Alzheimer's disease pathology in the neocortex and hippocampus of the western lowland gorilla (Gorilla gorilla gorilla)

“Although Ab toxicity may influence NFT-like pathology in the aged rhesus monkey cortex (Geula et al., 1998), diffuse and cored amyloid plaques are found in most aged mammalian brains without concomitant NFT pathology (Braak and Braak, 1991; Cork, 1993).”

“Ab42 has a high propensity to aggregate into insoluble fibrils and is more toxic than Ab40 (Younkin, 1998; Selkoe, 2001).”

“Conversely, neuritic plaques with swollen neurites, which were not observed in gorillas, have been described in other nonhuman primates (Walker et al., 1987; Poduri et al., 1994; Gearing et al., 1996; Kimura et al., 2003; Lemere et al., 2004, 2008) as well as in human AD (Serrano-Pozo et al., 2011).”

“Clinical pathological studies have demonstrated that, unlike diffuse plaques, neuritic plaques as well as the amount and distribution of NFT correlate with cognitive decline in AD (Arriagada et al., 1992; Nagy et al., 1995; Gomez-Isla et al., 1996; Giannakopoulos et al., 2003).”

“Clinical pathological studies have demonstrated that, unlike diffuse plaques, neuritic plaques as well as the amount and distribution of NFT correlate with cognitive decline in AD (Arriagada et al., 1992; Nagy et al., 1995; Gomez-Isla et al., 1996; Giannakopoulos et al., 2003).”

“The evolutionary mechanism(s) that trigger the vulnerability of telencephalic long projection neurons to form NFTs during the onset of AD are an area of great interest (Morrison and Hof, 1997).”

“Neocortical and hippocampal nomenclature was based on the cytoarchitecture of the human and monkey brain (Brodmann, 1909; Rosene and Van Hoesen, 1987).”

“In the current study, we also showed Ab oligomers in plaques, which are considered the most toxic Ab forms affecting synapses and inducing tau phosphorylation (Lacor et al., 2007; Lambert et al., 2007; De Felice et al., 2008).”

“Clinical pathological studies have demonstrated that, unlike diffuse plaques, neuritic plaques as well as the amount and distribution of NFT correlate with cognitive decline in AD (Arriagada et al., 1992; Nagy et al., 1995; Gomez-Isla et al., 1996; Giannakopoulos et al., 2003).”

“In humans Ab deposits tend to be localized in cortical arteries, arterioles, and capillaries, which show stronger reactivity for Ab40 (Pantelakis, 1954; Vinters, 1987; Attems et al., 2005).”

“To further examine Ab subtype pathology, we stained neocortical and hippocampal sections adjacent to those previously shown to contain extensive APP/Ab-ir plaques and vasculature, with antibodies that detect both Ab40 and Ab42/43 (MOAB-2) or individually for Ab40, Ab42, and oligomeric Ab (NU4) (Lacor et al., 2004; Lam…”

“Interestingly, the fossil record (Stephan, 1983) and comparative data suggests that the primate brain selectively expanded particularly during hominid evolution (Hill et al., 2010; Sherwood et al., 2012).”

“The western lowland gorilla represents one of the closest living relatives of humans, demonstrated by the recent sequencing of the gorilla genome (Scally et al., 2012), having shared a common ancestor with humans 9–20 million years ago (Langergraber et al., 2012).”

“The western lowland gorilla represents one of the closest living relatives of humans, demonstrated by the recent sequencing of the gorilla genome (Scally et al., 2012), having shared a common ancestor with humans 9–20 million years ago (Langergraber et al., 2012).”

“…al., 1997) and recognizing an early stage conformational tau epitope that marks neurons undergoing early degenerative events associated with NFT formation (Wolozin et al., 1986) (1:500 dilution, gift from Dr. Peter Davies, Albert Einstein School of Medicine, NY); MC1, a mouse IgG that recognizes…”

“The major constituent of NFTs is the intracellular aberrantly misfolded and abnormally hyperphosphorylated protein tau, a microtubule-stabilizing protein (Binder et al., 2005).”

“In the current study, we also showed Ab oligomers in plaques, which are considered the most toxic Ab forms affecting synapses and inducing tau phosphorylation (Lacor et al., 2007; Lambert et al., 2007; De Felice et al., 2008).”

