Studies of aging nonhuman primates illuminate the etiology of early‐stage Alzheimer's‐like neuropathology: An evolutionary perspective

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.

Nonhuman primates at the intersection of aging biology, chronic disease, and health: An introduction to the American Journal of Primatology Special Issue on aging, cognitive decline, and neuropathology in nonhuman primates

“…Within the comparative perspective of this Special Issue, the authors have addressed various aspects of the aging phenotype in wellcharacterized and emerging NHP models, ranging from prosimians to hominids, including: gray mouse lemurs (Chaudron et al 2021), common marmosets (Rothwell et al, 2021), vervet/African green monkeys (Frye et al, 2021), three macaque species: rhesus (Arnsten et al, 2021;Upright & Baxter, 2021), cynomolgus (Darusman et al, 2021), and Barbary (Rathke & Fischer, 2021); and chimpanzees (Mulholland et al, 2021). Four main themes emerge from this collection.…”

Hyperacute Excitotoxic Mechanisms and Synaptic Dysfunction Involved in Traumatic Brain Injury

“…Within the hyperacute phase of TBI, phosphorylated NR2B levels begin to rise and promote the upregulation of other NMDAr subunits, such as NR1 and NR2A ( Schumann et al, 2008 ). The NR2B subunit is responsible for high influxes on Ca 2+ into the neuron, with dysregulation of this subunit leading to excitotoxic conditions ( Arnsten et al, 2021 ). In cultured neurons, the loss of functional connectivity is primarily mediated through activation of NR2B subunit ( Patel et al, 2014 ).…”

PET Imaging in Animal Models of Alzheimer’s Disease

“…Non-human primates such as rhesus macaques and marmosets are not known to develop AD but do accumulate Aβ deposits and show tauopathy in their aged brains ( Paspalas et al, 2018 ; Haque and Levey, 2019 ; Arnsten et al, 2021b ; Datta et al, 2021 ; Leslie et al, 2021 ). Intracranial injection of Aβ 42 and thiorphan, an inhibitor of neprilysin that is responsible for Aβ clearance, has been employed to generate an AD model in middle-aged (16–17 years) rhesus monkeys ( Li et al, 2010 ).…”