Nearly half a century of neuropathological studies have confirmed that, like humans, nonhuman primates exhibit age- related deposition of Aβ in the brain parenchyma and vasculature (). Conversely, tau pathology appears to be relatively rare in nonhuman primates, and, when present, it is generally focal and often mild. Furthermore, nonhuman primates do not develop the widespread neuronal degeneration and profound cognitive impairments that characterize AD. However, the variations in cerebral Aβ amyloidosis among primate species can provide clues to the origins of different types of lesions, and perhaps also to the human-specific predisposition to AD. For example, by comparing gene expression in closely related species, it may be possible to determine why Aβ-proteopathy in monkeys is relatively benign compared to that in humans with AD.
Figure 7 Maximum known lifespans and approximate ages at which Aβ deposition is present [Senile Plaques (SP), and Cerebral Amyloid Angiopathy (CAA)] in some representative nonhuman primate species. Note that there is variability in age of lesion onset (more ...)
Most studies of nonhuman primates have relied on histochemical methods to characterize the age-associated lesions in the brain. New and emerging technologies will open avenues for investigators to perform enhanced biochemical, physicochemical, and high resolution neuroimaging studies of the Aβ and tau proteins at various points throughout the lifespans of primates, and to correlate these findings with longitudinal behavioral data. Quantitative ELISAs show that the levels of cerebral Aβ are comparable in humans with AD and aged chimpanzees, rhesus macaques, and squirrel monkeys [63
]. Surprisingly, however, binding assays with radiolabeled Pittsburgh Compound B (PIB) have revealed striking disparities in the affinity of the ligand for Aβ deposits between simians and humans, suggesting potentially important differences in the architecture and/or endogenous binding partners of Aβ aggregates that govern their neurotoxicity.
Recent research suggests that oligomeric Aβ may be a key source of neuronal dysfunction in AD [149
]. No studies of nonhuman primates have yet systematically measured oligomeric forms of Aβ (or tau). Thus, while previous studies have failed to find a correlation between plaque burden and cognitive dysfunction [110
], future investigations should examine non-fibrillar Aβ load for its potential relation to cognitive deficits. Additional studies that may further clarify the relative resistance of apes and monkeys to AD include an investigation of intracellular Aβ, a detailed analysis of the intracellular binding partners of Aβ and tau, a characterization of species-specific ApoE functionality, and the detection of neuroinflammatory components in and around brain lesions.
While each nonhuman primate model has advantages and disadvantages for these studies (lifespan, size, biological relatedness to humans, safety, status in the wild, etc), the rhesus macaque, because it has been well-studied, currently is the most accessible and practical nonhuman primate model in which to study AD-like proteopathic processes. Rhesus monkeys have a fairly long lifespan (up to 40 years), and large, neuroanatomically sophisticated brains; they show substantial Aβ deposition, and can be assessed for complex cognitive functions using tasks that, in many instances, are translatable to humans. On the other hand, the squirrel monkey is perhaps the most suitable nonhuman primate model of CAA and age-related microvascular disease, as this animal has a predilection to develop considerable vascular amyloid. Additional advantages are its small size and large brain-to-body weight ratio, although a disadvantage is that it is more distantly related to humans than are macaques. As noted above, prosimians also have advantages for certain analyses, owing to their small size and relatively short lifespan, and baboons may be the best natural animal model of tauopathy, although the relatively small amount of data on the prevalence of tauopathy in baboons underscores the need for further investigation.
Aged nonhuman primates are valuable models of normal human brain aging, and they also are biologically relevant research models for the development of diagnostics and therapeutics for AD and CAA. As we expand our understanding of conserved and divergent properties of cerebral proteopathies in the various primate species, we may begin to shed light on why the uniquely capable human brain is particularly sensitive to age-related neurodegenerative disorders such as Alzheimer’s disease.