Over 5 million Americans currently suffer from Alzheimer's disease (AD), and this number is projected to increase with an aging population. There are presently no FDA-approved drugs that halt or even slow the process of neurodegeneration in patients with AD, necessitating urgent action. AD is a progressive dementia caused by the accumulation of amyloid plaques containing A peptide as well as neurofibrillary tangles (NFTs) harboring aggregated tau protein in the central nervous system. The initiating event in AD is thought to be the accumulation and aggregation of A peptide in the brain, which ultimately leads to tau hyperphosphorylation and NFT formation. There is growing evidence that both A and tau may possess several prion-like properties including the potential to be transmitted under certain experimental conditions. In addition, recent experiments have suggested that aggregated A can adopt several different conformations or structures. In particular, fibrillar A species derived from AD brains are thought to be distinct from fibrillar A structures generated by polymerization of synthetic A peptide. This phenomenon is reminiscent of prion disease in which different conformations or 'strains' of the prion protein cause distinct disease phenotypes. However, it is currently unknown whether diverse A strains or conformations can exist in the human brain. Interestingly, transgenic (Tg) mouse models of AD based on expression of mutant human amyloid precursor protein (APP) exhibit age- dependent A deposition and amyloid plaque formation but do not develop NFTs. One possible explanation for the discrepancy between AD and Tg mouse brains is that fundamentally different A strains are present. Understanding this problem is highly important for the development of novel A -directed therapeutics since it is conceivable that compounds active against mouse brain-derived A conformations will be inefficacious against human brain-derived A strains, a problem that has been repeatedly encountered in prion disease. Thus, the objectives of this proposal are to develop methods for delineating and classifying the range of possible A conformations in the brain as well as techniques for assaying the biological relevance of different A strains. During two years of mentored postdoctoral studies (K99 phase) and three years of independent research (R00 phase), these experiments will determine whether different conformations of the A peptide exist in the brains of Tg mice and AD patients. These studies are the necessary first steps towards the development of novel cell and animal models that more accurately recapitulate the important biological events in AD, and which may be more informative for developing and testing potential AD therapeutics. PUBLIC HEALTH RELEVANCE: With an aging population and the absence of an effective treatment, the social and economic costs of Alzheimer's disease will skyrocket in the coming years. One potential explanation for the lack of therapeutic success is that the genetically modified mice used to study this disease are poor models of the human condition. This proposal will test whether the A peptide, the pathological entity that causes death of brain cells during Alzheimer's disease, is fundamentally different in the brains of mice and Alzheimer's disease patients, which could potentially lead to more informative tools for developing therapeutics.