Aβ and Tau Prions Causing Alzheimer’s Disease

神经病理学 疾病 长寿 阿尔茨海默病 生物 转基因小鼠 痴呆 病理 转基因 医学 遗传学 基因
作者
Carlo Condello,Gregory E. Merz,Atsushi Aoyagi,William F. DeGrado,Stanley B. Prusiner
出处
期刊:Methods in molecular biology [Springer Science+Business Media]
卷期号:: 293-337 被引量:15
标识
DOI:10.1007/978-1-0716-2655-9_16
摘要

Studies show that patients with Alzheimer’s disease (AD) have both Aβ and tau prions, and thus, AD is a double-prion disease. AD patients with the greatest longevity exhibited low levels of both Aβ and tau prions; tau prions were nearly absent in the brains of almost half of the patients who lived beyond 80 years of age. Using cellular bioassays for prions in postmortem samples, we found that both Aβ and tau proteins misfold into prions leading to AD, which is either a sporadic or familial dementing disorder. Although AD is transmissible experimentally, there is no evidence that AD is either communicable or contagious. Since the progression of AD correlates poorly with insoluble Aβ in the central nervous system (CNS), it was difficult to distinguish between inert amyloids and Aβ prions. To measure the progression of AD, we devised rapid bioassays to measure the abundance of isoform-specific Aβ prions in the brains of transgenic (Tg) mice and in postmortem human CNS samples from AD victims and people who died of other neurodegenerative diseases (NDs). We found significant correlations between the longevity of individuals with AD, sex, and genetic background, despite the fact that all postmortem brain tissue had essentially the same confirmed neuropathology. Although brains from all AD patients had measurable levels of Aβ prionsPrions at death, the oldest individuals had lower Aβ prionPrions levels than the younger ones. Additionally, the long-lived individuals had low tau prionPrions levels that correlated with the extent of phosphorylated tau (p-tau). Unexpectedly, a longevity-dependent decrease in tau prionsPrions was found in spite of increasing amounts of total insoluble tau. When corrected for the abundance of insoluble tau, the tau prionPrions levels decreased exponentially with respect to the age at death with a half-time of approximately one decade, and this correlated with the abundance of phosphorylated tau. Even though our findings with tau prionsPrions were not unexpected, they were counterintuitive; thus, tau phosphorylation and tau prionPrions activity decreased exponentially with longevity in patients with AD ranging from ages 37 to 99 years. Our findings demonstrated an inverse correlation between longevity in AD patients and the abundance of neurotoxic tau prionsPrions. Moreover, our discovery may have profound implications for the selection of phenotypically distinct patient populations and the development of diagnosticsDiagnostics and effective therapeutics for AD.
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