“…western blot 6E10 (Covance), 4G8 (Covance), MOAB-2 (Youmans et al., 2012), Ab40 (Millipore), Ab42 (Invitrogen), AT8 (Goedert et al., 1995a), Alz50 (Carmel et al., 1996; Jicha et al., 1997), and MC1 (Jicha et al., 1999), ChAT (Mufson et al., 1989), SMI-34 (Vickers et al., 1994), and GFAP (Gaillard…”

“The topographic distribution of Ab blood vessels in the neocortex and hippocampal formation in the oldest female gorilla is reminiscent of the hierarchical stage 3 of CAA in humans (Olichney et al., 1997; Thal et al., 2008a,b).”

“…selective alterations in the neuronal cytoskeleton (Di Patre, 1991), the neuropil (Semendeferi et al., 2011; Spocter et al., 2012), microstructure and connections (Krubitzer, 2007; Sherwood et al., 2011, 2008), as well as epigenetic (Zeng et al., 2012) or microRNA dysregulation during evolution.”

“…(1:100, Invitrogen, Grand Island, NY); NU4, an antibody raised against Abderived diffusible ligands that preferentially binds Ab oligomers over monomers (Lambert et al., 2007) (1:2,000, gift from Dr. William Klein, Northwestern University, Evanston, IL); Alz50, a mouse IgM raised against amino…”

“Moreover, the neocortical and hippocampal distribution patterns of Ab and tau pathology in the gorilla were different, suggesting that these lesions develop independently of each other, and amyloid deposition is not a necessary precondition for the formation of NFTs in the aged primate (Schultz et al., 2000) or that t…”

“Clinical pathological studies have demonstrated that, unlike diffuse plaques, neuritic plaques as well as the amount and distribution of NFT correlate with cognitive decline in AD (Arriagada et al., 1992; Nagy et al., 1995; Gomez-Isla et al., 1996; Giannakopoulos et al., 2003).”

“Ab42 has a high propensity to aggregate into insoluble fibrils and is more toxic than Ab40 (Younkin, 1998; Selkoe, 2001).”

“…beta protein (Ab) deposits (or senile plaques), Ab angiopathy, and neurofibrillary tangles (NFT) consisting of hyperphosphorylated tau aggregates are common pathological features in the brains of healthy aged humans and in Alzheimer’s disease (AD) (Braak and Braak, 1991; Bouras et al., 1994).”

“X-34 is a highly fluorescent derivative of Congo Red, which detects the full spectrum of amyloid pathology including neurofibrillary tangles and Ab plaques, with greater sensitivity than thioflavine S (Styren et al., 2000; Ikonomovic et al., 2006).”

“The maximum lifespan of wild western lowland gorillas ranges from 35 to 40 years (Bronikowski et al., 2011), whereas captive individuals have exceeded 50 years.”

“…selective alterations in the neuronal cytoskeleton (Di Patre, 1991), the neuropil (Semendeferi et al., 2011; Spocter et al., 2012), microstructure and connections (Krubitzer, 2007; Sherwood et al., 2011, 2008), as well as epigenetic (Zeng et al., 2012) or microRNA dysregulation during evolution.”

“Recently, the human neocortex was shown to exhibit two lateralized frontoparietal cortical networks, which displayed evolutionary expansion, that are not found topologically nor functionally in corresponding macaque monkey cortex (Mantini et al., 2013).”

“After finishing the standard protocol for single ChAT and Alz50 immunolabeling using nickel intensification (Perez et al., 2004, 2012a), sections were washed with TBS and incubated with APP/Ab (6E10) antibody for 24 hours in a medium containing TBS 0.25% Triton X-100 and 1% goat normal serum.”

“…primates have suggested that diffuse plaques (Bons et al., 2006), which have also been described in the brains of cognitively intact elderly people (Mufson et al., 1999; Price et al., 2009) represent an early stage in the AD plaque development, whereas compact/neuritic plaques are associated with…”

“…et al., 1991; Mufson et al., 1994; Poduri et al., 1994; Gearing et al., 1996), long-tailed macaques (Kimura et al., 2003), Caribbean vervets (Lemere et al., 2004), squirrel monkeys (Walker et al., 1987), and cotton-top tamarins (Lemere et al., 2008) display mainly Ab neuritic plaques and Ab…”

“…on the surrounding neuropil, including an increase in neurite curvature, dystrophic neurites and recruitment of astrocytes, compared to diffuse plaques, which do not trigger these changes in the neuropil (Masliah et al., 1990; Knowles et al., 1999; Lombardo et al., 2003; Vehmas et al., 2003).”

