrected Proof

2012-01-24

Abstract: Our aim was to identify the best diagnostic test sequence for predicting Alzheimer's disease (AD)-type dementia in subjects with mild cognitive impairment (MCI) using cerebrospinal fluid (CSF) and magnetic resonance imaging (MRI) biomarkers. We selected 153 subjects with mild cognitive impairment from a multicenter memory clinic-based cohort. We tested the CSF beta amyloid (Aβ)1–42/tau ratio using enzyme-linked immunosorbent assay (ELISA) and hippocampal volumes (HCVs) using the atlas-based learning embeddings for atlas propagation (LEAP) method. Outcome measure was progression to AD-type dementia in 2 years. At follow-up, 48 (31%) subjects converted to AD-type dementia. In multivariable analyses, CSF Aβ1–42/tau and HCV predicted AD-type dementia regardless of apolipoprotein E (APOE) genotype and cognitive scores. Test sequence analyses showed that CSF Aβ1–42/tau increased predictive accuracy in subjects with normal HCV (p < 0.001) and abnormal HCV (p = 0.025). HCV increased predictive accuracy only in subjects with normal CSF Aβ1–42/tau (p = 0.014). Slope analyses for annual cognitive decline yielded similar results. For selection of subjects for a prodromal AD trial, the best balance between sample size and number of subjects needed to screen was obtained with CSF markers. These results provide further support for the use of CSF and magnetic resonance imaging biomarkers to identify prodromal AD.

Toward a multifactorial model of Alzheimer disease - Corrected Proof

Martha Storandt, Denise Head, Anne M. Fagan, David M. Holtzman, John C. Morris — 2012-01-20

Abstract: Relations among antecedent biomarkers of Alzheimer disease (AD) were evaluated using causal modeling; although correlation cannot be equated to causation, causation does require correlation. Individuals aged 43 to 89 years (N = 220) enrolled as cognitively normal controls in longitudinal studies had clinical and psychometric assessment, structural magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) biomarkers, and brain amyloid imaging via positron emission tomography with Pittsburgh Compound B (PIB) obtained within 1 year. CSF levels of Aβ42 and tau were minimally correlated, indicating they represent independent processes. Aβ42, tau, and their interaction explained 60% of the variance in PIB. Effects of APOE genotype and age on PIB were indirect, operating through CSF markers. Only spurious relations via their common relation with age were found between the biomarkers and regional brain volumes or cognition. Hence, at least 2 independent hypothesized processes, one reflected by CSF Aβ42 and one by CSF tau, contribute to the development of fibrillar amyloid plaques preclinically. The lack of correlation between these 2 processes and brain volume in the regions most often affected in AD suggests the operation of a third process related to brain atrophy.

Age-related differences in corticospinal excitability and inhibition during coordination of upper and lower limbs - Corrected Proof

2012-01-19

Abstract: The ability to coordinate upper and lower limbs—a prerequisite for many everyday activities—is known to decline with age. Here we report 2 experiments in which transcranial magnetic stimulation (TMS) was used to assess corticospinal excitatory and inhibitory processes in younger and older adults during cyclical hand-foot movements. In experiment 1, motor evoked potentials (MEP) and silent period (SP) durations were measured from the active right extensor carpi radialis (ECR) muscle while it executed rhythmic oscillations in conjunction with the right or left foot. Younger adults exhibited increased SP with ipsilateral limb combinations and decreased SP with contralateral limb combinations, relative to a baseline hand only condition. Strikingly, older adults exhibited a reduced SP when ipsilateral limbs moved in opposite directions. This effect was found to be most pronounced in those older adults who exhibited poor coordination performance, suggesting that the inability to regulate inhibitory processes may underlie age-related degradation of task performance. Experiment 2 examined motor evoked potentials and SP duration in the left extensor carpi radialis which maintained a tonic contraction while the coordination task was undertaken by the right arm and right or left foot. For younger adults, coordination of ipsilateral limbs was accompanied by increased inhibition in the ipsilateral motor cortex than during the coordination of contralateral limbs. No differences in SP between conditions were noted for the older adults. In summary, older adults' reduced ability to coordinate upper and lower limbs may be related to the capacity to regulate inhibitory function in both hemispheres. This study suggests for the first time a direct link between age-related differences in interlimb coordination and the control of corticospinal inhibitory processes.

Sleep modulates word-pair learning but not motor sequence learning in healthy older adults - Corrected Proof

2012-01-16

Abstract: Sleep benefits memory across a range of tasks for young adults. However, remarkably little is known of the role of sleep on memory for healthy older adults. We used 2 tasks, 1 assaying motor skill learning and the other assaying nonmotor/declarative learning, to examine off-line changes in performance in young (20–34 years), middle-aged (35–50 years), and older (51–70 years) adults without disordered sleep. During an initial session, conducted either in the morning or evening, participants learned a motor sequence and a list of word pairs. Memory tests were given twice, 12 and 24 hours after training, allowing us to analyze off-line consolidation after a break that included sleep or normal wake. Sleep-dependent performance changes were reduced in older adults on the motor sequence learning task. In contrast, sleep-dependent performance changes were similar for all 3 age groups on the word pair learning task. Age-related changes in sleep or networks activated during encoding or during sleep may contribute to age-related declines in motor sequence consolidation. Interestingly, these changes do not affect declarative memory.

