Comparative neuropathology in aging primates: A perspective

Abstract

While humans exhibit a significant degree of neuropathological changes associated with deficits in cognitive and memory functions during aging, non-human primates (NHP) present with more variable expressions of pathological alterations among individuals and species. As such, NHP with long life expectancy in captivity offer an opportunity to study brain senescence in the absence of the typical cellular pathology caused by age-related neurodegenerative illnesses commonly seen in humans. Age-related changes at neuronal population, single cell, and synaptic levels have been well documented in macaques and marmosets, while age-related and Alzheimer's disease-like neuropathology has been characterized in additional species including lemurs as well as great apes. We present a comparative overview of existing neuropathologic observations across the primate order, including classic age-related changes such as cell loss, amyloid deposition, amyloid angiopathy, and tau accumulation. We also review existing cellular and ultrastructural data on neuronal changes, such as dendritic attrition and spine alterations, synaptic loss and pathology, and axonal and myelin pathology, and discuss their repercussions on cellular and systems function and cognition.

Keywords: brain senescence; glia; neuron morphology; non-human primates; proteinopathy.

Figure 1.. Amyloid burden in the marmoset brain.

Confocal image stacks showing amyloid β (red) and 4′,6-diamidino-2-phenylindole (DAPI, blue) a nuclear marker. Different degrees of amyloid deposits are observed in 7–9 year old marmosets in dorsolateral prefrontal cortex (dlPFC, area 8b/9, layer III). Both amyloid deposited in diffuse plaques and vascular deposits are detected in behaviorally characterized marmosets, suggesting different neurodegenerative trajectories between individuals. Scale bars = 100 μm.

Figure 2.. Dendritic spine density and morphology in rhesus macaques.

(A) Confocal image stacks from young (8 years old) (left) vs old (24 years old) (right) macaques show the spine loss associated with aging in dorsolateral prefrontal cortex (dlPFC). Scale bar = 5 μm. (Luebke et al., 2010). (B) Confocal image stacks of distal apical, mid-apical and basal dendritic branches (b/w inverted) showing the fewer dendritic spines and lower proportion of thin spines in visual cortex (V1) when compared to dorsolateral prefrontal cortex (dlPFC) neurons. Scale bar = 5 μm. (Amatrudo et al., 2012)

Figure 3.. White matter atrophy in rhesus macaques.

Electron micrographs showing myelinated nerve fibers in area 46. (A) In a young macaque (10 years of age) myelin sheaths around axons are compact, whereas (B) in an old individual (27 years of age) many of the myelin sheaths (labelled with a D in the picture) have begun to degenerate and show dense inclusions within their lamellae. Other sheaths (labelled with an asterisk in the picture) are empty because the axon has degenerated. Scale bar = 1 μm. (Luebke et al., 2010)

Figure 4.. Alzheimer’s disease pathology in great apes.

Photomicrographs of immunohistochemical staining in a 33-year-old female chimpanzee brain. Amyloid-β deposition occurs in plaques (A) and vessels (B), and tau deposition is present in pretangles (C), NFT (D), and neuritic clusters of dystrophic neurites (E), which appears unique to chimpanzees and gorillas. (F) Frontal cortex dual stained for choline acetyltransferase (fine fibers; arrows) and APP/Aβ amyloid plaques in a 55-year-old female Western lowland gorilla. Scale bars = 25 μm.