Elsevier

Neurobiology of Aging

Volume 32, Issue 9, September 2011, Pages 1651-1661
Neurobiology of Aging

Age-related brain pathology in Octodon degu: Blood vessel, white matter and Alzheimer-like pathology

https://doi.org/10.1016/j.neurobiolaging.2009.10.008Get rights and content

Abstract

Recently it has been shown that over 3-year-old wild-type South American rodents, Octodon degus, the “common degu” or degu, of their own accord develop Alzheimer's disease neuropathological hallmarks: amyloid-β-peptide depositions and accumulation of tau-protein. Here we analyzed brains of 1-, 3- and 6-year-old degu's, bred in standard animal facilities. Significant amounts of Aβ and tau deposits are present in the hippocampal formation of 6-year-old O. degus, primarily in the white matter, but these hippocampal Aβ and tau deposits are not present in younger ones. In contrast, significant Aβ deposits in blood vessel walls are already found in 3-year-old animals. The tau deposits in the hippocampal formation coincide with a significant decrease in staining for myelin in the same areas, indicating hippocampal disconnection and, likely, dysfunction. Our findings indicate that (1) cerebral amyloid angiopathy precedes brain parenchyma pathology in aged degu's and (2) the onset of disease seems to be delayed in the laboratory vs. wild-type degu's.

Introduction

Alzheimer's disease (AD) is the most common form of dementia in the elderly (Hebert et al., 2003, Hirtz et al., 2007); the two characteristic pathological markers of the disease are significant numbers of neurofibrillary tangles (NFTs) and neuritic plaques in the brain (e.g., Hyman and Trojanowski, 1997). Neurofibrillary tangles consist of hyperphosphorylated twisted filaments of the cytoskeletal protein tau (e.g., Lee et al., 2001), whereas plaques are primarily made up of amyloid β (Selkoe, 2001, Dickson and Vickers, 2001), a 39–43 amino acid long peptide derived from the proteolytic processing of the amyloid precursor protein (APP [e.g., Selkoe and Wolfe, 2007, Van Broeck et al., 2007]). When APP is sequentially cleaved by the β-secretase and the γ-secretase, the resulting breakdown product is Aβ, in contrast, cleavage by the α-secretase does not lead to Aβ production (Van Broeck et al., 2007).

It has been demonstrated that several mammalian species (e.g., cats, dogs, bears, sheep, goat, monkeys) with age develop Alzheimer's-like pathology (Selkoe et al., 1987, Cork et al., 1998, Johnstone et al., 1991, Braak et al., 1994, Colle et al., 2000, Härtig et al., 2000, Czasch et al., 2006). Recently, Inestrosa et al. (2005) demonstrated that the aged wild-type South American rodent, Octodon degus, also develops Alzheimer-like pathology. They suggested that this was due to the high homology (97.5%) between the human and degu Aβ. Moreover, our recent studies suggest that in old age, laboratory bred degu's, express cognitive deficits (Ortiz et al., 2005), anxiety (Popović et al., 2009) and unstable circadian rhythms of low amplitude (Vivanco et al., 2007), also seen in AD patients. In this article, for first time, we report that a laboratory bred South American rodent, O. degus, with age, spontaneously develops neuropathological signs of AD in cerebral vessels, but also shows signs of significant white matter disruption in aging.

Section snippets

Animals

According to their age, the female O. degus were divided into three groups: young (1 year old, n = 6), adult (3 years old, n = 6) and aged (6 years old, n = 3). The animals were obtained from a colony maintained at the Animal Service at the University of Alicante. Animals were individually housed in Plexiglas cages in an isolated room (Chronolab), with controlled humidity (60%), temperature (23 ± 1 °C) and under a 12:12 light/dark cycle (light on from 08:00 to 20:00 h). Light was provided by fluorescent

Age-related changes in brain of the degu

In the Nissl-stained sections of the degu brain there were no obviously visible age-related changes in any specific brain areas, i.e., no obvious lesions, tumors, or degeneration were visible. It should be noted, however, that whereas the hippocampal formation did not show any obvious differences with aging either (Fig. 1), at higher magnification a small decrease in the number of neurons in the hilus of the dentate gyrus of the hippocampus was visible (Fig. 1). Similarly, the staining with the