“It is possible that this neuroplasticity arose from selective alterations in the neuronal cytoskeleton (Di Patre, 1991), the neuropil (Semendeferi et al., 2011; Spocter et al., 2012), microstructure and connections (Krubitzer, 2007; Sherwood et al., 2011, 2008), as well as epigenetic (Zeng et al.,…”

“In humans Ab deposits tend to be localized in cortical arteries, arterioles, and capillaries, which show stronger reactivity for Ab40 (Pantelakis, 1954; Vinters, 1987; Attems et al., 2005).”

“Previous studies have shown that OD measurements reflect changes in protein expression, which parallel those obtained using a biochemical protein assay (Mufson et al., 1997).”

“Despite the similarity of tau protein sequence in nonhuman primates and humans (Haase et al., 2004), the interspecies differences in tau histopathology could be a reflection of diverse genetic factors as well as physiological and environmental conditions during primate evolution.”

“The inset shows high-power image of MOAB-2-positive plaques from the boxed area in panel E.”

“…selective alterations in the neuronal cytoskeleton (Di Patre, 1991), the neuropil (Semendeferi et al., 2011; Spocter et al., 2012), microstructure and connections (Krubitzer, 2007; Sherwood et al., 2011, 2008), as well as epigenetic (Zeng et al., 2012) or microRNA dysregulation during evolution.”

“In humans, Ab deposition in cerebral blood vessels is frequent in patients with vascular cognitive impairment, AD, and Down syndrome (Rensink et al., 2003; Attems et al., 2005), suggesting a strong association between paren- chymal and vascular Ab deposition across all hominids, perhaps a…”

“However, previous studies in great apes (Gearing et al., 1997) with the exception of a report in a old chimpanzee which suffered a stroke (Rosen et al., 2008), failed to AD pathology in the Gorilla brain The Journal of Comparative Neurology | Research in Systems Neuroscience 4333 reveal…”

“…on the surrounding neuropil, including an increase in neurite curvature, dystrophic neurites and recruitment of astrocytes, compared to diffuse plaques, which do not trigger these changes in the neuropil (Masliah et al., 1990; Knowles et al., 1999; Lombardo et al., 2003; Vehmas et al., 2003).”

“Both Ab40 and Ab42 were found in neocortical and hippocampal plaques as reported in other primates (Walker et al., 1987; Martin et al., 1991; Mufson et al., 1994; Poduri et al., 1994; Gearing et al., 1996, 1997; Kimura et al., 2001; Geula et al., 2002; Lemere et al., 2004, 2008; Bons et al., 2006;…”

“By comparison to amyloid profiles, there are relatively few reports of NFT pathology in nonhuman primates (Cork et al., 1988; Hartig et al., 2000; Schultz et al., 2000) and particularly in great apes (present study; Rosen et al., 2008).”

“…al., 1991; Mufson et al., 1994; Poduri et al., 1994; Gearing et al., 1996, 1997; Kimura et al., 2001; Geula et al., 2002; Lemere et al., 2004, 2008; Bons et al., 2006; Merrill et al., 2011) and nonprimate mammals (Roertgen et al., 1996; Tekirian et al., 1996; Brellou et al., 2005), as opposed to…”

“DOI 10.1002/cne.23428 Published online July 24, 2013 in Wiley Online Library (wileyonlinelibrary.com)VC 2013 Wiley Periodicals, Inc. 4318 The Journal of Comparative Neurology | Research in Systems Neuroscience 521:4318–4338 (2013) (Attems et al., 2004).”

“Interestingly, the fossil record (Stephan, 1983) and comparative data suggests that the primate brain selectively expanded particularly during hominid evolution (Hill et al., 2010; Sherwood et al., 2012).”

