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Inhibition of amyloid deposition in APPlPSl double Tg mice by modulation of HDL and apo A-l levels Alzheimer's disease (AD) is the major form of dementia in industrialized nations. If more effective therapies are not developed that either prevent AD or block progression of the disease in its early stages, the economic and societal cost of cari~gfo r AD patients will be devastating. AD is a disorder associated with progressive and irreversible memory loss and cognitive dysfunction. It is characterized by the presence of senile plaques in the brain composed primarily of amyloid-P peptide (AP). Though numerous studies have been conducted to investigate the role of apo E in the pathogenesis of AD, very little information is available on the effect of apo A-l on AD. Inflammation appears to be another factor enhancing AD plaque deposition. Low levels of serum HDL and apo A-I, the major protein component of HDL, correlate with increased risk for AD. Since inflammation is inversely correlated to the levels of HDL and apo A-I, the major protein component of plasma HDL, we hypothesize that agents that enhance levels of HDL and apo A-l would inhibit amyloid plaque deposition. Our laboratory has been instrumental in designing and studying the effect of an apo A-l mimetic peptide on atherosclerosis. This peptide called D-4F has only 18 amino acids, where as apo A-l has 243 a.a. residues. D-4F, though has no sequence homology to any of the known apolipoproteins, has been shown to modulate HDL and apo A-l levels. Oral administration of this peptide has been shown to inhibit atherosclerosis in various animal models. Apo A-l mimetics also synergize with statins to regress already existing atherosclerotic lesions. We have exciting preliminary results that demonstrate oral administration of an apo AI mimetic with statin improves the cognitive function in an Alzheimer's mouse model. This is accompanied by inhibition of brain amyloid deposition. In this proposal, we will test the hypothesis that the peptide administration to APP /PSI double Tg mice enhances apo A-l and HDL levels via increasing the levels of apo A-I. We propose to study the mechanism by which serum apo A-l and HDL levels increase and their correlation to the inhibition of amyloid plaque formation in the brain. To test this, we propose two specific aims: 1. Effect of oral administration of an apo A-l mimetic peptide with statin on the amyloid plaque formation. 2. The mechanism of by which these proteins may act on plasma HDL levels and its protein components especially apo A-l and apo E in APPIPSldE9 double Tg mice. Understanding the mechanism of inhibition of amyloid plaque formation by apo A-l mimetic peptide(s) would not only enhance the knowledge on changes in systemic plasma apo A-l and HDL levels but also provide a basis for future therapeutic avenues for treating this debilitating disease.