期刊
SYNAPSE
卷 72, 期 4, 页码 -出版社
WILEY
DOI: 10.1002/syn.22025
关键词
Alzheimer's disease; astrogliosis; brain aging; cerebral amyloidosis; tauopathy
资金
- Canadian Institutes of Health Research (CIHR) [FC-MOP 102532, IAO74443 IAP98997]
- Alzheimer Society Canada [FC-ASC 0516]
- Canada Foundation for Innovation [10307]
- Merck Canada
- Laval University Fonds d'Enseignement et de Recherche
- CHU de Quebec (Desjardins Fondation)
- Alzheimer Society Canada
- Fonds de la Recherche en Sante du Quebec (FRSQ)
- Clinical Research Initiative
- CIHR Institute of Aging [CAN76833]
No model fully recapitulates the neuropathology of Alzheimer's disease (AD). Although the triple-transgenic mouse model of AD (3xTg-AD) expresses A plaques and tau-laden neurofibrillary tangles, as well as synaptic and behavioral deficits, it does not display frank neuronal loss. Because old age is the most important risk factor in AD, senescence-related interactions might be lacking to truly establish an AD-like environment. To investigate this hypothesis, we bred the 3xTg-AD mouse with the senescence-accelerated mouse prone 8 (SAMP8), a model of accelerated aging. We generated four groups of heterozygous mice with either the SAMP8 or SAMR1 (senescence-resistant-1) genotype, along with either the 3xTg-AD or non-transgenic (NonTg) genotype. Despite no differences among groups in total latency to escape the Barnes maze, a greater number of errors were noticed before entering the target hole in 19-month-old P8/3xTg-AD mice at day 5, compared to other groups. Postmortem analyses revealed increased cortical levels of phospho-tau (Thr231) in female P8/3xTg-AD mice (+277% vs. R1/3xTg-AD mice), without other tau-related changes. Female P8/3xTg-AD mice exhibited higher cortical soluble A40 and A42 concentrations (A40, +85%; A42, +35% vs. R1/3xTg-AD), whereas insoluble forms remained unchanged. Higher A42 load coincided with increased astroglial activation in female P8/3xTg-AD mice, as measured with glial fibrillary acidic protein (GFAP) (+57% vs. R1/3xTg-AD mice). To probe neuronal degeneration, concentrations of neuronal nuclei (NeuN) were measured, but no differences were detected between groups. Altogether, the SAMP8 genotype had deleterious effects on spatial memory and exerted female-specific aggravation of AD neuropathology without overt neurodegeneration in 3xTg-AD mice.
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