Amyloid beta's other half -- the cleavage fragment AICD -- implicated in AD pathology . . .
>>Alzheimer's disease-like pathological features in transgenic mice expressing the APP intracellular domain<<
Kaushik Ghosala,1, Daniel L. Vogta,1, Man Lianga, Yong Shenb, Bruce T. Lamba and Sanjay W. Pimplikara,2
+ Author Affiliations
aDepartment of Neurosciences, Lerner Research Institute, Cleveland Clinic, Mail Code NC30, 9500 Euclid Avenue, Cleveland, OH 44195; and
bHaldeman Laboratory of Molecular and Cellular Neurobiology, Sun Health Research Institute, 10515 West Santa Fe Drive, Sun City, AZ 85351
?1K.G. and D.L.V. contributed equally to this work.
Edited by Thomas C. Südhof, Stanford University School of Medicine, Palo Alto, CA, and approved September 11, 2009 (received for review July 20, 2009)
Abstract
The hypothesis that amyloid-ß (Aß) peptides are the primary cause of Alzheimer's disease (AD) remains the best supported theory of AD pathogenesis. Yet, many observations are inconsistent with the hypothesis. Aß peptides are generated when amyloid precursor protein (APP) is cleaved by presenilins, a process that also produces APP intracellular domain (AICD). We previously generated AICD-overexpressing transgenic mice that showed abnormal activation of GSK-3ß, a pathological feature of AD. We now report that these mice exhibit additional AD-like characteristics, including hyperphosphorylation and aggregation of tau, neurodegeneration and working memory deficits that are prevented by treatment with lithium, a GSK-3ß inhibitor. Consistent with its potential role in AD pathogenesis, we find AICD levels to be elevated in brains from AD patients. The in vivo findings that AICD can contribute to AD pathology independently of Aß have important therapeutic implications and may explain some observations that are discordant with the amyloid hypothesis.<<
Full text freebie: pnas.org
Cheers, Tuck |
