Regular articleAged chimpanzees exhibit pathologic hallmarks of Alzheimer's disease
Introduction
Alzheimer's disease (AD) is a progressive, irreversible proteinopathy, resulting in cognitive impairment, and characterized by pathologic aggregations of the amyloid-beta (Aβ) and tau proteins in the form of plaques and neurofibrillary tangles (NFTs) and selective neuronal loss (Bussière et al., 2003a, Bussière et al., 2003b; Montine et al., 2012). It has been suggested that humans are uniquely susceptible to AD, potentially due to genetic differences, changes in cerebral structure and function during evolution, and an increased life span (Hof et al., 2002, Rapoport and Nelson, 2011, Sherwood et al., 2011, Walker and Cork, 1999). Although Aβ and tau pathology have been identified in nonhuman primates, these animals typically present with only amyloid plaque pathology (Head et al., 2001, Heuer et al., 2012, Hof et al., 2002, Oikawa et al., 2010, Walker and Cork, 1999). In addition, aged primates demonstrate cognitive deficits in working memory, learning tasks, long-term retention, and cognitive flexibility similar to elderly humans (Joly et al., 2014, Lacreuse et al., 2014, Nagahara et al., 2010, Picq et al., 2015). Previous studies in aged monkeys and great apes confirmed the presence of diffuse and neuritic amyloid plaques as well as vascular amyloid (Gearing et al., 1994, Gearing et al., 1996, Gearing et al., 1997, Geula et al., 2002, Heuer et al., 2012, Kimura et al., 2003, Lemere et al., 2004, Lemere et al., 2008, Martin et al., 1991, Mufson et al., 1994, Oikawa et al., 2010, Perez et al., 2013, Perez et al., 2016, Poduri et al., 1994, Rosen et al., 2008, Walker et al., 1987). The presence of abnormally phosphorylated tau has been reported in neurons and glia in rhesus monkeys (Macaca mulatta) and squirrel monkeys (Saimiri sciureus) as well as baboons (Papio anubis) (Elfenbein et al., 2007, Hartig et al., 2000, Oikawa et al., 2010, Schultz et al., 2000, Selkoe et al., 1987). In great apes, captive and wild gorillas (Gorilla gorilla gorilla and Gorilla beringei beringei) exhibited hyperphosphorylated tau-immunoreactive (ir) neurons in the neocortex in close association with Aβ plaques, but the perikarya lacked classic AD tau histopathologic abnormalities (Perez et al., 2013, Perez et al., 2016). Several pathologic examinations of the chimpanzee (Pan troglodytes) and orangutan (Pongo pygmaeus) brain revealed diffuse Aβ plaques and vascular amyloid, but not tau-positive NFT and neuropil threads (Gearing et al., 1994, Gearing et al., 1996, Gearing et al., 1997). The only evidence of NFT and Aβ pathology coexisting in a primate species other than humans was reported in a 41-year-old female chimpanzee that suffered a stroke before death and had a history of high cholesterol (Rosen et al., 2008). This ape presented with scarce diffuse senile plaques and vascular amyloid, NFT, neuropil threads, and clusters of tau-positive neurites in the neocortex, which may have been the result of a rare ischemic event, as risk of dementia after stroke is increased twofold in humans (Schneider and Bennett, 2010).
Chimpanzees share 100% sequence homology and all 6 tau isoforms with humans (Chimpanzee Sequencing and Analysis Consortium, 2005, Holzer et al., 2004, Nelson et al., 2009). Moreover, amyloid precursor protein 695 (APP695) is more than 99% identical in chimpanzees and humans and can be cleaved into Aβ 40/42 peptides with 100% sequence homology to humans (Cervenáková et al., 1994, Götz and Ittner, 2008, Heuer et al., 2012). As one of our closest living primate relatives, chimpanzees demonstrate greater behavioral complexity and longer life spans than nonprimate AD animal models (Hakeem et al., 1996, Hill et al., 2001). In captivity, the average life span for chimpanzees ranges from 30 to 35 years with the oldest recorded age of 62 years (Dyke et al., 1995). Therefore, chimpanzees are ideal candidates to investigate the pathobiology of AD from an evolutionary neurobiological perspective.
