Distribution, progression and chemical composition of cortical amyloid-β deposits in aged rhesus monkeys: similarities to the human

Sani, Sepehr; Traul, David; Klink, Annelies; Niaraki, Nayson; Gonzalo-Ruiz, A.; Wu, Chuang Kuo; Geula, Changiz

doi:10.1007/s00401-002-0626-5

Cited by 71 publications

(46 citation statements)

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“…Concomitant age-dependent accumulation of Aβ and neuronal tau deposits in the brains of primates [4, 6] has led to the proposal that AD-like pathology may occur during normal aging in primates. However, it has been unclear whether these deposits are really representative of AD pathogenesis or not.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, primates may provide a better model for this disease [2] based on their long life spans, the similarity of their brains to human brains, and the occurrence of age-associated deposits of amyloid beta (Aβ) and tau in their brains. Initially, only Aβ deposits were identified in these primate brains [3, 4]. However, subsequent improvements in rearing prolonged primate life span such that tau-positive lesions could also be observed [5, 6].…”

Section: Introductionmentioning

confidence: 99%

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Tau pathology in aged cynomolgus monkeys is progressive supranuclear palsy/corticobasal degeneration- but not Alzheimer disease-like -Ultrastructural mapping of tau by EDX-

Uchihara

Endo

Kondo

et al. 2016

acta neuropathol commun

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Concomitant deposition of amyloid -beta protein (Aβ) and neuronal tau as neurofibrillary tangles in the human brain is a hallmark of Alzheimer disease (AD). Because these deposits increase during normal aging, it has been proposed that aging brains may also undergo AD-like changes. To investigate the neuropathological changes that occur in the aging primate brain, we examined 21 brains of cynomolgus monkeys (7–36 years old) for Aβ- and tau-positive lesions. We found, 1) extensive deposition of Aβ in brains of cynomolgus monkeys over 25 years of age, 2) selective deposition of 4-repeat tau as pretangles in neurons, and as coiled body-like structures in oligodendroglia-like cells and astrocytes, 3) preferential distribution of tau in the basal ganglia and neocortex rather than the hippocampus, and 4) age-associated increases in 30–34 kDa AT8- and RD4-positive tau fragments in sarkosyl-insoluble fractions. We further labeled tau-positive structures using diaminobezidine enhanced with nickel, and visualized nickel-labeled structures by energy-dispersive X-ray (EDX) analysis of ultrathin sections. This allowed us to distinguish between nickel-labeled tau and background electron-dense structures, and we found that tau localized to 20–25 nm straight filaments in oligodendroglia-like cells and neurons. Our results indicate that the cytopathology and distribution of tau deposits in aged cynomolgus brains resemble those of progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) rather than AD. Thus, even in the presence of Aβ, age-associated deposition of tau in non-human primates likely does not occur through AD-associated mechanisms.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0385-5) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Tau pathology in aged cynomolgus monkeys is progressive supranuclear palsy/corticobasal degeneration- but not Alzheimer disease-like -Ultrastructural mapping of tau by EDX-

Uchihara

Endo

Kondo

et al. 2016

acta neuropathol commun

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“…The plaques were present in the same lobes where CAA was found. In the rhesus monkey, the deposits of Aβ were observed principally in the cortical, paralimbic, and core limbic cortical zones corresponding to mild, moderate, and heavy burden, respectively (Sani et al, 2003). Along with Nishimura et al (2012), this study of rhesus monkeys also emphasizes the higher proportion of Aβ 40 compared with the Aβ 42 .…”

Section: Discussionmentioning

confidence: 99%

“…Low levels of circulating Aβ 42 and elevated total tau (t-tau) and phosphorylated tau (p-tau), are related with the development of SP and NFT, respectively (Brody et al, 2008; Blennow et al, 2010; Jack et al, 2010; Albert et al, 2011). In rhesus monkeys, the incidence, distribution, and chemical composition of the Aβ deposits in the brain of young and aged individuals have been described (Sani et al, 2003; Nishimura et al, 2012) with higher level of Aβ 1–40 (Aβ 40 ) than the Aβ 42 .…”

Section: Introductionmentioning

confidence: 99%

Amyloid Beta1â€“42 and the Phoshorylated Tau Threonine 231 in Brains of Aged Cynomolgus Monkeys (Macaca fascicularis)

Darusman

Gjedde

Sajuthi

et al. 2014

Front. Aging Neurosci.