Screening of the SOD1, FUS, TARDBP, ANG, and OPTN mutations in Korean patients with familial and sporadic ALS - Corrected Proof

2012-01-16

Abstract: About 5% of amyotrophic lateral sclerosis (ALS) cases are known to be familial (fALS) and mutations in SOD1 and other genes are found in more than 20% of fALS patients and in 2%–4% of apparently sporadic ALS (sALS) cases. However, there are few reports on the proportion of fALS and the frequency of mutations in Korean patients with ALS. We screened mutations in the SOD1, FUS, TARDBP, ANG, and OPTN genes in 258 consecutively enrolled Korean patients with ALS from October 2006 to November 2010. The frequency of fALS was estimated to be 3.5% (9/258), and mutations were identified in 88.9% (8/9) of fALS patients but only in 2.8% (7/249) of sALS patients. Seven fALS and 3 sALS patients had mutations in SOD1 gene while all the others had FUS gene. The proportion of fALS was lower than that reported in Caucasian populations but the frequency of SOD1 gene mutations in Korean fALS patients (77.8%, 7/9) was much higher than that reported in other ethnic groups. These findings might suggest that there is an ethnic difference in the proportion of fALS and the genetic background of ALS.

Whole brain N-acetylaspartate concentration is conserved throughout normal aging - Corrected Proof

2012-01-16

Abstract: We hypothesize that normal aging implies neuronal durability, reflected by age-independent concentrations of their marker—the amino acid derivative N-acetylaspartate (NAA). To test this, we obtained the whole-brain and whole-head N-acetylaspartate concentrations (WBNAA and WHNAA) with proton magnetic resonance (MR) spectroscopy; and the fractional brain parenchyma volume (fBPV)—a metric of atrophy, by segmenting the magnetic resonance image (MRI) from 42 (18 male) healthy young (31.9 ± 5.8 years old) and 100 (64 male, 72.6 ± 7.3 years old) cognitively normal elderly. The 12.8 ± 1.9 mM WBNAA of the young was not significantly different from the 13.1 ± 3.1 mM in the elderly (p > 0.05). In contrast, both fBPV (87.3 ± 4.7% vs. 74.8 ± 4.8%) and WHNAA (11.1 ± 1.7 mM vs. 9.8 ± 2.4 mM) were significantly higher in the young (approximately 14%; p < 0.0001 for both). The similarity in mean WBNAA between 2 cohorts 4 decades of normal aging apart suggests that neuronal integrity is maintained across the lifespan. Clinically, WBNAA could be used as a marker for normal (hence, also abnormal) brain aging. In contrast, WHNAA and fBPV seem age-related suggesting that brain atrophy may occur without compromising the remaining tissue.

Lipofuscin can be eliminated from the retinal pigment epithelium of monkeys - Corrected Proof

Sylvie Julien, Ulrich Schraermeyer — 2012-01-16

Abstract: Lipofuscin is a cytologic hallmark of aging in metabolically active postmitotic cells including neurons, cardiac muscle cells, and the retinal pigment epithelium (RPE). High levels of lipofuscin are involved in the pathogenesis of age-related macular degeneration (AMD), the main cause of blindness in the elderly population in the western world. Degradation and exocytosis of lipofuscin by RPE cells have not been observed in vivo until now, and no drug is known to eliminate the intracellular amount of lipofuscin. Here, we show that in monkeys treated with a small molecule belonging to the tetrahydropyridoethers class (n = 36 of 48 monkeys), RPE cells significantly release lipofuscin. In 4 eyes, macrophages were detected which had taken up lipofuscin. They were located between the Bruch's membrane and the RPE, and in the choroid. The quantification of pigment granules was performed by transmission electron microscopy. Our findings open the way to develop therapeutic strategies to remove lipofuscin from RPE cells, which may have implications for the treatment of age-related macular degeneration in which lipofuscin accumulation in cells is a causative factor.

Quantitative EEG and LORETA: valuable tools in discerning FTD from AD? - Corrected Proof

2012-01-16

Abstract: Drawing a clinical distinction between frontotemporal dementia (FTD) and Alzheimer's disease (AD) is tricky, particularly at the early stages of disease. This study evaluates the possibility in differentiating 39 FTD, 39 AD, and 39 controls (CTR) by means of power spectral analysis and standardized low resolution brain electromagnetic tomography (sLORETA) within delta, theta, alpha 1 and 2, beta 1, 2, and 3 frequency bands. Both analyses revealed in AD patients, relative to CTR, higher expression of diffuse delta/theta and lower central/posterior fast frequency (from alpha1 to beta2) bands. FTD patients showed diffuse increased theta power compared with CTR and lower delta relative to AD patients. Compared with FTD, AD patients showed diffuse higher theta power at spectral analysis and, at sLORETA, decreased alpha2 and beta1 values in central/temporal regions. Spectral analysis and sLORETA provided complementary information that might help characterizing different patterns of electroencephalogram (EEG) oscillatory activity in AD and FTD. Nevertheless, this differentiation was possible only at the group level because single patients could not be discerned with sufficient accuracy.

Body mass index is associated with biological CSF markers of core brain pathology in Alzheimer's disease - Corrected Proof

Ali Jawaid, Henning Leske, Manuela Neumann — 2012-01-16

demonstrate an association between lower body mass index (BMI) and positive Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers in a cohort comprising individuals with AD, minimal cognitive impairment (MCI), and healthy controls. This study is an important addition to the repertoire of evidence which suggests that metabolic pathways may be related to pathophysiology of neurodegenerative disorders.

