Brain aging and Alzheimer’s disease, a perspective from non-human primates

β-amyloid and tau pathology in Cercopithecidae subfamily Cercopithecinae

Cynomolgus monkey (Macaca fascicularis) (Figure 1)

Figure 1. Aged cynomolgus monkey. Cerebral amyloid angiopathy involves blood vessels of the meninge (A), frontal cortex (FC), parietal cortex (Par C), and amygdala (Amyg) with additional β-amyloid (Aβ) deposition in the perivascular spaces. In contrast with the extensive cerebral amyloid angiopathy, a few neurons containing hyper-phosphorylated tau (antibody AT8) are scattered in the frontal and parietal cortex, and hippocampus. Paraffin sections slightly counterstained with haematoxylin. Upper two rows, bar = 180 μm; lower row, bar = 25 μm.

First studies in aged cynomolgus monkeys showed the presence of abundant β-amyloid plaques in the cerebral cortex [111–114].

Diffuse plaques, primitive plaques, and classical plaques were stained with anti-Aβ42(43) antibodies; diffuse plaques and only about one-third of classical plaques were not stained with anti-Aβ40. CAA in arterioles reacted with anti-Aβ42(43) and anti-Aβ40 antibodies; cortical capillaries were decorated with anti-Aβ42(43) but rarely with anti-Aβ40. APP, ubiquitin, and microtubule-associated protein-2, but not tau, accumulated in the swollen neurites of mature plaques [112, 113].

A more extensive study was performed by the same group using the brains of 64 cynomolgus monkeys [114]. Diffuse and mature plaques were located in the temporal cortex and amygdala in 16 out of 25 monkeys 20 years old or older. CAA was found in 10 out of 16 animals older than 22 years. Plaques and CAA were stained with anti-Aβ40 antibodies, whereas antibodies raised against Aβ8-17 did not detect diffuse plaques and only one-third of diffuse plaques [114].

Additional biochemical and morphological studies were analyzed in thirty cynomolgus monkey brains. Nine brains were from young monkeys (age 4-8 years), 16 were from adult monkeys (age 11-22 years), and five were from aged monkeys (age 30-36 years) [115]. SPs were detected in ten individuals aged 19 years or older; NFTs were not detected. SPs were stained with the antibodies 4G8 and ApoE, whereas the antibody β-APP₆₉₅ stained swollen neurites of SPs; neurites of SPs were not detected with the AT8 antibody. Western blot analyses showed that full-length APP695 protein was mainly expressed in the brains of young monkeys, whereas APP751 protein was increased in the brains of older monkeys [115].

Going further in the study of the same series plus four aged monkeys, Western blotting studies showed an accumulation of insoluble Aβ in the temporal and frontal cortex and hippocampal regions in animals aged 20 years, and their levels increased with age. Soluble Aβ was detected only in animals over the age of 30. Western blotting showed increased levels of soluble tau and phosphorylated tau in the hippocampus of aged monkeys. Insoluble tau in the hippocampus of the animals aged 6, 17, 19, 25, and 32 years was not detected [116]. AT8-immunoreactive, Gallyas positive NFTs in neurons, glial cells, and clustered neurites were found in the medial temporal cortex adjacent to the amygdala in one monkey. Another aged monkey showed a positive neuron [116].

In an attempt to correlate clinical symptoms and neuropathological changes, six cynomolgus monkeys aged from 27 to 30 years (three with low levels of Aβ42 in the CSF and poor delayed reported tasks (DRT) performance and three age-matched controls) and two young aged 7 and 9 years, were assessed in another study. CAA was observed in small brain vessels of the aged monkeys; SPs were only found in two monkeys with poor DRT performance. Only one aged monkey with poor DRT performance showed P-tau Thr231 immunoreactivity in the cytoplasm of neurons of the temporal and occipital lobe [117].

Another study reported the presence of cortical diffuse plaques in cynomolgus monkeys aged 18 and 19 years [118].

A different neuropathological disorder was observed in two separate reports.

In the first one, an albino male cynomolgus monkey aged more than 35 years showed gait disturbances, trembling, decreased activity, and drowsing tendency. The neuropathological examination revealed marked neuronal loss in the substantia nigra, globus pallidus, putamen, thalamic nuclei, pyramidal cell layer of the hippocampus, and Purkinje layer of the cerebellum. Gallyas-Braak positive, phospho-tau-immunoreactive glial fibrillary tangles and NFTs were dominant features. Glial fibrillary tangles, including coiled bodies and thorn-shaped astrocytes, together with argyrophilic threads, were located in the putamen, caudate nucleus, thalamic nuclei, substantia nigra, red nucleus, globus pallidus, trapezoid body, pyramid, pons, and medulla oblongata; neurofibrillary tangles in the thalamus. Ubiquitin-positive eosinophilic grumose or foamy spheroid bodies were observed in the substantia nigra and globus pallidus. Numerous SPs, visualized with PAM and Aβ40, ubiquitin, and APP immunohistochemistry, were seen in the cerebral cortex, putamen, caudate nucleus, and hippocampus. Some swollen neurites at the periphery of the plaques in the hippocampus were immunoreactive for neurofilament 200 but negative for phospho-tau. CAA was near plaques [119].

