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The aged rhesus macaque manifests Braak stage III/IV Alzheimer's-like pathology.

ABSTRACT: INTRODUCTION:An animal model of late-onset Alzheimer's disease is needed to research what causes degeneration in the absence of dominant genetic insults and why the association cortex is particularly vulnerable to degeneration. METHODS:We studied the progression of tau and amyloid cortical pathology in the aging rhesus macaque using immunoelectron microscopy and biochemical assays. RESULTS:Aging macaques exhibited the same qualitative pattern and sequence of tau and amyloid cortical pathology as humans, reaching Braak stage III/IV. Pathology began in the young-adult entorhinal cortex with protein kinase A-phosphorylation of tau, progressing to fibrillation with paired helical filaments and mature tangles in oldest animals. Tau pathology in the dorsolateral prefrontal cortex paralleled but lagged behind the entorhinal cortex, not afflicting the primary visual cortex. DISCUSSION:The aging rhesus macaque provides the long-sought animal model for exploring the etiology of late-onset Alzheimer's disease and for testing preventive strategies.

SUBMITTER: Paspalas CD

PROVIDER: S-EPMC6178089 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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The aged rhesus macaque manifests Braak stage III/IV Alzheimer's-like pathology.

Paspalas Constantinos D CD Carlyle Becky C BC Leslie Shannon S Preuss Todd M TM Crimins Johanna L JL Huttner Anita J AJ van Dyck Christopher H CH Rosene Douglas L DL Nairn Angus C AC Arnsten Amy F T AFT

Alzheimer's & dementia : the journal of the Alzheimer's Association 20171211 5

<h4>Introduction</h4>An animal model of late-onset Alzheimer's disease is needed to research what causes degeneration in the absence of dominant genetic insults and why the association cortex is particularly vulnerable to degeneration.<h4>Methods</h4>We studied the progression of tau and amyloid cortical pathology in the aging rhesus macaque using immunoelectron microscopy and biochemical assays.<h4>Results</h4>Aging macaques exhibited the same qualitative pattern and sequence of tau and amyloid ...[more]

PMID: 29241829

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Project description:See Herholz (doi:10.1093/brain/awx340) for a scientific commentary on this article.Autopsy data have proposed that a topographical pattern of tauopathy occurs in the brain with the development of dementia due to Alzheimer's disease. We evaluated the findings of tau-PET to better understand neurofibrillary tangle development as it is seen in cognitively unimpaired and impaired individuals. The evolution of Alzheimer's disease tauopathy in cognitively unimpaired individuals needs to be examined to better understand disease pathogenesis. Tau-PET was performed in 86 cognitively impaired individuals who all had abnormal amyloid levels and 601 cognitively unimpaired individuals. Tau-PET findings were assessed for relationships with clinical diagnosis, age, and regional uptake patterns relative to Braak stage. Regional and voxel-wise analyses were performed. Topographical findings from tau-PET were characterized using hierarchical clustering and clinical characteristic-based subcategorization. In older cognitively unimpaired individuals (≥50 years), widespread, age-related elevated tau signal was seen among those with normal or abnormal amyloid status as compared to younger cognitively unimpaired individuals (30-49 years). More frequent regional tau signal elevation throughout the brain was seen in cognitively unimpaired individuals with abnormal versus normal amyloid. Elevated tau signal was seen in regions that are considered high Braak Stage in cognitively unimpaired and cognitively impaired individuals. Hierarchical clustering and clinical characteristic-based categorizations both showed different patterns of tau signal between groups such as greater tau signal in frontal regions in younger onset Alzheimer's disease dementia participants (most of whom had a dysexecutive clinical presentation). Tau-PET signal increases modestly with age throughout the brain in cognitively unimpaired individuals and elevated tau is seen more often when amyloid brain accumulation is present. Tau signal patterns in cognitively unimpaired correspond to early Braak stage but also suggest tangle involvement in extra-medial temporal and extra-temporal regions that are considered more advanced in the Braak scheme even when amyloid negative. Our findings also suggest the possibility of widespread development of early tangle pathology rather than a pattern defined exclusively by adjacent, region-to-region spread, prior to onset of clinical symptoms. Distinct patterns of neurofibrillary tangle deposition in younger-onset Alzheimer's disease dementia versus older-onset Alzheimer's disease dementia provide evidence for variability in regional tangle deposition patterns and demonstrate that different disease phenotypes have different patterns of tauopathy. Pathological correlation with imaging is needed to assess the implications of these observations.

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Dataset Information

The aged rhesus macaque manifests Braak stage III/IV Alzheimer's-like pathology.

Publications

The aged rhesus macaque manifests Braak stage III/IV Alzheimer's-like pathology.

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