Nuclear localization of Klotho in brain: an anti-aging protein - Corrected Proof

Dwight C. German, Ida Khobahy, Johanne Pastor, Makoto Kuro-o, Xinran Liu — 2012-01-16

Abstract: Klotho is a putative age-suppressing gene whose overexpression in mice results in extension of life span. The Klotho gene encodes a single-pass transmembrane protein whose extracellular domain is shed and released into blood, urine, and cerebrospinal fluid, potentially functioning as a humoral factor. The extracellular domain of Klotho has an activity that increases the expression of antioxidant enzymes and confers resistance to oxidative stress in cultured cells and in whole animals. The transmembrane form of the Klotho protein directly binds to multiple fibroblast growth factor receptors and modifies their ligand affinity and specificity. The purpose of the present study was to determine the precise cellular localization of Klotho in the mouse brain. Using light microscopic immunohistochemical methods, we found the highest levels of Klotho immunoreactivity in 2 brain regions: the choroid plexus, and cerebellar Purkinje cells. In the choroid plexus cells, Klotho was found not only on the plasma membrane but also in large amounts near the nuclear membrane. Likewise, in the Purkinje cell Klotho was found throughout the cell including dendrites, axon and soma with large amounts near the nuclear membrane. Using immunoelectron microscopy, we found Klotho in the cell membrane, but the highest concentration was localized in the peripheral portion of the nucleus and the nucleolus in both cell types. This new finding suggests that in addition to Klotho being secreted from cells in brain, it also has a nuclear function.

Development of large-scale functional networks over the lifespan - Corrected Proof

2012-01-12

Abstract: The development of large-scale functional organization of the human brain across the lifespan is not well understood. Here we used magnetoencephalographic recordings of 53 adults (ages 18–89) to characterize functional brain networks in the resting state. Slow frequencies engage larger networks than higher frequencies and show different development over the lifespan. Networks in the delta (2–4 Hz) frequency range decrease, while networks in the beta/gamma frequency range (> 16 Hz) increase in size with advancing age. Results show that the right frontal lobe and the temporal areas in both hemispheres are important relay stations in the expanding high-frequency networks. Neuropsychological tests confirmed the tendency of cognitive decline with older age. The decrease in visual memory and visuoconstructive functions was strongly associated with the age-dependent enhancement of functional connectivity in both temporal lobes. Using functional network analysis this study elucidates important neuronal principles underlying age-related cognitive decline paving mental deterioration in senescence.

Neuroprotection provided by dietary restriction in rats is further enhanced by reducing glucocortocoids - Corrected Proof

2012-01-09

Abstract: Glucocorticoids (GC)—corticosterone (CORT) in rodents and cortisol in primates—are stress-induced hormones secreted by adrenal glands that interact with the hypothalamic pituitary axis. High levels of cortisol in humans are observed in neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), as well as in diabetes, post-traumatic stress syndrome, and major depression. Experimental models of diabetes in rats and mice have demonstrated that reduction of CORT reduces learning and memory deficits and attenuates loss of neuronal viability and plasticity. In contrast to the negative associations of elevated GC levels, CORT is moderately elevated in dietary restriction (DR) paradigms which are associated with many healthy anti-aging effects including neuroprotection. We demonstrate here in rats that ablating CORT by adrenalectomy (ADX) with replenishment to relatively low levels (30% below that of controls) prior to the onset of a DR regimen (ADX-DR) followed by central administration of the neurotoxin, kainic acid (KA), significantly attenuates learning deficits in a 14-unit T-maze task. The performance of the ADX-DR KA group did not differ from a control group (CON) that did not receive KA and was fed ad libitum (AL). By contrast, the sham-operated DR (SHAM-DR KA) group, SHAM-AL KA group, and ADX-AL KA group demonstrated poorer learning behavior in this task compared to the CON group. Stereological analysis revealed equivalent DR-induced neuroprotection in the SH–DR KA and ADX-DR KA groups, as measured by cell loss in the CA2/CA3 region of the hippocampus, while substantial cell loss was observed in SH-AL and ADX-AL rats. A separate set of experiments was conducted with similar dietary and surgical treatment conditions but without KA administration to examine markers of neurotrophic activity, brain-derived neurotrophic factor (BDNF), transcriptions factors (pCREB), and chaperone proteins (HSP-70). Under these conditions, we noted elevations in both BDNF and pCREB in ADX DR rats compared to the other groups; whereas, HSP-70, was equivalently elevated in ADX-DR and SH–DR groups and was higher than observed in both SH-AL and ADX-AL groups. These results support findings that DR protects hippocampal neurons against KA-induced cellular insult. However, this neuroprotective effect was further enhanced in rats with a lower-than control level of CORT resulting from ADX and maintained by exogenous CORT supplementation. Our results then suggest that DR-induced physiological elevation of GC may have negative functional consequences to DR-induced beneficial effects. These negative effects, however, can be compensated by other DR-produced cellular and molecular protective mechanisms.

What predicts cognitive decline in de novo Parkinson's disease? - Corrected Proof

2012-01-09

Abstract: Subtle cognitive impairment can be detected in early Parkinson's disease (PD). In a consecutive series of de novo, drug-naive PD patients, we applied stepwise regression analysis to assess which clinical, neuropsychological, and functional neuroimaging (dopamine transporter [DAT] and perfusion single photon emission computed tomography [SPECT]) characteristics at baseline was predictive of cognitive decline during an average follow-up time of about 4 years. Decline both in executive (R2 = 0.54; p = 0.0001) and visuospatial (R2 = 0.56; p = 0.0001) functions was predicted by the couple of Unified Parkinson's Disease Rating Scale (UPDRS)-III score and caudate dopamine transporter (DAT) uptake in the less affected hemisphere (LAH). Verbal memory and language decline was predicted instead by caudate DAT uptake and brain perfusion in a posterior parieto-temporal area of the less affected hemisphere (R2 = 0.42; p = 0.0005). No significant effect was shown for age, baseline neuropsychological scores, and levodopa equivalent dose at follow-up. The combined use of clinical structured examination and brain functional assessment by means of dual single photon emission computed tomography imaging appears as a powerful approach to predict cognitive decline in de novo PD patients.