The other report analyzed twenty-one brains from cynomolgus monkeys aged 7-36, [120]. Aβ plaques were frequent in the brains of eight cynomolgus monkeys over 25. Phospho-tau-containing neurons, astrocytes, oligodendrocytes (coiled bodies), and neuropil threads predominated in the basal ganglia and neocortex rather than the hippocampus in five animals aged 30 years or more. Phospho-tau inclusions consisted of 4Rtau. Western blot studies of sarkosyl-insoluble fractions showed increased density of a band stained with AT8 and 4Rtau antibodies and decreased 3Rtau in monkeys with tauopathy. Finally, tau localized in 20-25 nm straight filaments in oligodendroglia-like cells and neurons, as revealed with electron microscopy [120].

The last two descriptions best refer to a different tauopathy in cynomolgus monkeys close to progressive supranuclear palsy (PSP) in humans, added to age-related Aβ deposition [119, 120].

Rhesus monkey (Macaca mulatta)

Several studies have shown the presence of β-amyloid plaques and CAA in aged rhesus macaques [121–128]. Plaques are stained with anti-Aβ antibodies and some of them with anti-apoE [122, 123, 126, 129]; a smaller proportion contain heparin sulfate proteoglycans and alpha1-anti-chymotrypsin [126]. Interestingly, there is an increase in the Aβ40:Aβ42 ratio in plaques of rhesus macaques compared with humans [126]; Aβ40:Aβ42, 1.4 [122] or 2.8 [124] in rhesus monkeys, and 0.33 [11] or 0.88 [124] in humans. Animals before age 20 have no plaques; the number of plaques increases with age but with marked individual variations [125, 128, 130, 131]. CAA is only found in the oldest monkeys [130].

Most studies note the presence of a few neuritic processes stained with anti-neurofilament antibodies but the lack of tau-containing dystrophic neurites in macaque SPs [123]. However, in a series of eleven aged (25 to 31 years old, three males and eight females) rhesus monkeys, most plaques were diffuse, and a minority were compact and thioflavin S positive. Compact plaques showed a few dystrophic neurites stained with anti-PHF-1 antibodies and were accompanied by microglia [131]. Aβ deposits in aged rhesus monkey brains include 3-mer, 5-mer, 9-mer, 10-mer, and 12-mer oligomers, but not Aβ dimers. It is suggested that Aβ deposits devoid of Aβ dimers induce glial pathology but not tau pathology, neurodegeneration, and synapsis loss [132].

SPs first appear in the neocortex; lower densities are found in the amygdala and insula and cingulate, limbic temporal, and temporal, occipital, and parietal association cortices; the lowest densities are in the hippocampus; the primary motor and sensory areas are not affected [121, 126]. In another study, the highest density of SPs was found in the prefrontal cortex, followed by the amygdala and surrounding temporal gyri; plaques were less frequent in the hippocampus [127, 128].

In an extensive study of 81 brains from animals ranging from 16 to 39 years old, Aβ plaques were found in 38, 10 of which were associated with CAA [128]. Twelve aged monkeys had an involvement of amyloidosis in the liver, the adrenal, or the pancreatic islets, but no positivity to the β-amyloid was demonstrated in the brain [127, 128]. Previous studies in a cohort of 186 rhesus monkeys aged 20 to 36 showed an incidence of cerebral β-amyloidosis associated with plaque formation and CAA in 51 brains of rhesus monkeys aged 25 to 36 years [127].

Plaque density was measured in fourteen rhesus monkeys aged 5-30 years and compared with the cognitive status of every monkey [125]. Cognitive dysfunction and plaque density increased with age. However, plaque density did not correlate with cognitive impairment since some cognitively impaired animals had few amyloid plaques, and others with abundant plaques showed discrete cognitive impairment [125].

Cytoplasmic Aβ immunoreactivity without concomitant β-amyloid plaques has been reported in basal forebrain cholinergic neurons in aged rhesus monkeys [133].

No NFTs were detected in an extensive series of macaques [128]. However, early electron microscopic studies revealed dystrophic neurites and PHFs in the prefrontal cortex of old macaques [134]. Moreover, abnormally phosphorylated tau, as detected with AT100, PHF-1, and TG-3 antibodies, was reported in the hippocampus and entorhinal cortex in a 28-year-old rhesus monkey [135].

