Nonhuman primate models of Alzheimer-like cerebral proteopathy

Abstract

Nonhuman primates are useful for the study of age-associated changes in the brain and behavior in a model that is biologically proximal to humans. The Aβ and tau proteins, two key players in the pathogenesis of Alzheimer's disease (AD), are highly homologous among primates. With age, all nonhuman primates analyzed to date develop senile (Aβ) plaques and cerebral β-amyloid angiopathy. In contrast, significant tauopathy is unusual in simians, and only humans manifest the profound tauopathy, neuronal degeneration and cognitive impairment that characterize Alzheimer's disease. Primates thus are somewhat paradoxical models of AD-like pathology; on the one hand, they are excellent models of normal aging and naturally occurring Aβ lesions, and they can be useful for testing diagnostic and therapeutic agents targeting aggregated forms of Aβ. On the other hand, the resistance of monkeys and apes to tauopathy and AD-related neurodegeneration, in the presence of substantial cerebral Aβ deposition, suggests that a comparative analysis of human and nonhuman primates could yield informative clues to the uniquely human predisposition to Alzheimer's disease.

Figure 1

Senile plaques in a human with AD (A) and in a 35 year old female rhesus macaque (B). (A) Dense core plaque (black arrow); ‘primitive’ plaque (arrowhead); diffuse plaque (gray arrow). Antibody 6E10 specific amino acids 1–17 of Aβ. Bars = 50μm.

Figure 2

Cerebral β-amyloid angiopathy immunostained with antibodies to Aβ in a human AD patient (A) and in a 27-year old female squirrel monkey (B). Superficial vessels are indicated by arrows, and parenchymal vessels by arrowheads. Antibody 10D5 specific to residues 3–6 of Aβ (A) and β/A4 specific to Aβ phosphorylated at threonine 743. (B), courtesy of Dale Schenk and Colin Masters, respectively. Bars = 50μm.

Figure 3

Cortical neurons immunoreactive for abnormally phosphorylated tau in a human patient with AD (A) and in a 41 year-old female Chimpanzee (B). Note also the neuropil ‘threads’ surrounding the somata. Antibody AT8 specific for Tau doubly phosphorylated at Ser202/Thr205. Bars = 50μm.

Figure 4

Ultrastructure of a neurofibrillary tangle in a cortical neuron from a 41-year old female chimpanzee. The paired helical filaments (arrow marks an isolated PHF) are identical in size and periodicity to those in humans with AD. Bar = 200nm.

Figure 5

Reactive gliosis associated with senile plaques in aged rhesus monkeys. A) Activated astrocytes (red) surrounding a cortical senile plaque in a 34 year old male rhesus monkey (antibody to GFAP). B) Activated microglia (brown) in a cortical senile plaque (antibody to CD68 epitope PG-M1, which is specific for macrophages and microglia) of a 30 year old male rhesus monkey. Note that microglia tend to be spatially more centrally located; note also the relatively quiescent glia more distant from the plaques. Bars = 50μm.

Figure 6

Abnormally distended neurites in a senile plaque from the hippocampal formation of a ~30 year old male rhesus monkey. Note the normal-appearing neuronal processes distal to the plaque. Antibody 6–17 to phosphorylated neurofilaments recognizes NF-H in axons. Bar = 50μm.

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 (indicated by the hatched bars) among members of the same species. Some estimates are approximate, due to the relatively small numbers of aged animals studied.