“Staining with SMI-34 revealed a virtual absence of dystrophic neurites and only occasional SMI-34-ir neurons in the neocortex and hippocampus in the oldest female gorilla.”

“However, previous studies in great apes (Gearing et al., 1997) with the exception of a report in a old chimpanzee which suffered a stroke (Rosen et al., 2008), failed to AD pathology in the Gorilla brain The Journal of Comparative Neurology | Research in Systems Neuroscience 4333 reveal…”

“In contrast, the brains of several New and Old World monkeys, such as marmosets (Geula et al., 2002), rhesus monkeys (Martin et al., 1991; Mufson et al., 1994; Poduri et al., 1994; Gearing et al., 1996), long-tailed macaques (Kimura et al., 2003), Caribbean vervets (Lemere et al., 2004), squirrel…”

“In humans Ab deposits tend to be localized in cortical arteries, arterioles, and capillaries, which show stronger reactivity for Ab40 (Pantelakis, 1954; Vinters, 1987; Attems et al., 2005).”

“…selective alterations in the neuronal cytoskeleton (Di Patre, 1991), the neuropil (Semendeferi et al., 2011; Spocter et al., 2012), microstructure and connections (Krubitzer, 2007; Sherwood et al., 2011, 2008), as well as epigenetic (Zeng et al., 2012) or microRNA dysregulation during evolution.”

“…are not exclusive to humans and have been described in several other mammalian species (Brellou et al., 2005; Roertgen et al., 1996; Tekirian et al., 1996), including a large number of nonhuman primate species (Walker et al., 1987, 1990; Martin et al., 1991; Mufson et al., 1994; Poduri et al.,”

“Conversely, neuritic plaques with swollen neurites, which were not observed in gorillas, have been described in other nonhuman primates (Walker et al., 1987; Poduri et al., 1994; Gearing et al., 1996; Kimura et al., 2003; Lemere et al., 2004, 2008) as well as in human AD (Serrano-Pozo et al., 2011).”

“Interestingly, the fossil record (Stephan, 1983) and comparative data suggests that the primate brain selectively expanded particularly during hominid evolution (Hill et al., 2010; Sherwood et al., 2012).”

“…that this neuroplasticity arose from selective alterations in the neuronal cytoskeleton (Di Patre, 1991), the neuropil (Semendeferi et al., 2011; Spocter et al., 2012), microstructure and connections (Krubitzer, 2007; Sherwood et al., 2011, 2008), as well as epigenetic (Zeng et al., 2012) or…”

“Recent gene array studies have shown a shift from 3-repeat to 4-repeat tau in NFTladen human cholinergic basal forebrain neurons in prodromal AD (Ginsberg et al., 2006).”

“The relevance of evolutionary pressure on the development of AD lesions is an area that has received relatively little attention (Rapoport, 1990, 1999; Benzing et al., 1993).”

“…in the gorilla were different, suggesting that these lesions develop independently of each other, and amyloid deposition is not a necessary precondition for the formation of NFTs in the aged primate (Schultz et al., 2000) or that there are species differences between human and ape amyloid.”

“Plaques in the brains of gorillas were weakly reactive for thioflavine S, 6-CN-PiB (Rosen et al., 2011), b-pleated sheet-specific markers found in neuritic AD plaques.”

“Both Ab40 and Ab42 were found in neocortical and hippocampal plaques as reported in other primates (Walker et al., 1987; Martin et al., 1991; Mufson et al., 1994; Poduri et al., 1994; Gearing et al., 1996, 1997; Kimura et al., 2001; Geula et al., 2002; Lemere et al., 2004, 2008; Bons et al., 2006;…”

“…(Geula et al., 2002), rhesus monkeys (Martin et al., 1991; Mufson et al., 1994; Poduri et al., 1994; Gearing et al., 1996), long-tailed macaques (Kimura et al., 2003), Caribbean vervets (Lemere et al., 2004), squirrel monkeys (Walker et al., 1987), and cotton-top tamarins (Lemere et al., 2008)…”

“…have also been described in nondiseased or injured nonhuman primate brain (Hartig et al., 2000; Kiatipattanasakul et al., 2000; Schultz et al., 2000; Bons et al., 2006) as well as in nonprimate species (Cork et al., 1988; Braak and Braak, 1991; Nelson et al., 1994; Roertgen et al., 1996).”

