ReviewAPOE and neuroenergetics: an emerging paradigm in Alzheimer's disease
Introduction
Despite decades of intense research, the causes of Alzheimer's disease (AD) remain poorly understood and truly effective therapies remain out of reach. AD is expected to become markedly more prevalent over the next half century (Ferri et al., 2005), which further intensifies the need to develop therapies as soon as possible. Since the initial reports linking APOE to AD in the early 1990s (Corder et al., 1993; Strittmatter et al., 1993), considerable research has focused on elucidating the mechanisms by which the gene contributes to risk for the disease. Current evidence supports APOE-encoded apolipoprotein E (apoE) isoforms differentially modulating β-amyloid aggregation and clearance (Bu, 2009; Holtzman et al., 2012; Kim et al., 2009). Genetically, APOE ε4 is associated with dramatically increased risk, APOE ε3 is associated with neutral risk, and APOE ε2 is associated with decreased risk (Bertram and Tanzi, 2008; Gomez-Isla et al., 1996). APOE-related risk is gene–dose dependent: in the United States, when compared with persons homozygous for risk-neutral APOE ε3, APOE ε4 homozygotes have up to 15 times and APOE ε4 heterozygotes up to 4 times the risk for developing AD (Ashford and Mortimer, 2002; Raber et al., 2004). Therefore, ameliorating APOE ε4’s powerful effects might be a viable strategy to decrease AD incidence—delaying the average age of onset by 5 years could reduce the number of cases by more than 50% and save nearly $300 billion in Medicare spending in coming years (Sperling et al., 2011).
Though findings regarding apoE and its interactions with β-amyloid are essential to the current understanding of AD pathophysiology, it is important to further develop knowledge of the potential for APOE to affect brain function in a manner that might precede or be independent of β-amyloid pathology. Notably, apoE has known effects on cholesterol transport, inflammation, neurodevelopment, and synaptic plasticity, and study in these contexts clearly represents vital avenues of research. Mitochondrial energy metabolism and cellular bioenergetics in the brain (i.e., neuroenergetics) have also begun to be linked to the genetic risk conferred by APOE. Therefore, the intent of this article is to review the brain imaging background and potential cellular and molecular mechanisms for this emerging avenue of approach, with the hope that this rapidly evolving knowledge might stimulate innovative research approaches and the identification of tractable therapeutic targets for treatment and/or prevention of disease.
Section snippets
Metabolic brain imaging in Alzheimer's disease
Long-standing efforts have focused on the relevance of neuroenergetics in AD both as a mediator of β-amyloid-induced changes and as an independent driver (Reddy and Beal, 2008; Smith et al., 2002; Swerdlow et al., 2010; Yao et al., 2011). The energetic needs of the human brain are remarkable; despite comprising only 2% of gross body mass, the brain accounts for 20% of the body's glucose and oxygen consumption (Jolivet et al., 2009). The provision of energy to the synapse is vital for the
Metabolic brain imaging and APOE in older populations
The use of brain imaging to investigate APOE's effects is rooted in the idea of using APOE-related changes in CMRgl as an endophenotype—a quantitative, genetically-based biomarker associated with disease risk (Reiman, 2007). Thus, we have proposed CMRgl as an end point in the evaluation of AD treatments and/or preventive therapies, with the underlying assertion being that region-specific CMRgl alterations correlate with disease risk (Reiman et al., 2001), perhaps as a measure of cognitive
Brain imaging and APOE in young adults
In addition to studies of middle- and late-middle age individuals, we have used FDG PET to study even earlier effects of APOE ε4 on brain functional measures. In a study of cognitively normal subjects 20–39 years old, APOE ε4 carriers exhibited significantly decreased CMRgl in the PCC and other cortical regions associated with metabolic defects in older APOE ε4 carriers and AD patients, in this case several decades before the potential onset of dementia, and also several decades before any
Limitations and future directions of metabolic brain imaging
Importantly, both FDG PET and cytochrome oxidase studies have an inherent limitation in not being able to identify with certainty whether neurons or glial cells (particularly astrocytes) are the cellular source of the metabolic signal. Though the brain contains different cell types with different bioenergetic profiles, the compartmentalization of these bioenergetic processes has often been ignored, in part because of the limited resolution of brain imaging. For example, the astrocyte-neuron
