Studies of aging nonhuman primates illuminate the etiology of early‐stage Alzheimer's‐like neuropathology: An evolutionary perspective
Open Access
- 7 May 2021
- journal article
- review article
- Published by Wiley in American Journal of Primatology
- Vol. 83 (11), e23254
- https://doi.org/10.1002/ajp.23254
Abstract
Tau pathology in Alzheimer's disease (AD) preferentially afflicts the limbic and recently enlarged association cortices, causing a progression of mnemonic and cognitive deficits. Although genetic mouse models have helped reveal mechanisms underlying the rare, autosomal‐dominant forms of AD, the etiology of the more common, sporadic form of AD remains unknown, and is challenging to study in mice due to their limited association cortex and lifespan. It is also difficult to study in human brains, as early‐stage tau phosphorylation can degrade postmortem. In contrast, rhesus monkeys have extensive association cortices, are long‐lived, and can undergo perfusion fixation to capture early‐stage tau phosphorylation in situ. Most importantly, rhesus monkeys naturally develop amyloid plaques, neurofibrillary tangles comprised of hyperphosphorylated tau, synaptic loss, and cognitive deficits with advancing age, and thus can be used to identify the early molecular events that initiate and propel neuropathology in the aging association cortices. Studies to date suggest that the particular molecular signaling events needed for higher cognition—for example, high levels of calcium to maintain persistent neuronal firing‐ lead to tau phosphorylation and inflammation when dysregulated with advancing age. The expression of NMDAR‐NR2B (GluN2B)—the subunit that fluxes high levels of calcium—increases over the cortical hierarchy and with the expansion of association cortex in primate evolution, consistent with patterns of tau pathology. In the rhesus monkey dorsolateral prefrontal cortex, spines contain NMDAR‐NR2B and the molecular machinery to magnify internal calcium release near the synapse, as well as phosphodiesterases, mGluR3, and calbindin to regulate calcium signaling. Loss of regulation with inflammation and/or aging appears to be a key factor in initiating tau pathology. The vast expansion in the numbers of these synapses over primate evolution is consistent with the degree of tau pathology seen across species: marmoset < rhesus monkey < chimpanzee < human, culminating in the vast neurodegeneration seen in humans with AD.Keywords
Funding Information
- Alzheimer's Association (AARF‐17‐533294)
- NIH Office of the Director (P51 OD011132)
- National Institute on Aging (DP1AG047744, R01AG061190)
- American Federation for Aging Research (Diamond Postdoctoral Fellowship)
This publication has 121 references indexed in Scilit:
- Nicotinic α7 receptors enhance NMDA cognitive circuits in dorsolateral prefrontal cortexProceedings of the National Academy of Sciences of the United States of America, 2013
- Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the LiteratureJournal of Neuropathology and Experimental Neurology, 2012
- The ageing cortical synapse: hallmarks and implications for cognitive declineNature Reviews Neuroscience, 2012
- Neuropil distribution in the cerebral cortex differs between humans and chimpanzeesJournal of Comparative Neurology, 2012
- Neuronal basis of age-related working memory declineNature, 2011
- Caloric Restriction Delays Disease Onset and Mortality in Rhesus MonkeysScience, 2009
- Molecular evolution of the cytochrome c oxidase subunit 5 A gene in primatesBMC Evolutionary Biology, 2008
- Causes of oxidative stress in Alzheimer diseaseCellular and Molecular Life Sciences, 2007
- PKA modulates GSK‐3β‐ and cdk5‐catalyzed phosphorylation of tau in site‐ and kinase‐specific mannersFEBS Letters, 2006
- Neuropathological stageing of Alzheimer-related changesActa Neuropathologica, 1991