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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:Genome-wide association studies have described several genes as genetic susceptibility loci for Alzheimer's disease (AD). Among them, CD2AP encodes CD2-associated protein, a scaffold protein implicated in dynamic actin remodeling and membrane trafficking during endocytosis and cytokinesis. Although a clear link between CD2AP defects and glomerular pathology has been described, little is known about the function of CD2AP in the brain. The aim of this study was to analyze the distribution of CD2AP in the AD brain and its potential associations with tau aggregation and β-amyloid (Aβ) deposition. First, we performed immunohistochemical analysis of CD2AP expression in brain tissue from AD patients and controls (N = 60). Our results showed granular CD2AP immunoreactivity in the human brain endothelium in all samples. In AD cases, no CD2AP was found to be associated with Aβ deposits in vessels or parenchymal plaques. CD2AP neuronal inclusions similar to neurofibrillary tangles (NFT) and neuropil thread-like deposits were found only in AD samples. Moreover, immunofluorescence analysis revealed that CD2AP colocalized with pTau. Regarding CD2AP neuronal distribution, a hierarchical progression from the entorhinal to the temporal and occipital cortex was detected. We found that CD2AP immunodetection in neurons was strongly and positively associated with Braak neurofibrillary stage, independent of age and other pathological hallmarks. To further investigate the association between pTau and CD2AP, we included samples from cases of primary tauopathies (corticobasal degeneration [CBD], progressive supranuclear palsy [PSP], and Pick's disease [PiD]) in our study. Among these cases, CD2AP positivity was only found in PiD samples as neurofibrillary tangle-like and Pick body-like deposits, whereas no neuronal CD2AP deposits were detected in PSP or CBD samples, which suggested an association of CD2AP neuronal expression with 3R-Tau-diseases. In conclusion, our findings open a new road to investigate the complex cellular mechanism underlying the tangle conformation and tau pathology in the brain.

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.

Project description:BackgroundUntil recently, few genomic reagents specific for non-human primate research have been available. To address this need, we have constructed a macaque-specific high-density oligonucleotide microarray by using highly fragmented low-pass sequence contigs from the rhesus genome project together with the detailed sequence and exon structure of the human genome. Using this method, we designed oligonucleotide probes to over 17,000 distinct rhesus/human gene orthologs and increased by four-fold the number of available genes relative to our first-generation expressed sequence tag (EST)-derived array.ResultsWe constructed a database containing 248,000 exon sequences from 23,000 human RefSeq genes and compared each human exon with its best matching sequence in the January 2005 version of the rhesus genome project list of 486,000 DNA contigs. Best matching rhesus exon sequences for each of the 23,000 human genes were then concatenated in the proper order and orientation to produce a rhesus "virtual transcriptome." Microarray probes were designed, one per gene, to the region closest to the 3' untranslated region (UTR) of each rhesus virtual transcript. Each probe was compared to a composite rhesus/human transcript database to test for cross-hybridization potential yielding a final probe set representing 18,296 rhesus/human gene orthologs, including transcript variants, and over 17,000 distinct genes. We hybridized mRNA from rhesus brain and spleen to both the EST- and genome-derived microarrays. Besides four-fold greater gene coverage, the genome-derived array also showed greater mean signal intensities for genes present on both arrays. Genome-derived probes showed 99.4% identity when compared to 4,767 rhesus GenBank sequence tag site (STS) sequences indicating that early stage low-pass versions of complex genomes are of sufficient quality to yield valuable functional genomic information when combined with finished genome information from a closely related species.ConclusionThe number of different genes represented on microarrays for unfinished genomes can be greatly increased by matching known gene transcript annotations from a closely related species with sequence data from the unfinished genome. Signal intensity on both EST- and genome-derived arrays was highly correlated with probe distance from the 3' UTR, information often missing from ESTs yet present in early-stage genome projects.

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

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

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