“This dual staining resulted in an easily identifiable two-colored profile: dark blue/black for Alz50 and ChAT profiles and brown or red for APP/Ab-positive plaques/blood vessels (Perez et al., 2011, 2012a).”

“By comparison to amyloid profiles, there are relatively few reports of NFT pathology in nonhuman primates (Cork et al., 1988; Hartig et al., 2000; Schultz et al., 2000) and particularly in great apes (present study; Rosen et al., 2008).”

“…plaques and blood vessels are not exclusive to humans and have been described in several other mammalian species (Brellou et al., 2005; Roertgen et al., 1996; Tekirian et al., 1996), including a large number of nonhuman primate species (Walker et al., 1987, 1990; Martin et al., 1991;…”

“For example, nonhuman primates are homozygous at seven positions for the H2 compared to the H1 haplotype that characterize human tau suggesting that H1, which is the more prevalent of the two haplotypes is human specific and may play a role in developing NFT pathology in AD (Holzer et al., 2004).”

“The relevance of evolutionary pressure on the development of AD lesions is an area that has received relatively little attention (Rapoport, 1990, 1999; Benzing et al., 1993).”

“APP/Ab-ir plaques and blood vessels were surrounded by GFAP-positive astrocytes, but qualitatively capillaries appeared to display stronger GFAP immunoreactivity compared to plaques (Fig.”

“The topographic distribution of Ab blood vessels in the neocortex and hippocampal formation in the oldest female gorilla is reminiscent of the hierarchical stage 3 of CAA in humans (Olichney et al., 1997; Thal et al., 2008a,b).”

“After finishing the standard protocol for single ChAT and Alz50 immunolabeling using nickel intensification (Perez et al., 2004, 2012a), sections were washed with TBS and incubated with APP/Ab (6E10) antibody for 24 hours in a medium containing TBS 0.25% Triton X-100 and 1% goat normal serum.”

“Slide-mounted tissue sections were also processed for X-34 (0.04 g/l) as previously reported (Ikonomovic et al., 2006).”

“Both Ab40 and Ab42 were found in neocortical and hippocampal plaques as reported in other primates (Walker et al., 1987; Martin et al., 1991; Mufson et al., 1994; Poduri et al., 1994; Gearing et al., 1996, 1997; Kimura et al., 2001; Geula et al., 2002; Lemere et al., 2004, 2008; Bons et al., 2006;…”

“The histomorphology of Ab-positive vessels in gorilla are similar to CAA described in squirrel monkeys, indicating a speciesspecific predilection for CAA rather than parenchymal plaques (Elfenbein et al., 2007).”

“…macaques (Kimura et al., 2003), Caribbean vervets (Lemere et al., 2004), squirrel monkeys (Walker et al., 1987), and cotton-top tamarins (Lemere et al., 2008) display mainly Ab neuritic plaques and Ab vascular deposits similar to those seen in humans, indicative of similar mechanisms…”

“…1998a), which are often seen in other tauopathies without amyloid pathology (e.g., corticobasal degeneration, progressive supranuclear palsy, and amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam (Ikeda et al., 1998b; Li et al., 1996; Mizutani et al., 1998; Oyanagi et al., 2001).”

“While numerous studies exploring the presence of AD-like pathology have been carried out in aged New and Old World monkeys, only a few studies have been performed in apes (Gearing et al., 1996, 1997; Kimura et al., 2001; Rosen et al., 2008).”

“…plaques than Ab vessels, whereas aged female gorillas showed much more cortical and hippocampal parenchymal plaque deposition, suggesting sex differences in Ab production similar to that described in transgenic mouse models of AD, which overexpress Ab (HirataFukae et al., 2008; Overk et al., 2012).”

“Sections were outlined at 13 magnification, and distribution/counts of plaques and Alz50-ir profiles in the cortex and hippocampus was performed manually at 103 magnification and fiduciary landmarks were used to prevent repeat counting of labeled profiles (Perez et al., 2012b).”

“It has been speculated that more recently evolved cortical systems are more plastic and are particularly responsive to environmental and to internal factors (Rapoport and Nelson, 2011).”

