Year: 2010
Type: article
Abstract: Accumulation of amyloid-β (Aβ) and tau is an invariant feature of Alzheimer disease (AD). The upstream role of Aβ accumulation in disease pathogenesis is widely accepted, and there is strong evidence showing that Aβ accumulation causes cognitive impairments. However, the molecular mechanisms linking Aβ to tau and cognitive decline remain to be elucidated. Using a mouse model of AD, we employ multidisciplinary approaches to dissect the molecular mechanisms linking Aβ, tau and mTOR signaling. Here we show that the buildup of Aβ increases the mammalian target of rapamycin (mTOR) signaling, while decreasing mTOR signaling reduces Aβ levels, thereby highlighting an interrelation between mTOR signaling and Aβ. The mTOR pathway plays a central role in controlling protein homeostasis and hence neuronal functions; indeed mTOR signaling regulates different forms of learning and memory and tau expression levels. Using an animal model of AD, we show that pharmacologically restoring mTOR signaling with rapamycin rescues cognitive deficits and ameliorates Aβ and tau pathology by increasing autophagy. Indeed, we further show that autophagy induction is necessary for the rapamycin-mediated reduction in Aβ levels. The results presented here provide a molecular basis for the Aβ-induced cognitive deficits and suggest that alterations in mTOR signaling may bridge Aβ and tau accumulation. Finally, we show that rapamycin, an FDA approved drug, improves learning and memory and reduces Aβ and tau pathology.
Source: Alzheimer s & Dementia
Author: Salvatore Oddo
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2096775546