NOVEL AB FRAGMENTS AS MEDIATORS OF ALZHEIMERS DISEASE

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The deposition of amyloid beta (Abeta) peptides in senile plaques is a seminal event in the pathogenesis of Azheimer's disease (AD) and Abeta is generated from beta-amyloid precursor protein (APP) by the sequential cleavage by a recently identified beta-secretase known as BACE1 (beta-site APP cleavage enzyme 1) and the presenilin (PS) containing gamma-secretase complex. Surprisingly, BACE1 was shown to cleavage APP at both Asp 1 and Glu 11 of Abeta generating both full length Abeta1-40/42 as well as the N-terminally truncated Abeta11-40/42 peptides. However, despite the fact that Abeta11-40/42 peptides have been detected at high levels in brains of AD and Down's syndrome patients, that certain familial AD associated PS1 and APP mutations increase the deposition of the N-terminal truncated Abeta peptides and that these peptides aggregate more readily than full length Abeta peptides, the mechanism regulating the production and aggregation of Abeta11-40/42 and its role in AD pathogenesis remains unknown. In this competitive renewal application, Project 2 will test the hypothesis that Abeta11-40/42 may play a major role in increasing Abeta fibril formation, Abeta aggregation and Abeta toxicity. To accomplish our goals, we will assess and compare the distribution of Abeta11-40/42 with Abeta1-40/42 in brains of patients with mild cognitive impairment (MCI), with AD, with Down's syndrome and in control patients with no cognitive impairments (NCI). We will also compare the structure and the fibrillization properties of Abeta11-40/42 with the Abeta1-40/42 peptides. Transgenic animal models will be developed to assess the role of Abeta11-40/42 peptides in senile plaque formation, in cognitive function and in neurodegeneration. Finally we will evaluate the specific role of Abeta1-40/42 and Abeta11-40/42 oligomers in learning and memory in transgenic mouse models of AD amyloidosis. Successful completion of the proposed studies will help define the roles of Abeta11-40/42 peptides in the pathogenesis of AD.