Thirst deficits in aged rats are reversed by dietary omega-3 fatty acid supplementation - Corrected Proof

Denovan P. Begg, Andrew J. Sinclair, Richard S. Weisinger — 2012-01-09

Abstract: During heat waves many elderly individuals die as a consequence of dehydration. This is partially due to deficits in mechanisms controlling thirst. Reduced thirst following dipsogenic stimuli is well documented in aged humans and rodents. Low in vivo long-chain omega-3 fatty acid levels, as can occur in aging, have been shown to alter body fluid and sodium homeostasis. Therefore, the effect of dietary omega-3 fatty acid supplementation on drinking responses in aged rats was examined. Omega-3 fatty acids reversed thirst deficits in aged rats following dehydration and hypertonic stimuli; angiotensin (ANG) II induced drinking was unaffected in aged rats. Plasma atrial natriuretic peptide (ANP) and arginine vasopressin (AVP) were altered with age, but not affected by diet. Aged omega-3 fatty acid deficient animals displayed increased hypothalamic cytosolic phospholipase A2 (cPLA2), cyclooxygenase (COX)-2, and prostaglandin E (PGE) synthase messenger (m)RNA expression, compared with animals that received omega-3 fatty acids. The aged low omega-3 fatty acid fed animals had significantly elevated hypothalamic PGE2 compared with all other groups. Hypothalamic PGE2 was negatively correlated with drinking induced by both dehydration and hypertonicity. The results indicate that PGE2 may be the underlying mechanism of the reduced thirst observed in aging.

Receptor for advanced glycation endproducts (RAGE) deficiency protects against MPTP toxicity - Corrected Proof

2012-01-09

Abstract: Parkinson's disease (PD) is a common neurodegenerative disorder of unknown pathogenesis characterized by the loss of nigrostriatal dopaminergic neurons. Oxidative stress, microglial activation and inflammatory responses seem to contribute to the pathogenesis. The receptor for advanced glycation endproducts (RAGE) is a multiligand receptor of the immunoglobulin superfamily of cell surface molecules. The formation of advanced glycation end products (AGEs), the first ligand of RAGE identified, requires a complex series of reactions including nonenzymatic glycation and free radical reactions involving superoxide-radicals and hydrogen peroxide. Binding of RAGE ligands results in activation of nuclear factor-kappaB (NF-κB). We show that RAGE ablation protected nigral dopaminergic neurons against cell death induced by the neurotoxin MPTP that mimics most features of PD. In RAGE-deficient mice the translocation of the NF-κB subunit p65 to the nucleus, in dopaminergic neurons and glial cells was inhibited suggesting that RAGE involves the activation of NF-κB. The mRNA level of S100, one of the ligands of RAGE, was increased after MPTP treatment. The dopaminergic neurons treated with MPP+ and S100 protein showed increased levels of apoptotic cell death, which was attenuated in RAGE-deficient mice. Our results suggest that activation of RAGE contributes to MPTP/MPP+-induced death of dopaminergic neurons that may be mediated by NF-κB activation.

Age-dependent disruption in hippocampal theta oscillation in amyloid-β overproducing transgenic mice - Corrected Proof

2012-01-09

Abstract: Transgenic mice are used to model increased brain amyloid-β (Aβ) and amyloid plaque formation reflecting Alzheimer's disease pathology. In our study hippocampal network oscillations, population spikes, and long-term potentiation (LTP) were recorded in APPswe/PS1dE9 (APP/PS1) and presenilin1 (PS1) transgenic and wild type mice at 2, 4, and 8 months of age under urethane anesthesia. Hippocampal theta oscillations elicited by brainstem stimulation were similar in wild type and PS1 mice at all age groups. In contrast, APP/PS1 mice showed an age-dependent decrease in hippocampal activity, characterized by a significant decline in elicited theta power and frequency at 4 and 8 months. Magnitudes of population spikes and long-term potentiation in the dentate gyrus were similar across groups at both 4 and 8 months. In APP/PS1 mice, soluble and insoluble Aβ, and hippocampal and cortical plaque load increased with age, and the disruption in hippocampal theta oscillation showed a significant correlation with plaque load. Our study shows that, using in vivo electrophysiological methods, early Aβ-related functional deficits can be robustly detected in the brainstem-hippocampus multisynaptic network.

Musical experience offsets age-related delays in neural timing - Corrected Proof

Alexandra Parbery-Clark, Samira Anderson, Emily Hittner, Nina Kraus — 2012-01-09

Abstract: Aging disrupts neural timing, reducing the nervous system's ability to precisely encode sound. Given that the neural representation of temporal features is strengthened with musical training in young adults, can musical training offset the negative impact of aging on neural processing? By comparing auditory brainstem timing in younger and older musicians and nonmusicians to a consonant-vowel speech sound /da/. we document a musician's resilience to age-related delays in neural timing.

Tau acts as an independent genetic risk factor in pathologically proven PD - Corrected Proof

2012-01-06

Abstract: MAPT has been repeatedly linked with Parkinson's disease (PD) in association studies. Although tau deposition may be seen in PD, its relevance to the pathogenesis of the condition remains unclear. The presence of tau-positive inclusions is, however, the defining feature of progressive supranuclear palsy (PSP), which may often be clinically misdiagnosed as idiopathic PD. On a genetic level, variants in MAPT are the strongest risk factor for PSP. These facts raise the question whether the MAPT association in PD results from contamination with unrecognized cases of PSP. Using only neuropathologically proven PD, we show that the MAPT association remains and is independent of the PSP Association.