Brain samples from great apes, particularly aged individuals, are incredibly scarce. In the wild, chimpanzees have an average life expectancy of 33 years (maximum age noted was 53 years), and only 10% of captive male chimpanzees survive to age 45 and captive females to age 55 (Dyke et al., 1995, Hill et al., 2001, Wood et al., 2017). In addition, prior neuropathologic studies in apes were limited to small samples sizes. The present study evaluated 4 brain regions affected by AD pathology in humans—prefrontal cortex (PFC), middle temporal gyrus (MTG), and CA1 and CA3 hippocampal subfields—in a large group of aged chimpanzees (Table 1) for Aβ-positive plaques, vascular amyloid, and tau lesions (i.e., pretangles, NFT, and neuritic clusters). We also developed an overall pathology scoring system based on clinical staging parameters for Aβ and NFT deposition in humans (see Section 2.6 and Table 2) (Attems et al., 2007, Braak and Braak, 1991, Braak et al., 2006, Mirra et al., 1991, Montine et al., 2012, Thal et al., 2002, Vonsattel et al., 1991). Here, we show that pretangles, NFT, and clusters of tau-ir dystrophic neurites (NC) co-occur with amyloid-positive plaques and vasculature in aged chimpanzees. These findings indicate that AD-like pathology is not limited to the human brain.
Section snippets
Specimens and sample processing
Postmortem brain specimens from 20 aged chimpanzees (Table 1) were acquired from Association of Zoos and Aquariums–accredited zoos or American Association for Accreditation of Laboratory Animal Care–accredited research institutions and maintained in accordance with each institution's animal care guidelines. Chimpanzee brain specimens were provided by the National Chimpanzee Brain Resource (supported by NIH grant NS092988), and health information has been included when possible (Table S1). The
APP/Aβ and Aβ42 plaque volume
To evaluate Aβ protein aggregates in the aging chimpanzee brain, we measured volume occupied by plaques using immunostaining against 2 peptides, APP/Aβ and Aβ42. Of the 20 chimpanzees, 13 had APP/Aβ-ir plaques (Fig. 1A–B, E), whereas 5 of those individuals also presented with Aβ42-ir plaques (Fig. 1C–D, F). Of those with Aβ42 plaques, 4 were the oldest individuals (57–62 years). Aβ42 plaques were not found in the youngest subjects (39–44 years). Diffuse and dense-core plaques were identified in
Discussion
To date, fewer than 50 brains of aged apes have been examined for AD pathology across all prior studies (Finch and Austad, 2015). Here, we present an investigation of AD neuropathology in the largest cohort of any great ape species consisting of 20 chimpanzee brains aged 37–62 years. Our findings establish that aged chimpanzees can exhibit the 2 main histological markers found in the brain of humans with AD, Aβ plaques, and NFT.
APP/Aβ and Aβ42-ir diffuse and dense-core plaques were most
Conclusions
Tau and Aβ lesions were identified in the neocortex and hippocampus in a large cohort of aged chimpanzees. Surprisingly, AT8-ir pretangles and Aβ-positive vessels were exhibited in all 20 apes, whereas Aβ plaques were found in two-thirds of individuals. We also demonstrated thioflavin S-positive NFTs in aged chimpanzees, although electron microscopic analysis is planned to confirm filament structure. Neuritic plaques with an Aβ core were absent, but clusters of AT8-ir tau neurites were
Acknowledgements
The authors would like to thank Jennifer Chilton for her assistance with health records, Dr. Jason R. Richardson for his editorial revisions, Dr. Peter Davies for providing tau antibodies, Dr. Michael Model for his confocal microscopy expertise, and Cheryl Stimpson, Bridget Wicinski, and Emily Munger for their technical assistance. Supported by grants from the NSF (BCS-1316829 to MAR), NIH (NS042867, NS073134, and NS092988 to WDH and CCS; AG017802 to JJE; AG014308 to JME; AG005138 to PRH; and
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