“D; 50 lm insets in A,C. AD pathology in the Gorilla brain The Journal of Comparative Neurology | Research in Systems Neuroscience 4331 accumulation resembling dyshoric angiopathy as described in capillaries in CAA and AD (Clifford et al., 2008; Thal et al., 2008b).”

“The relevance of evolutionary pressure on the development of AD lesions is an area that has received relatively little attention (Rapoport, 1990, 1999; Benzing et al., 1993).”

“Mainly Ab40 and/ or Ab42 diffuse plaques have been described in the brain of aged nonprimate mammals including camels (Nakamura et al., 1995), polar bears (Tekirian et al., 1996), wolverines (Roertgen et al., 1996), dogs (Tekirian et al., 1996), and cats (Brellou et al., 2005).”

“Mainly Ab40 and/ or Ab42 diffuse plaques have been described in the brain of aged nonprimate mammals including camels (Nakamura et al., 1995), polar bears (Tekirian et al., 1996), wolverines (Roertgen et al., 1996), dogs (Tekirian et al., 1996), and cats (Brellou et al., 2005).”

“Moreover, tau aggregates have also been described in nondiseased or injured nonhuman primate brain (Hartig et al., 2000; Kiatipattanasakul et al., 2000; Schultz et al., 2000; Bons et al., 2006) as well as in nonprimate species (Cork et al., 1988; Braak and Braak, 1991; Nelson et al., 1994; Roertgen…”

“After finishing the standard protocol for single ChAT and Alz50 immunolabeling using nickel intensification (Perez et al., 2004, 2012a), sections were washed with TBS and incubated with APP/Ab (6E10) antibody for 24 hours in a medium containing TBS 0.25% Triton X-100 and 1% goat normal serum.”

“Hippocampal CA1 projection neurons, which display NFT pathology, demonstrate an increase in the expression of modulators of cytoskeletal reorganization early in disease progression suggestive of regenerative events (Kao et al., 2010).”

“Although Ab toxicity may influence NFT-like pathology in the aged rhesus monkey cortex (Geula et al., 1998), diffuse and cored amyloid plaques are found in most aged mammalian brains without concomitant NFT pathology (Braak and Braak, 1991; Cork, 1993).”

“It is noteworthy that the maximum lifespan of gorillas in the wild ranges from 35 to 40 years (Bronikowski et al., 2011), whereas in captivity it can reach upwards of 50 years (Atsalis and Margulis, 2008).”

“…al., 1994; Poduri et al., 1994; Gearing et al., 1996, 1997; Kimura et al., 2001; Geula et al., 2002; Lemere et al., 2004, 2008; Bons et al., 2006; Merrill et al., 2011) and nonprimate mammals (Roertgen et al., 1996; Tekirian et al., 1996; Brellou et al., 2005), as opposed to the human condition…”

“It is possible that this neuroplasticity arose from selective alterations in the neuronal cytoskeleton (Di Patre, 1991), the neuropil (Semendeferi et al., 2011; Spocter et al., 2012), microstructure and connections (Krubitzer, 2007; Sherwood et al., 2011, 2008), as well as epigenetic (Zeng et al.,…”

“Great apes accumulate Aβ in the brain, resulting in the development of amyloid plaques and CAA in aged animals [43, 44, 78, 112, 113, 124].”

“Importantly, our results suggest that these functional interactions in a subset of ExNs and astrocytes seem to be phylogenetically specific to OldWorldmonkeys and apes (parvorder Catarrhini), species that show more marked signs of pathology related to aging, such as AD, than other species (Perez et al., 2013; Finch an…”

“As one of the hallmarks of AD, the NFTs eventually occupy the whole of the cytoplasm in certain classes of cell in the neocortex, hippocampus , brain stem, and diencephalon (Alafuzoff et al. 2008; Perez et al. 2013).”

“NHPs show close genetic homology to humans [484, 485, 487].”

“Tau protein, in addition to amyloid plaques, has been detected with immunohistochemistry and immunofluorescence in the brains of older lowland gorillas from zoos.(193) The study examined frontal cortex and/or hippocampus from female gorillas 32, 35, 50, and 55 yo and males 13, 22, 42, 43, and 49 yo, using a panel of m…”

“…amyloid (Gearing et al., 1997, 1996, 52 1994; Geula et al., 2002; Heuer et al., 2012; Kimura et al., 2003; Lemere et al., 2008, 2004; Martin et al., 53 1991; E J Mufson et al., 1994; Oikawa et al., 2010; Perez et al., 2016, 2013; Poduri et al., 1994; Rosen et 54 al., 2008; Walker et al., 1987).”