Genetic testing in familial and young-onset Alzheimer's disease: mutation spectrum in a Serbian cohort - Corrected Proof

2012-01-06

Abstract: Alzheimer's disease (AD) is the most common form of dementia. To date, more than 200 mutations in three genes have been identified as cause of early-onset autosomal dominant inherited AD. The aim of this study was to characterize the mutation spectrum and describe genotype-phenotype correlations in Serbian patients with positive family history of AD or/and early-onset AD. We performed a genetic screening for mutations in the coding regions of Presenilins 1 and 2 (PSEN1 and PSEN2), as well as exons 16 and 17 of the Amyloid Precursor Protein gene (APP) in a total of 47 patients from Serbia with a clinical diagnosis of familial and/or early-onset AD (mean age at onset of 60.3 years; range 32–77). We found one novel mutation in PSEN1, one novel variant in PSEN2, and three previously described variants, one in each of the analyzed genes. Interestingly, we identified one patient harboring two heterozygous mutations: one in APP (p.L723P) and one in PSEN1 (p.R108Q).

S-adenosylmethionine reduces the progress of the Alzheimer-like features induced by B-vitamin deficiency in mice - Corrected Proof

2012-01-06

Abstract: Methylation reactions linked to homocysteine in the one-carbon metabolism are increasingly elicited in Alzheimer's disease, although the association of hyperhomocysteinemia and of low B vitamin levels with the disease is still debated. We previously demonstrated that hyperhomocysteinemia and DNA hypomethylation induced by B vitamin deficiency are associated with PSEN1 and BACE1 overexpression and amyloid production. The present study is aimed at assessing S-adenosylmethionine effects in mice kept under a condition of B vitamin deficiency. To this end, TgCRND8 mice and wild-type littermates were assigned to control or B vitamin deficient diet, with or without S-adenosylmethionine supplementation. We found that S-adenosylmethionine reduced amyloid production, increased spatial memory in TgCRND8 mice and inhibited the upregulation of B vitamin deficiency-induced PSEN1 and BACE1 expression and Tau phosphorylation in TgCRND8 and wild-type mice. Furthermore, S-adenosylmethionine treatment reduced plaque spreading independently on B vitamin deficiency. These results strengthen our previous observations on the possible role of one-carbon metabolism in Alzheimer's disease, highlighting hyperhomocysteinemia-related mechanisms in dementia onset/progression and encourage further studies aimed at evaluating the use of S-adenosylmethionine as a potential candidate drug for the treatment of the disease.

The early events of Alzheimer's disease pathology: from mitochondrial dysfunction to BDNF axonal transport deficits - Corrected Proof

Xuan Ye, Wenjiao Tai, Dan Zhang — 2012-01-04

Abstract: Although there are numerous studies regarding Alzheimer's disease (AD), the cause and progression of AD are still not well understood. The researches in the past decade implicated amyloid-beta (Aβ) overproduction as a causative event in disease pathogenesis, but still failed to clarify the mechanism of pathology from Aβ production to central neural system defects in AD. The present review raises the hypothesis that the onset of AD pathology is closely related with mitochondrial dysfunction induced by Aβ and brain-derived neurotrophic factor (BDNF) axonal transport deficits. It is well-known that axonal transport defect and attenuation of BDNF-neurotrophic tyrosine receptor kinase 2 (TrkB) signal are fatal to neuronal function and survival. We hypothesized that abnormal amyloid precursor protein (APP) processing and Aβ production in mitochondria disturb the axonal transport by impairing mitochondrial function and attenuate BDNF-neurotrophic tyrosine receptor kinase 2 signal subsequently. For this hypothesis, the factors related with the initiation of AD pathology are not only limited to the neurons per se but also expanded to the microenvironment around neurons, such as the secretion of BDNF from astrocytes. The modification of the origin in this pathway may contribute to slow down the disease progression of AD.

Impact of aging and diet restriction on retinal function during and after acute intraocular pressure injury - Corrected Proof

2012-01-04

Abstract: Advancing age is a major risk factor for many neurodegenerative diseases but the underlying pathophysiology is not clear. We hypothesize that aging impairs the ability of neurons in the central nervous system to recover functionally after injury. To test this in retinal ganglion cells in vivo, we developed an optic nerve “stress test” which monitors the functional capacity of the optic nerve and retina, during and after a subischemic injury induced by intraocular pressure elevation. We report that older (18-month) C57BL/6J mice suffered greater loss of inner retinal function compared with younger adult mice following intraocular pressure (IOP) challenge. To investigate whether age-related vulnerability to IOP challenge can be modified, we subjected 12-month-old mice to dietary restriction (DR) (alternate-day fasting) for 6 months. Compared with age-matched ad libitum fed controls, DR mice showed greater recovery in inner retinal function following IOP challenge. DR was associated with reduced oxidative stress level following injury and improved mitochondrial oxidative phosphorylation enzyme activity compared with ad libitum controls. Taken together, this study provides in vivo evidence that DR improves functional recovery of the retina following injury and points to the potential benefits of therapies that target mitochondria for the protection of the aging retina and optic nerve against injury.

Vascular predictors of cognitive decline in patients with mild cognitive impairment - Corrected Proof

2012-01-04

Abstract: Our aim in this study was to assess the relationship between the state of cerebral vessels and the risk of conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD). We included 117 MCI patients. They underwent an ultrasonographic assessment of common carotid arteries intima-media thickness (IMT) and carotid plaque index. Cerebrovascular reactivity to hypercapnia in the middle cerebral arteries was calculated with the Breath-Holding Index (BHI). After a 12-month follow-up period, neuropsychological examinations demonstrated a progression to dementia in 21 patients. Pathological values of BHI and IMT significantly increased the risk of conversion (BHI: odds ratio, 5.80; 95% confidence interval, 1.83–18.37, p < 0.05; IMT: odds ratio, 3.08; 95% confidence interval, 1.02–9.33; p < 0.05, multinomial logistic regression analysis). Comparison between patients with all normal values and those with the simultaneous alteration of the 2 vascular indexes showed an increase in the risk of conversion from 9% to 33% (ordinal regression analysis). Our findings show that alterations of cerebral vessel functional and anatomic status increase the risk of conversion from MCI to dementia.