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Pathological hallmarks indicative of Alzheimer’s disease (AD), which are the plaques of amyloid beta1–42 and neurofibrillary tangles, were found in brain of aged cynomolgus monkey. The aim of this study was to investigate if aged monkeys exhibiting spatial memory impairment and levels of biomarkers indicative of AD, had brain lesions similar to human patients suffering from senile dementia. Generating immunohistochemistry technique to biomarkers of amyloid beta1–42 and the phosphorylated tau 231, our study assessed the amyloidopathy, such as indicative to the senile plaques and cerebral amyloid angiopathy, and the tauopathy, to possible neurofibrillary tangles. Six aged monkeys were selected based on their spatial memory performance and profile of biomarkers of AD, divided equally to affected aged subject – with Memory-affected and low amyloid level, and aged with higher performance in memory and amyloid, as the age-matched subjects. Using immunohistochemistry, plaques of amyloid beta1–42 were observed in two out of three brains of aged subjects with memory impairment and biomarkers indicative of AD. The cerebral amyloid angiopathy was observed in both aged monkey groups, and unlike in the human, the amyloids were found to deposit in the small veins and capillaries. In one of the affected individuals, phosphorylated tau was positively stained intracellularly of the neurons, indicating a possibility of an early stage of the formation of tangles. These findings add to the body of evidence of the utility of the aged cynomolgus monkeys as a spontaneous model for Alzheimer-related disease.

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“…It is well known that the most common animal model species for AD (mouse) does not develop any similar conditions, requiring the use of transgenics or drug–induced defects. Monkeys, on the other hand, have shown the spontaneous presence of β–amyloid plaque [32]. and many genes known to be involved in human neurological disorders have been shown to be present and regulated in cynomolgus monkeys [33].…”

Section: Introductionmentioning

confidence: 99%

Lifespan Profiles of Alzheimer's Disease-Associated Genes and Products in Monkeys and Mice

Dosunmu

Adwan

et al. 2009

JAD

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Alzheimer's disease (AD) is characterized by plaques of amyloid–beta (Aβ) peptide, cleaved from amyloid–β precursor protein (AβPP). Our hypothesis is that lifespan profiles of AD-associated mRNA and protein levels in monkeys would differ from mice, and that differential lifespan expression profiles would be useful to understand human AD pathogenesis. We compared profiles of AβPP mRNA, AβPP protein, and Aβ levels in rodents and primates. We also tracked a transcriptional regulator of the AβPP gene, specificity protein 1 (SP1), and the β amyloid precursor cleaving enzyme (BACE1). In mice, AβPP and Sp1 mRNA and their protein products were elevated late in life; Aβ levels declined in old age. In monkeys, Sp1, AβPP, and BACE1 mRNA declined in old age, while protein products and Aβ levels rose. Proteolytic processing in both species did not match production of Aβ. In primates, AβPP and Sp1 mRNA levels coordinate, but an inverse relationship exists with corresponding protein products, as well as Aβ levels. Comparison of human DNA and mRNA sequences to monkey and mouse counterparts revealed structural features that may explain differences in transcriptional and translational processing. These findings are important for selecting appropriate models for AD and other age–related diseases.

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Distribution, progression and chemical composition of cortical amyloid-β deposits in aged rhesus monkeys: similarities to the human

Cited by 71 publications

References 43 publications

Tau pathology in aged cynomolgus monkeys is progressive supranuclear palsy/corticobasal degeneration- but not Alzheimer disease-like -Ultrastructural mapping of tau by EDX-

Tau pathology in aged cynomolgus monkeys is progressive supranuclear palsy/corticobasal degeneration- but not Alzheimer disease-like -Ultrastructural mapping of tau by EDX-

Amyloid Beta1â€“42 and the Phoshorylated Tau Threonine 231 in Brains of Aged Cynomolgus Monkeys (Macaca fascicularis)

Lifespan Profiles of Alzheimer's Disease-Associated Genes and Products in Monkeys and Mice

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