“, [50, 51]), whereas transgenic mice expressing human FAD mutated APP (often in combination with mutated human PS1) typically develop Aβ deposits and plaques without substantial neuronal degenerationor neurofibrillary pathology such as paired helical filaments and highly modified tau.”

“2008) and several western lowland gorillas (Perez et al. 2013).”

“…hoc analysis Tukey (∗p < 0.05; ∗∗p < 0.01; ∗∗∗p < 0.001). in the cortex (Cork et al., 1990; Gearing et al., 1996, 1997; Giannakopoulos et al., 1997; Kimura et al., 2003; Bons et al., 2006; Lemere et al., 2008; Oikawa et al., 2010; Perez et al., 2013; Sridharan et al., 2013; Darusman et al., 2014).”

“Very old apes, monkeys, and some other mammals like bears, dogs and cats may have diffuse Aβ deposits and minor CAA, but not full AD pathology or neurodegeneration [26, 55, 97, 112] Thus, tg mice and rats have become invaluable to study Aβ aggregation in vivo.”

“Perez et al. (2013) reported, on brains from the Great Ape Aging Project, which provides zoo specimens that died “of natural causes,” again in the Journal of Comparative Neurology.”

“Humans, on the other hand, have experienced a very rapid increase in longevity much more recently from an evolutionary point of view, and neuroprotective mechanisms may not have evolved accordingly [34,97,102,103].”

“X-34 and 6-CN-PiB histofluorescence was used to assess amyloid burden in the FC and striatum [105].”

“At the present time there are only two reports of the existence of neurofibrillary tangles in great apes including one in a 41 year old chimpanzee (Rosen et al., 2008), and more recently in a sample of lowland gorillas (Perez et al., 2013).”

“Generally, the distribution of tau pathology is not correlated to amyloid deposits, with the exception of gorillas and chimpanzees, where tau is observed in proximity to Aβ plaques (Edler et al., 2017; Perez et al., 2013, 2016).”

“A-3), was used to label mouse and human unaggregated, oligomeric and fibrillar forms of Aβ42 and unaggregated forms of Aβ40, but not APP from either species (Youmans et al., 2012a,b; Perez et al., 2013; Katsouri et al., 2014; Zhao et al., 2014a,b), was used.”

“Previous studies have found abundant tau lesions in the glia of aged primate brains [6, 14, 15].”

“Finally, these findings may provide insight into the evolution of vulnerability to neurodegenerative disorders (Dong et al. 2009; Gardoni et al. 2009; Perez et al. 2013), which are unique in humans, as some of these diseases target”

“…the presence of senile plaques and tau pathology (Edler et al., 2017; Gearing, Rebeck, Hyman, Tigges, & Mirra, 1994; Gearing, Tigges, Mori, & Mirra, 1996; Gearing, Tigges, Mori, & Mirra, 1997; Kimura et al., 2001; Perez et al., 2013; Rosen et al., 2008; Selkoe, Bell, Podlisny, Price, & Cork, 1987).”

“This has presented a challenge in phylogenetically synthesizing the evolution of p-tau tangles— as chimpanzees, baboons, gorillas, and cynomolgus monkeys have all shown evidence of cortical tauopathy (Schultz et al., 2000; Oikawa et al., 2010; Perez et al., 2013; Edler et al., 2020), along with some smaller simians su…”

“Yet, until recently, evidence of the spontaneous co-occurrence of both Aβ and tau patho- logical markers of AD had not been found in species other than humans with the exception of a single aged chimpanzee and aged gorillas (Perez et al., 2013, 2013; Rosen et al., 2008).”

“clusters are seen in the neocortex and hippocampus of the oldest gorillas [45].”

“…tau filaments formation in neurons, oligodendrocytes and astrocytes (Darusman et al., 2014; Härtig et al., 2000; Oikawa, Kimura, & Yanagisawa, 2010; Perez et al., 2013; Rodriguez-Callejas et al., 2016; Schultz, Dehghani, et al., 2000; Schultz, Hubbard, Rüb, Braak, & Braak, 2000).”