Aberrant heart rate and brainstem brain-derived neurotrophic factor (BDNF) signaling in a mouse model of Huntington's disease - Corrected Proof

2012-01-04

Abstract: Huntington's disease (HD) is associated with profound autonomic dysfunction including dysregulation of cardiovascular control often preceding cognitive or motor symptoms. Brain-derived neurotrophic factor (BDNF) levels are decreased in the brains of HD patients and HD mouse models, and restoring BDNF levels prevents neuronal loss and extends survival in HD mice. We reasoned that heart rate changes in HD may be associated with altered BDNF signaling in cardiovascular control nuclei in the brainstem. Here we show that heart rate is elevated in HD (N171-82Q) mice at presymptomatic and early disease stages, and heart rate responses to restraint stress are attenuated. BDNF levels were significantly reduced in brainstem regions containing cardiovascular nuclei in HD mice and human HD patients. Central administration of BDNF restored the heart rate to control levels. Our findings establish a link between diminished BDNF expression in brainstem cardiovascular nuclei and abnormal heart rates in HD mice, and suggest a novel therapeutic target for correcting cardiovascular dysfunction in HD.

Vitamin D rejuvenates aging eyes by reducing inflammation, clearing amyloid beta and improving visual function - Corrected Proof

Vivian Lee, Elissa Rekhi, Jaimie Hoh Kam, Glen Jeffery — 2012-01-04

Abstract: Vitamin D3 plays a key role in immune regulation and may protect against the aging process. A focal point for age-related changes is the outer retina of the eye where there is high metabolic demand resulting in a gradual increase in extracellular deposition, inflammation, and cell loss giving rise to visual decline. Here, we demonstrate that vitamin D3 administration for only 6 weeks in aged mice significantly impacts on this aging process. Treated mice showed significant reductions in retinal inflammation and levels of amyloid beta (Aβ) accumulation, which is a hallmark of aging. They also had significant reductions in retinal macrophage numbers and marked shifts in their morphology. These changes were reflected in a significant improvement in visual function, revealing that vitamin D3 is a route to avoiding the pace of age-related visual decline. Excess amyloid beta deposition and inflammation are risk factors leading to age-related macular degeneration (AMD), the largest cause of blindness in those older than 50 years in developed countries. Recently, vitamin D3 has been linked epidemiologically to protection against age-related macular degeneration. Hence, vitamin D3 enrichment is likely to represent a beneficial route for those at risk.

Age-associated learning and memory deficits in two mouse versions of the stone T-maze - Corrected Proof

2012-01-04

Abstract: We have previously reported that a modified Stone T-maze (STM), using escape from water as motivation, was effective in evaluating learning and memory ability in young C57/BL6 mice. Here we report on the effectiveness and sensitivity of the STM in the assessment of age-related learning and memory deficits in mice using either escape from foot shock or water as the motivational manipulations. C57BL/6Nia mice 7-, 12-, 20- and 24-months old received 15 massed trials in the escape from foot shock motivated STM while C57BL/6Nia mice 5-, 12-, and 25-months old were tested in the escape from water STM. Analysis of errors, the main performance variable, revealed similar results in both versions of the task with younger mice making fewer errors. Notably, mice of all ages in the water-motivated version moved quickly through the maze, while all ages of mice in the shock-motivated version tended to wait for shock to be initiated to move forward. Overall, both versions of the STM appear to be sensitive to age-related changes in learning and memory and provide an alternative to other testing paradigms such as the Morris water maze which are susceptible to performance confounds which can lead to uninterpretable results.

Selective inhibition of the membrane attack complex of complement by low molecular weight components of the aurin tricarboxylic acid synthetic complex - Corrected Proof

Moonhee Lee, Jian-Ping Guo, Claudia Schwab, Edith G. McGeer, Patrick L. McGeer — 2012-01-04

Abstract: Complement plays a vital role in both the innate and adaptive immune systems. It recognizes a target, opsonizes it, generates anaphylatoxins, and directly kills cells through the membrane attack complex (MAC). This final function, which assembles C5b-9(n) on viable cell surfaces, can kill host cells through bystander lysis. Here we identify for the first time compounds that can inhibit bystander lysis while not interfering with the other essential functions of complement. We show that aurin tricarboxylic acid (ATA), aurin quadracarboxylic acid (AQA), and aurin hexacarboxylic acid (AHA), block the addition of C9 to C5b-8 so that the MAC cannot form. These molecules inhibit hemolysis of human, rat, and mouse red cells with a half maximal inhibitory concentration (IC50) in the nanomolar range. When given orally to Alzheimer disease type B6SJL-Tg mice, they inhibit MAC formation in serum and improve memory retention. On autopsy, they show no evidence of harm to any organ. Aurin tricarboxylic acid, aurin quadracarboxylic acid, and aurin hexacarboxylic acid may be effective therapeutic agents in Alzheimer disease and other degenerative disorders where self damage from the MAC occurs.

