APP/ABeta chemistry in transgenic, familial and sporadic AD

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DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a dementia that affects 4 million elderly individuals in the USA. This devastating neurodegenerative disorder strikes 4% of individuals at 65 years of age and as many as 40% of those at age 85 at a cost of about 80 billion dollars annually. Due to an impressive increase in longevity there is a projected tripling in the number of AD dementia cases by the year 2050. Therefore, there is an urgent need for effective therapeutic interventions that may prevent AD or delay the age of onset or alter the course of this dementia. The creation of transgenic (tg) mice expressing human AD genes has provided vital tools to investigate both the pathogenesis and treatment of this dementia. Our goal is to better understand the strengths and limitations of tg mice models by determining the degree of biochemical similarities existing between tg animal amyloid and that deposited in human AD patients. Amyloid produced in several tg animal constructs that express mutations in the large amyloid precursor molecule and the key proteolytic processing enzyme presenilin will be purified and chemically characterized to determine composition and structure in comparison to human sporadic and familial AD patient amyloid. Soluble and deposited amyloid remaining after anti-Abeta immunization of tg mice and human AD patients will be examined using the same chemical techniques to assess the effects of immunization on amyloid dynamics and toxicity. This study will aid in the accurate interpretation of tg mouse experimental results and will help elucidate at the molecular level the direct and indirect effects of anti-Abeta immunization. A complete understanding of the tg mice phenotypes and responses to experimental therapeutic interventions will enable new results to be applied to human AD patients with minimum delay and maximum confidence in efficacy and safety.