The brain of a rhesus monkey aged 43 with symptoms of cognitive impairment showed widespread amyloid and tau pathology. Amyloid plaques were seen in the neocortex and less abundant in the hippocampus. Mild CAA was also seen in the same regions. Amyloid deposits were composed of Aβ40, Aβ42, Aβ43, AβN1, and 4 AβpN3. The entorhinal cortex, hippocampus, and inferior temporal gyrus neurons contained phosphorylated tau. In the cerebral cortex, phospho-tau was localized in scattered neurites. Only a tiny percentage of tau-containing neurons were stained with Gallyas [136].

A comprehensive study of β-amyloid and tau pathology was performed in a series of eleven rhesus macaques (aged 4.5-31 years) using the antibodies P-tauSer214, AT8 (P-tauSer202 + P-TauThr205), P-tauThr181, P-Thr231, anti-Aβ1-42, and anti-APP) [137]. Macaque brains were obtained after transcardial fixation and zero post-mortem interval, thus preserving weak phosphorylation sites that are usually rapidly dephosphorylated with post-mortem delay. P-tauSer214 was found in layer II of the entorhinal cortex in young-adult macaques (7-9 years); P-tau aggregated along microtubules in dendrites, transporting endosomes, trafficking between neurons at plasma membranes and the synapses. AT8 neuronal immunoreactivity appeared later in macaques aged 24-26 years and increased in density and distribution following Braak stages from stage I in younger macaques to stage IV in animals aged 33-34. Immunoelectron microscopy revealed the presence of P-tau-immunoreactivity in the cytoplasm of neurons and AT8-immunoreactive straight and paired 10-nm filaments and typical 80-nm PHFs. P-tauSer214 immunoreactivity appeared in the dorsolateral prefrontal cortex in macaques aged 31-34 years in glutamatergic-like synapses and over the spine apparatus. Autophagic vacuoles in the soma and proximal dendrites, accumulation of late-phase lysosomes, and dystrophic neurites were also observed in layer II cortical neurons of the entorhinal cortex [137].

Aβ42-immunoreactive plaques, mainly localized in layer V, and CAA were also observed in aged macaques. Dense plaques had a core composed of 10-nm straight fibrils. Intracellular Aβ was found in endosomes localized next to mitochondria and on the plasma membrane in dendrites and axons [137].

Additional biochemical studies further demonstrated early tau phosphorylation in vulnerable cortices, probably modulated by calcium levels and mediated by specific kinases. Age-related calbindin and phosphodiesterase PDE4D reductions in pyramidal cell dendrites of the dorsolateral prefrontal cortex support this hypothesis [138].

Stump-tailed macaque (Macaca arctoides)

A unique series of monkeys showed altered behavior and impaired delayed matching and nonmatching-to-sample responses in individuals aged 25-34. The post-mortem examination demonstrated the presence of numerous polymorphous Aβ plaques in the prefrontal cortex, hippocampus, and parahippocampal regions and scarce neuronal granular deposits. All these deposits were stained with anti-Aβ42 and Aβ40 antibodies, with Aβ40 immunoreactivity as the predominant form. Although hyper-phosphorylated tau accumulated in neurons, a detailed description of tau pathology was lacking [139].

Lion-tailed macaque (Macaca silenius)

One study included Lion-tailed macaques and rhesus monkeys (n = 11) ranging from 4 to 41 years. The study did not make the distinction between the two species. APP immunoreactivity was seen in neuronal perikarya, proximal dendrites, and the axon’s initial segment in layers III and V of the neocortex. APP immunoreactivity increased with age. In older animals, senile plaques were distributed in the cerebral cortex; plaques contained Aβ, and many of them were also stained with anti-APP, anti-neurofilament, and anti-synaptophysin antibodies; enlarged axons and bulbous or knob-shaped swellings were found in mature plaques [140].

Japanese macaque (Macaca fuscata)

The distribution of β-amyloid was examined in the amygdala of aged (from 23 to 30 years old) Japanese macaques. The distribution of Aβ in the different subnuclei is similar to that seen in aged humans and parallels with zinc distribution [141]. No similar studies are available in other macaques.

African green monkey, vervet (Chlorocebus aethiops sabaeus)

Eleven African green monkeys aged 6-32 years were analyzed in one study [142]. Amyloid plaques appeared in aged animals, and their density increased with age, with predominance in the frontal cortex and entorhinal cortex and less correlation in the hippocampus and visual cortex. Biochemically, Aβ42 levels significantly correlated with age, whereas Aβ40 levels showed a trend toward a correlation with age. Tau pathology was revealed with antibody AT8 and Gallyas staining in two animals older than 20. NFTs localized in the entorhinal cortex and the stratum radiatum layers of CA1-4 of the hippocampus, thus suggesting neuronal origin, albeit tau in glial cells was also considered.

