Proteinopathy-induced neuronal senescence a hypothesis for brain failure in Alzheimers and other neurodegenerative diseases 英文参考文献.docVIP

Available online /content/1/2/5 Review Proteinopathy-induced neuronal senescence: a hypothesis for brain failure in Alzheimer’s and other neurodegenerative diseases Todd E Golde and Victor M Miller 1Department of Neuroscience, Mayo Clinic, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, Florida 32224, USA Corresponding author: Todd E Golde, tgolde@ Published: 13 October 2009 Alzheimer’s Research Therapy 2009, 1:5 (doi:10.1186/alzrt5) This article is online at /content/1/2/5 ? 2009 BioMed Central Ltd Genetic, pathological, biochemical, animal and cell modeling studies provide strong support for the general hypothesis that accumulation of misfolded, aggregated proteins in the brain triggers a complex series of events that result in neuronal degeneration [1-4]. In Alzheimer’s disease (AD) aggregation Abstract Background: Alzheimer’s disease (AD) and a host of other neurodegenerative central nervous system (CNS) proteinopathies are characterized by the accumulation of misfolded protein aggre- gates. Simplistically, these aggregates can be divided into smaller, soluble, oligomeric and larger, less-soluble or insoluble, and accumulation of the amyloid β (Aβ) protein and microtubule associated protein tau (MAPT) have both been implicated as key pathogenic ‘triggers’ [5]. Aβ accumulates in senile plaques, cerebral vessels, and, to a more limited extent, within neurons [6]. Tau accumulates inside cells as neuro- fibrillary tangles and tau neurites [7]. In genetic forms of AD the data overwhelmingly support the ‘Aβ aggregate/amyloid cascade’ hypothesis, which posits that Aβ aggregation and accumulation precedes, and therefore drives, tau accumu- lation [3]. In ‘sporadic’ cases it is also possible that the two pathologies may arise, at least in part, through independent pathways [8]. Like familial AD, mutations in a