Discussion

Overall, our findings demonstrate that brains from aged O. degu present molecular markers strongly reminiscent of both normal aging and AD neuropathology, and they suggest that the degu is probably the first rodent model that develops “natural” AD pathology. Further, the development of the striking white matter pathology is very similar to changes in the white matter in aging humans (Ikeda et al., 1989, Morris et al., 1996). Moreover, this research shows that cerebral amyloid angiopathy (CAA)

Conflict of interest

The authors disclose that no actual or potential conflicts of interest including any financial, personal or other relationships with other people or organizations within 3 years of beginning the work submitted that could inappropriately influence (bias) their work exist.

Acknowledgements

We thank Songlian Zhou for her assistance with the histology; we thank Dr. Checler for the kind gift of the Aβ antibody, Dr. Davies for the tau antibodies, and Dr. Thinakaran for the kind gift of the APLP antibodies. Part of this work was supported by the Spanish Seneca Foundation (PI/05700/07), by the Instituto de Salud Carlos III (RETICEF, RD06/0013/0019), by the Spanish Ministry of Education and Science (BFU2007-60658/BFI), and by NIH grant P50 AG016582-10.

References (53)

  • N. Ida et al.

    Analysis of heterogeneous A4 peptides in human cerebrospinal fluid and blood by a newly developed sensitive Western blot assay

    J. Biol. Chem.

    (1996)
  • N.C. Inestrosa et al.

    Human-like rodent amyloid-beta-peptide determines Alzheimer pathology in aged wild-type Octodon degu

    Neurobiol. Aging

    (2005)
  • E.M. Johnstone et al.

    Conservation of the sequence of the Alzheimer's disease amyloid peptide in dog, polar bear and five other mammals by cross-species polymerase chain reaction analysis

    Mol. Brain Res.

    (1991)
  • I. Kadish et al.

    Transgenic mice expressing the human presenilin 1 gene demonstrate enhanced hippocampal reorganization following entorhinal cortex lesions

    Brain Res. Bull.

    (2002)
  • L. Lewejohann et al.

    Transgenic Alzheimer mice in a semi-naturalistic environment: more plaques, yet not compromised in daily life

    Behav. Brain Res.

    (2009)
  • N. Popović et al.

    Aging and time-of-day effects on anxiety in female Octodon degus

    Behav. Brain Res.

    (2009)
  • S.R. Robinson et al.

    Challenges and directions for the pathogen hypothesis of Alzheimer's disease

    Neurobiol. Aging

    (2004)
  • L.C. Schmued et al.

    Fluoro-Jade C results in ultra high resolution and contrast labeling of degenerating neurons

    Brain Res.

    (2005)
  • L. Schmued et al.

    Introducing Black-Gold II, a highly soluble gold phosphate complex with several unique advantages for the histochemical localization of myelin

    Brain Res.

    (2008)
  • D.J. Selkoe et al.

    Presenilin: running with scissors in the membrane

    Cell

    (2007)
  • I. Sotiropoulos et al.

    Stress and glucocorticoid footprints in the brain-the path from depression to Alzheimer's disease

    Neurosci. Biobehav. Rev.

    (2008)
  • G.S. Spear et al.

    The pancreas in the degu

    Exp. Mol. Pathol.

    (1984)
  • D.T. Stephenson et al.

    Amyloid precursor protein accumulates in regions of neurodegeneration following focal cerebral ischemia in the rat

    Brain Res.

    (1992)
  • T. Van Groen et al.

    Diffuse amyloid deposition, but not plaque number, is reduced in amyloid precursor protein/presenilin 1 double-transgenic mice by pathway lesions

    Neuroscience

    (2003)
  • T. van Groen et al.

    Deposition of mouse amyloid beta in human APP/PS1 double and single AD model transgenic mice

    Neurobiol. Dis.

    (2006)
  • Y. Yoshiike et al.

    Specific compositions of amyloid-beta peptides as the determinant of toxic beta-aggregation

    J. Biol. Chem.

    (2003)
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