Impaired TrkB receptor signaling contributes to memory impairment in APP/PS1 mice - Corrected Proof

2012-01-03

Abstract: Brain-derived neurotrophic factor (BDNF) plays an important role in neuronal plasticity, learning, and memory. Levels of BDNF and its main receptor TrkB (TrkB.TK) have been reported to be decreased while the levels of the truncated TrkB (TrkB.T1) are increased in Alzheimer's disease. We show here that incubation with amyloid-β increased TrkB.T1 receptor levels and decreased TrkB.TK levels in primary neurons. In vivo, APPswe/PS1dE9 transgenic mice (APdE9) showed an age-dependent relative increase in cortical but not hippocampal TrkB.T1 receptor levels compared with TrkB.TK. To investigate the role of TrkB isoforms in Alzheimer's disease, we crossed AP mice with mice overexpressing the truncated TrkB.T1 receptor (T1) or the full-length TrkB.TK isoform. Overexpression of TrkB.T1 in APdE9 mice exacerbated their spatial memory impairment while the overexpression of TrkB.TK alleviated it. These data suggest that amyloid-β changes the ratio between TrkB isoforms in favor of the dominant-negative TrkB.T1 isoform both in vitro and in vivo and supports the role of BDNF signaling through TrkB in the pathophysiology and cognitive deficits of Alzheimer's disease.

Age- and genotype-related neurophysiologic reactivity to oxidative stress in healthy adults - Corrected Proof

2011-12-29

Abstract: The epsilon4 allele of the apolipoprotein E gene (ApoE), as well as aging increase the risk of Alzheimer's and vascular diseases. Electroencephalogram (EEG) reactivity to hyperventilation (HV) depends on hypocapnia-induced cerebral vasoconstriction, which may be impaired in subjects with subclinical cerebrovascular disease. Quantitative EEG at rest and under 3-minute HV was examined in 125 healthy subjects divided into younger (age range 28–50) and older (age range 51–82) cohorts and stratified by ApoE genotype. The younger ApoE-epsilon4 carriers had excessive EEG reactivity to HV characterized by the manifestation of high-voltage delta, theta activity and sharp waves, and larger HV-induced changes in EEG relative powers than in the younger ApoE-epsilon4 noncarriers. EEG reactivity to HV decreased with aging, and in the ApoE-epsilon4 carriers the decrease was more pronounced than in the ApoE-epsilon4 noncarriers. The older ApoE-epsilon4 carriers had smaller HV-induced changes in EEG relative powers than the older ApoE-epsilon4 noncarriers. A marked decline of EEG reactivity to HV in the older ApoE-epsilon4 carriers suggests the possible impact of vascular factors on the pathogenesis of ApoE-induced Alzheimer disease.

Synaptic protein deficits are associated with dementia irrespective of extreme old age - Corrected Proof

2011-12-29

Abstract: Recent evidence shows that despite high incidence of dementia in the very old, they exhibit significantly lower levels of Alzheimer's disease (AD) neuropathology relative to younger persons with dementia. The levels and distributions of some synaptic proteins have been found to be associated with dementia severity, even in the oldest-old, but the molecular and functional nature of these deficits have not been studied in detail. The objective of this study was to assess the relationship of dementia with gene and protein expression of a panel of synaptic markers associated with different synaptic functions in young-, middle-, and oldest-old individuals. The protein and messenger RNA (mRNA) levels of 7 synaptic markers (complexin-1, complexin-2, synaptophysin, synaptobrevin, syntaxin, synaptosomal-associated protein 25 (SNAP-25), and septin-5) were compared in the brains of nondemented and demented individuals ranging from 70 to 103 years of age. One hundred eleven brains were selected to have either no significant neuropathology or only AD-associated pathology (neuritic plaques [NPs] and neurofibrillary tangles [NFTs]). The cohort was then stratified into tertiles as young-old (70–81 years old), middle-old (82–88), and oldest-old (89–103). The brains of persons with dementia evidenced significantly lower levels of gene and protein expression of synaptic markers regardless of age. Importantly, dementia was associated with reductions in all measured synaptic markers irrespective of their role(s) in synaptic function. Although other dementia-associated hallmarks of AD neuropathology (neuritic plaques and neurofibrillary tangles) become less prominent with increasing age, synaptic marker abnormalities in dementia remain constant with increasing age and may represent an independent substrate of dementia spanning all ages.

Calpastatin modulates APP processing in the brains of β-amyloid depositing but not wild-type mice - Corrected Proof

2011-12-29

Abstract: We report that neuronal overexpression of the endogenous inhibitor of calpains, calpastatin (CAST), in a mouse model of human Alzheimer's disease (AD) β-amyloidosis, the APP23 mouse, reduces β-amyloid (Aβ) pathology and Aβ levels when comparing aged, double transgenic (tg) APP23/CAST with APP23 mice. Concurrent with Aβ plaque deposition, aged APP23/CAST mice show a decrease in the steady-state brain levels of the amyloid precursor protein (APP) and APP C-terminal fragments (CTFs) when compared with APP23 mice. This CAST-dependent decrease in APP metabolite levels was not observed in single tg CAST mice expressing endogenous APP or in younger, Aβ plaque predepositing APP23/CAST mice. We also determined that the CAST-mediated inhibition of calpain activity in the brain is greater in the CAST mice with Aβ pathology than in non-APP tg mice, as demonstrated by a decrease in calpain-mediated cytoskeleton protein cleavage. Moreover, aged APP23/CAST mice have reduced extracellular signal-regulated kinase 1/2 (ERK1/2) activity and tau phosphorylation when compared with APP23 mice. In summary, in vivo calpain inhibition mediated by CAST transgene expression reduces Aβ pathology in APP23 mice, with our findings further suggesting that APP metabolism is modified by CAST overexpression as the mice develop Aβ pathology. Our results indicate that the calpain system in neurons is more responsive to CAST inhibition under conditions of Aβ pathology, suggesting that in the disease state neurons may be more sensitive to the therapeutic use of calpain inhibitors.