Another study analyzed nine middle-aged (8.2-13.5 years) and nine aged (19.5–23.4 years) female vervet African green monkeys [143]. Amyloid plaques (detected with the 6E10 antibody) were found in aged monkeys. Aβ plaques were localized in the anterior middle temporal gyrus, anterior cingulate gyrus, insular cortex, supramarginal cortex, superior frontal cortex, precentral and postcentral gyri, and occipital cortex; Aβ plaques in the superior parietal lobule and anterior superior temporal gyrus were found less frequently. Most plaques were diffuse, but neuritic plaques were also identified with the Bielchowsky silver stain. Guanidine-extracted Aβ42 or Aβ40 levels in the temporal and parietal cortex were significantly greater in aged vervets than in middle-aged animals. AT8 immunoreactivity was observed in all animals, but tau immunoreactivity was rarely reminiscent of pre-tangles and never as classical NFTs [143].

The deposition of phosphorylated (P-Ser8Aβ) and non-phosphorylated (npAβ) variants of Aβ was assessed in the brains of 15 Caribbean vervets ranging from 7.4 to 32 years of age. Eight out of nine monkeys older than 15 years had abundant deposits of P-Ser8Aβ and npAβ peptides. Diffuse and dense-core plaques were found in the frontal cortex, temporal cortex, and hippocampal region. In addition, P-Ser8Aβ was also observed in meningeal and parenchymal blood vessels [144].

Baboon (Papio)

One study examined the brains of four aged baboons (Papio hamadryas). The estimated ages and genders of the animals were 20 years (female), 24 years (female), 26 years (male), and 30 years (male) [145]. Numerous Gallyas positive and tau-immunoreactive, as revealed with the antibodies AT8, AT100, AT20, PHF-1, and TG-3, neuronal and glial inclusions were found in the two older animals. Neuronal deposits occurred in the cytoplasm, dendrites, and plexiform layers of the hippocampus proper. The dentate gyrus was also affected in the two older animals, principally in the male aged 30. Dense neuropil changes, immunopositive for phospho-tau, were seen in the plexiform layer of the hilus and the inner third of the molecular layer; NFTs were also seen in the granule cell layer. In addition, tau-containing astrocytes reminiscent of thorn-shaped astrocytes were seen in the periventricular, subpial, and perivascular regions of limbic brain areas such as the hippocampal formation, and the peri-amygdaloid cortex. Coiled bodies were abundant in the limbic fiber tracts. Electron microscopical examination demonstrated tau-positive straight filaments (10-14 nm) in neurons and glial cells. Diffuse plaques and CAA, as revealed with the 4G8 antibody, were found in the two aged baboons and restricted to the temporal lobe, sparing the hippocampal formation and parahippocampal gyrus [145].

The same authors also analyzed the brains of 50 baboons (Papio anubis) ranging in age from 1 to 30 years [146]. Animals were categorized into four age groups: Group I: 1-10 years (n = 9), group II: 11-20 years (n = 13), group III: 21-25 years (n = 17), group IV: 26-30 years (n = 11). Phospho-tau pathology involved the hippocampus proper, dentate gyrus, and entorhinal cortex in most affected individuals of group IV. Mild to moderate tau pathology in the hippocampus and dentate gyrus occurred in some groups II, III, and IV specimens, respectively. As in the previous study, tau pathology was not restricted to neurons and neuronal fibers; thorn-shaped astrocytes and coiled bodies were equally seen in the same regions as in aged Papio hamadryas. Mild or moderate Aβ deposits were seen in basal frontal and temporal isocortical areas in some individuals of groups II, III, and IV without correlation with tau pathology [146].

Another study focused on the characteristics of β-amyloidopathy in baboons [147]. Formalin-fixed brain tissue from six baboons (P. hamadryas, P. cynocephalus, and P. anubis; n = 2 each) aged from 18 to 28 years. Neocortical plaques were mainly localized in layers 3-5 and usually involved blood vessels; plaques in the hippocampus were localized in the pyramidal cell layer. Diffuse plaques were primarily composed of Aβ42 over Aβ40; in addition, cotton-wool-like plaques, immunoreactive to 4G8 and NU1 antibodies, were observed in the cerebral cortex; numerous plaques contained Aβ oligomers. Punctate Aβ immunoreactivity was also observed in the cytoplasm of neurons near plaques. CAA was also present; compared to plaques, equal Aβ42 and Aβ40 immunoreactivity occurred in blood vessels [147]. Tau pathology in these animals was scanty, following the previous report of two P. hamadryas also analyzed in the present series [135].

Acknowledgments

I am grateful to Dr. A. Rábano, Fundación CIEN, Madrid, and Dr. M. Pumarola, Faculty of Veterinary, Bellaterra, Barcelona, Spain, for allowing the neuropathological study of several non-human primate species.

Conflicts of Interest

The author declares no conflict of interest.

Funding

No funding was provided for this study.

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