Cellular functions of apoE in the brain
Though brain imaging can provide a great deal of insight to the effects of APOE, an understanding of cellular function and mechanisms conferring risk is essential for any effective therapeutic development. The primary function of apoE in the brain is to traffic cholesterol and other lipids. Though it is expressed in several peripheral tissues, apoE is most highly expressed in the liver and brain (Elshourbagy et al., 1985). In the brain, apoE is the primary apolipoprotein that associates with
ApoE structure and its relevance to disease
Aspects of apoE structure are thought to be a driving force in its role in AD risk. ApoE is a 34 kDa, 299 amino acid glycoprotein with 2 major functional domains: the N-terminal domain exists as a 4 helix bundle and contains the apoE receptor binding region at residues 136–150; the C-terminal domain is highly α-helical and contains the major lipid binding region at residues 244–272 (Aggerbeck et al., 1988; Dong et al., 1994; Wetterau et al., 1988; Wilson et al., 1991). When unbound by lipid,
Mechanisms of apoE cleavage and processing
As previously emphasized, the cellular source of apoE is highly regulated, and neuronal production of apoE appears to be driven by astrocytic signaling mechanisms (Harris et al., 2004b), particularly as a result of neural injury. It has been demonstrated in postmortem human samples that apoE4 undergoes neuron-specific proteolysis (Huang et al., 2001); this dramatic increase in intracellular cleavage of apoE4 compared with apoE3 and apoE2 is thought to be because of apoE4's much greater tendency
Effects of apoE on cytoskeletal components and intracellular trafficking
ApoE cleavage fragments have been shown to have a number of effects on the cytoskeleton and related intracellular trafficking functions (Fig. 3). In Neuro-2a cells, expressed apoE4 (Δ272–299) has been found to interact with cytoskeletal proteins to form neurofibrillary tangle-like structures containing phosphorylated tau (Huang et al., 2001). Mice expressing high levels of apoE4 (Δ272–299) in neurons display AD-like neurofibrillary tangles and die at 2–4 months. With lower levels of expression
ApoE and mitochondrial function
In addition to its deleterious effects on intracellular transport, apoE4 has been shown to have direct effects on mitochondria. In an early study, apoE4 was shown to bind the α and β subunits of the F1 portion of ATP synthase in liver (Mahley et al., 1989). Though direct effects on enzyme function were not assessed in that study, neuronal apoE4 fragments have subsequently been shown to perturb mitochondrial function. In Neuro-2a cultures expressing apoE4 (Δ272–299), apoE4 fragments that escape
ApoE effects on astrocytes
Beyond the effects shown in neurons, apoE4 also appears to alter function in astrocytes. ApoE4 induces endoplasmic reticulum stress in astrocytes (Zhong et al., 2009) that does not occur in neurons (Brodbeck et al., 2011). However, again pointing to the cell type-specific importance of apoE expression, mouse primary astrocyte cultures expressing apoE4 do not show significant changes in ETC gene expression (Chen et al., 2011). Additionally, transgenic mice that express apoE4 under the control of
Potential roles for TOMM40
APOE is located in a region of linkage disequilibrium on chromosome 19 that also encompasses TOMM40 and APOC1. TOMM40, which encodes Tom40, the pore-forming subunit of the translocase of the outer mitochondrial membrane, has now been proposed as a potential genetic risk factor for AD (Roses et al., 2010). However, the exact nature of the relationship, at least partly, but perhaps not entirely attributable, to linkage disequilibrium, is not yet understood as the initial findings have not been
Conclusions
The strong association between APOE and AD has been known for nearly 2 decades, during which time significant advances have been made in understanding how APOE might contribute to disease risk. Though considerably more research is needed to establish the mechanistic effects of APOE on disease processes, mounting evidence linking APOE to alterations in neuroenergetics has illuminated exciting new areas for research. Because of the apparently early nature of these functional changes (i.e., often
Disclosure statement
All authors report no conflicts of interest.
Acknowledgements
This work was supported by the Arizona Alzheimer's Consortium, the State of Arizona, and the Arizona Alzheimer's Disease Core Center (P30 AG19610).
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