Neuropathology and apolipoprotein E profile of aged chimpanzees: implications for Alzheimer disease.

Abstract

It might be expected that great apes, because of their genetic similarity to humans (1-3), would be the most appropriate models for the study of the neuropathological changes seen in the brain in aging and Alzheimer disease (AD). These changes include senile plaques (extracellular aggregates of amyloid, often surrounded by degenerating neuronal processes), neurofibrillary tangles [intraneuronal cytoplasmic aggregates of paired helical filaments composed of abnormally phosphorylated microtubule-associated protein, tau (4-7)], and vascular amyloid deposition involving meningeal and cortical blood vessels. The amyloid in plaques and blood vessels is composed primarily of the amyloid a-protein (,B/A4), which is cleaved from the larger amyloid precursor protein (APP) (8-10).Given the relative rarity ofgreat apes in captivity combined with their long fife-spans (=w50-60 yr in captivity), studies of age-related changes in the brains ofthese primates have been extremely rare. Senile plaques and vascular amyloid have been described in a 46-yr-old orangutan (11), and vascular amyloid was noted in a 56-yr-old chimpanzee (these observations were made on a portion offrontal lobe from the brain of the same 56-yr-old chimpanzee included in the present study; ref. (28-31). Thus, the combination of senile plaques, vascular amyloid, and neurofibrillary tangles observed in AD has not yet been described in any animal species.Molecular studies suggest that, of the great apes, chimpanzees are most closely related to humans (1-3). Chimpanzees rarely survive past the age of 35 yr in the wild but may live well into the sixth decade in captivity (32). Gamma, the 59-yr-old chimpanzee in our study, was the oldest known chimpanzee. In contrast, the maximum ifMe-span for rhesus monkeys has been estimated at just under 40 yr, with aging in rhesus monkeys estimated to occur at about three times the rate in humans (12,(32)(33)(34)(35). We had the opportunity to examine the brains of three aged chimpanzees (Pan troglodytes), two females aged 56 (Bula) and 59 yr (Gamma) and a male (Frans) aged 45 yr, and to compare the changes observed with those seen in the brains of four elderly rhesus monkeys (Macaca mulatta), aged 20, 21, 29, and 30 yr, and in the brains of individuals with AD.

Neuropeptide Y-Like Immunoreactivity in Area 17 of Chimpanzee

“…The oldest chimpanzee (C-612) was 56 years old, which is close to the 59 years recorded for the oldest specimen (Gamma) of this species (Gearing et al, 1994). The neuronal types and their laminar distribution do not basically differ in young and old chimpanzees.…”

Primate aging in the mammalian scheme: the puzzle of extreme variation in brain aging

“…Notably, the hippocampus was not involved. Cerebrovascular Aβ was also present, consistent with prior findings in aging apes (Gearing et al 1994(Gearing et al , 1996(Gearing et al , 1997. The authors' absence of comment on neuron loss should not be interpreted as its absence.…”

“…The brain aging changes appear to be milder than in the mouse lemur, monkeys, or humans of equivalent demographic age, but very few specimens have been studied (Table 2). Neurofibrillary degeneration has been considered absent in aging great apes (Gearing et al 1994(Gearing et al , 1996(Gearing et al , 1997. However, we now have one case of classic Alzheimer tauopathy and neurofibrillary degeneration in a 41-year-old female who was euthanized after a stroke ; this individual had notable obesity and hypercholesterolemia, which are risk factors in human AD and, which in AD-transgenic mice, accelerate neurodegeneration (Cole et al 2010;Leduc et al 2010).…”

“…Chimpanzees and other great apes also accumulate low levels of diffuse Aβ peptides at later ages, with notable amounts of Aβ (1-40) as well as Aβ(1-42) (Gearing et al 1994(Gearing et al , 1996(Gearing et al , 1997. The brain aging changes appear to be milder than in the mouse lemur, monkeys, or humans of equivalent demographic age, but very few specimens have been studied (Table 2).…”

“…The differences between general aging changes and clinical disease may be described as eugeric vs. pathogeric age changes (Finch 1972). For example, in US-wide samples of the NHANES, fluid intelligence scores peak at about 25 years and decline progressively at about a Chimpanzee, 41 years , 59 years (Gearing et al 1994(Gearing et al , 1996, and 2 "aged," no age given (Gearing et al 1994); gorilla, 44 years (Kimura et al 2001); orangutans-28, 31, and 36 years (Gearing et al 1997); baboon (Schultz et al 2000); and lemur (Bons et al 2006;Kraska et al 2011;Marchal et al 2012) 0.5%/year up through age 70 (McArdle 2009;Salthouse 2009). Complex multi-tasking ("walking while memorizing") also declines progressively across middle age (Li et al 2001).…”