“on age-related changes in the great ape brain (Gearing et al. 1994, 1997; Rosen et al. 2008; Perez et al. 2013; Edler et al. 2017), the results reported here are somewhat novel.”

“While AD appears to be a human-specific disease, agedependent SP formation has been reported in several non-human primates, including chimpanzees [10], orangutans [11], and gorillas [12].”

“…astrocytes and activated microglia have been reported adjacent to Aβ and tau lesions in marmosets, macaques, gorillas, and chimpanzees (Edler et al., 2018; Härtig et al., 1997; Martin et al., 1994; Munger et al., 2019; Perez et al., 2013; Rodriguez- Callejas et al., 2016; Schultz et al., 2000).”

“, 2016) and some great apes like the western lowland gorilla (Kimura et al., 2001; Perez et al., 2013).”

“…Demeter et al., 1990; Morrison and Hof, 1997; Suzuki and Amaral, 2004; Braak and Del Trecidi, 2015), and aged macaques and great apes exhibit early signs of Alzheimer’s disease-like amyloid and Tau pathology (Perez et al., 2013; Finch and Austad, 2015; Edler et al., 2017; Paspalas et al., 2018).”

“the fields of interest (ENT-O, ENT-I, CA1, CA2/3, Sub-C and Sub-F) displaying strong AT8 immunostaining in an average of 14 sections per case as previously described [42,65].”

“Non-human primates have the limitations of long lifespan, high price, immature cognitive behavioral paradigm, rare tauopathy and ethical concerns for research studies (Drummond and Wisniewski, 2017; Heuer et al., 2012; Perez et al., 2013).”

“As evidenced by [125], amyloid plaques and cerebral amyloid angiopathy were found in aged great apes [126–128].”

“Studies confirm amyloid plaque formation in aged monkeys and great apes [175–177].”

“Age-related accumulations of tau were reported in some nonhuman primate brains (Oikawa et al., 2010; Perez et al., 2013), yet systematic analysis of the cellular localization of tau accumulation across aging is not well studied.”

“Such species include the gorilla (Gorilla gorilla gorilla [71] and Gorilla beringei beringei [72]), Ursidae species [16, 88, 95], cetacean species [88], and pinniped species [92].”

“…only primates and cetaceans naturally develop histologic changes that include amyloid-β plaques, hyperphosphorylated tau proteins, and neurofibrillary tangles, and as such, it is hypothesized that these changes are a result of longevity and post-reproductive lifespan, not just aging [40,46].”

“NFT formation in nonhuman primates is limited to a few reports in a chimpanzee [19], cynomolgus monkeys [27 ] and rhesus monkeys [ 14], as well as hyperphosphorylated tau deposition [ 6, 15].”

“Chimpanzees and other great apes at advanced ages have modest accumulations of brain Aβ aggregates that would not qualify as the senile plaques of AD [3, 4].”

“This is true for both captive (Gorilla gorilla gorilla) and wild (Gorilla beringei beringei) gorillas (Perez et al., 2013; Perez et al., 2016).”

“…on the paucity of advanced fibrillar pathology in brains of very old subjects (Carlyle et al., 2014; Cramer et al., 2018; Edler et al., 2017; Hartig et al., 2000; Oikawa et al., 2010; Paspalas et al., 2017; Perez et al., 2013; Rosen et al., 2008; Schultz, Hubbard, Rub, Braak, & Braak, 2000).”

“Scientists studied the brains of zoo gorillas (Gorilla gorilla) to help understand the origins of and pathology associated with Alzheimer’s disease [30].”

“Additionally, spontaneous APP /A-immunoreactive (ir) plaques were discovered in the neocortex and hippocampus areas of 55-year-old female gorillas (Perez et al. 2013).”

“…densities (/mm 3 ) in hippocampus (HC; CA1 and CA3) versus pretangle density (/mm 3 ) in HC. et al. 2018; Ferretti et al. 2018; Zhu, Montagne, and Zhao 2021), and minor sex differences in A β burden have been described in the brains of nonhuman primates (Edler et al. 2017; Perez et al. 2013).”