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APOE ?2 is associated with increased tau pathology in primary tauopathy.

ABSTRACT: Apolipoprotein E (APOE) ?4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease mainly by modulating amyloid-? pathology. APOE ?4 is also shown to exacerbate neurodegeneration and neuroinflammation in a tau transgenic mouse model. To further evaluate the association of APOE genotype with the presence and severity of tau pathology, we express human tau via an adeno-associated virus gene delivery approach in human APOE targeted replacement mice. We find increased hyperphosphorylated tau species, tau aggregates, and behavioral abnormalities in mice expressing APOE ?2/?2. We also show that in humans, the APOE ?2 allele is associated with increased tau pathology in the brains of progressive supranuclear palsy (PSP) cases. Finally, we identify an association between the APOE ?2/?2 genotype and risk of tauopathies using two series of pathologically-confirmed cases of PSP and corticobasal degeneration. Our data together suggest APOE ?2 status may influence the risk and progression of tauopathy.

SUBMITTER: Zhao N

PROVIDER: S-EPMC6197187 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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APOE ε2 is associated with increased tau pathology in primary tauopathy.

Zhao Na N Liu Chia-Chen CC Van Ingelgom Alexandra J AJ Linares Cynthia C Kurti Aishe A Knight Joshua A JA Heckman Michael G MG Diehl Nancy N NN Shinohara Mitsuru M Martens Yuka A YA Attrebi Olivia N ON Petrucelli Leonard L Fryer John D JD Wszolek Zbigniew K ZK Graff-Radford Neill R NR Caselli Richard J RJ Sanchez-Contreras Monica Y MY Rademakers Rosa R Murray Melissa E ME Koga Shunsuke S Dickson Dennis W DW Ross Owen A OA Bu Guojun G

Nature communications 20181022 1

Apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease mainly by modulating amyloid-β pathology. APOE ε4 is also shown to exacerbate neurodegeneration and neuroinflammation in a tau transgenic mouse model. To further evaluate the association of APOE genotype with the presence and severity of tau pathology, we express human tau via an adeno-associated virus gene delivery approach in human APOE targeted replacement mice. We find increased hyperpho ...[more]

PMID: 30348994

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Project description:Alzheimer's disease (AD), the most common tauopathy, is an age-dependent, progressive neurodegenerative disease. Epidemiological studies implicate the role of genetic background in the onset and progression of AD. Despite mutations in familial AD, several risk factors have been implicated in sporadic AD, of which the onset is unknown. In AD, there is a sequential and hierarchical spread of tau pathology to other brain areas. Studies have strived to understand the factors that influence this characteristic spread. Using transgenic rat models with different genetic backgrounds, we reported that the genetic background may influence the manifestation of neurofibrillary pathology. In this study we investigated whether genetic background has an influence in the spread of tau pathology, using hippocampal inoculations of insoluble tau from AD brains in rodent models of tauopathy with either a spontaneously hypertensive (SHR72) or Wistar-Kyoto (WKY72) genetic background. We observed that insoluble tau from human AD induced AT8-positive neurofibrillary structures in the hippocampus of both lines. However, there was no significant difference in the amount of neurofibrillary structures, but the extent of spread was prominent in the W72 line. On the other hand, we observed significantly higher levels of AT8-positive structures in the parietal and frontal cortical areas in W72 when compared to SHR72. Interestingly, we also observed that the microglia in these brain areas in W72 were predominantly phagocytic in morphology (62.4% in parietal and 47.3% in frontal), while in SHR72 the microglia were either reactive or ramified (67.2% in parietal and 84.7% in frontal). The microglia in the hippocampus and occipital cortex in both lines were reactive or ramified structures. Factors such as gender or age are not responsible for the differences observed in these animals. Put together, our results, for the first time, show that the immune response modulating genetic variability is one of the factors that influences the propagation of tau neurofibrillary pathology.

Dataset Information

APOE ?2 is associated with increased tau pathology in primary tauopathy.

Publications

APOE ε2 is associated with increased tau pathology in primary tauopathy.

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