A new neuronal target for beta-amyloid peptide in the rat hippocampus - Corrected Proof

2011-12-29

Abstract: In Alzheimer's disease, amyloid beta peptide (Aβ) accumulation is associated with hippocampal network dysfunction. Intrahippocampal injections of Aβ induce aberrant inhibitory septohippocampal (SH) network activity in vivo and impairment of memory processing. In the present study, we observed, after hippocampal Aβ treatment, a selective loss of neurons projecting to the medial septum (MS) and containing calbindin (CB) and/or somatostatin (SOM). Other GABAergic neuronal subpopulations were not altered. Thus, the present study identifies hippocamposeptal neuron populations as specific targets for Aβ deposits. We observed that in Aβ-treated rats but not in controls, glutamate agonist application induced rhythmic bursting in 55% of the slow-firing neurons in the medial septum. This suggests that hippocampal Aβ can trigger modifications of the septohippocampal pathway via the alteration of a specific neuronal population. Long-range hippocamposeptal GABA/calbindin neurons, targets of hippocampal amyloid deposits, are implicated in supporting network synchronization. By identifying this target, we contribute to the understanding of the mechanisms underlying deleterious effects of Aβ, one of the main agents of dementia in Alzheimer's disease.

Environmental enrichment ameliorated high-fat diet-induced Aβ deposition and memory deficit in APP transgenic mice - Corrected Proof

2011-12-26

Abstract: The pathogenesis of Alzheimer's disease (AD) is tightly associated with metabolic dysfunctions. In particular, a potential link between type 2 diabetes (T2DM) and AD has been suggested epidemiologically, clinically, and experimentally, and some studies have suggested that exercise or dietary intervention reduces risk of cognitive decline. However, there is little solid molecular evidence for the effective intervention of metabolic dysfunctions for prevention of AD. In the present study, we established the AD model mice with diabetic conditions through high-fat diet (HFD) to examine the effect of environmental enrichment (EE) on HFD-induced AD pathophysiology. Here, we demonstrated that HFD markedly deteriorated memory impairment and increased β-amyloid (Aβ) oligomers as well as Aβ deposition in amyloid precursor protein (APP) transgenic mice, which was reversed by exposure to an enriched environment for 10 weeks, despite the continuation of HFD. These studies provide solid evidence that EE is a useful intervention to ameliorate behavioral changes and AD pathology in HFD-induced aggravation of AD symptoms in APP transgenic mice.

Mutation analysis of VCP in familial and sporadic amyotrophic lateral sclerosis - Corrected Proof

Kelly L. Williams, Jennifer A. Solski, Garth A. Nicholson, Ian P. Blair — 2011-12-26

Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive loss of motor neurons in the motor cortex, brain stem and spinal cord. Mutations in the valosin-containing protein gene (VCP) were recently described in ALS families. Some of these families included diagnoses of other clinical features including frontotemporal dementia, Paget's disease, inclusion body myopathy, Parkinsonism and limb weakness. We sought to determine the prevalence of VCP mutations in Australian familial (n = 131) and sporadic (n = 48) ALS cohorts diagnosed with classic ALS. No mutations were identified indicating that VCP mutations are not a common cause of classic ALS among Australian cases with predominantly European ancestry.

A review of the structural alterations in the cerebral hemispheres of the aging rhesus monkey - Corrected Proof

Alan Peters, Thomas Kemper — 2011-12-23

Abstract: Like humans, rhesus monkeys show cognitive decline and this review considers what structural age-related changes underlie this decline. Some structural measures do not alter significantly with age. These include brain weight, overall cortical thickness; numbers of cortical neurons; and numbers of astrocytes and microglial cells. Other structural measures change with age, but the change does not correlate with cognitive decline. These changes include nerve fiber loss from some fiber tracts, degeneration, and regeneration of myelin sheaths, and increase in the frequency of oligodendrocytes. Among the structural measures that increase in frequency with age and also correlate with cognitive decline are the increased frequency of degenerating myelin sheaths and a loss of nerve fibers from some fiber tracts; and the loss of synapses and dendritic spines from upper layers of prefrontal cortex. Consequently, the existing data suggest that cognitive decline correlates with changes in myelinated nerve fibers and with disconnections between and within cortical areas, as reflected by the age-related loss of synapses and of dendritic spines from some cortical areas.

Critical role of cPLA2 in Aβ oligomer-induced neurodegeneration and memory deficit - Corrected Proof

2011-12-22

Abstract: Soluble beta-amyloid (Aβ) oligomers are considered to putatively play a critical role in the early synapse loss and cognitive impairment observed in Alzheimer's disease. We previously demonstrated that Aβ oligomers activate cytosolic phospholipase A2 (cPLA2), which specifically releases arachidonic acid from membrane phospholipids. We here observed that cPLA2 gene inactivation prevented the alterations of cognitive abilities and the reduction of hippocampal synaptic markers levels noticed upon a single intracerebroventricular injection of Aβ oligomers in wild type mice. We further demonstrated that the Aβ oligomer-induced sphingomyelinase activation was suppressed and that phosphorylation of Akt/protein kinase B (PKB) was preserved in neuronal cells isolated from cPLA2−/− mice. Interestingly, expression of the Aβ precursor protein (APP) was reduced in hippocampus homogenates and neuronal cells from cPLA2−/− mice, but the relationship with the resistance of these mice to the Aβ oligomer toxicity requires further investigation. These results therefore show that cPLA2 plays a key role in the Aβ oligomer-associated neurodegeneration, and as such represents a potential therapeutic target for the treatment of Alzheimer's disease.