Molecular Mechanisms of Memory Loss in a Transgenic Model of Alzheimer Disease

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DESCRIPTION (provided by applicant): Alzheimer disease is marked by the accumulation of amyloid plaques and neurofibrillary tangles (NFTs). Clinically, AD patients show a progressive deterioration of memory and other cognitive functions. Recent evidence points to soluble Ap as an excellent candidate for the initial trigger of memory loss. A focus of this proposal is to elucidate the pathways by which Ap and tau interact. We are uniquely position to address this question, as we have generated a transgenic model of AD (3xTg-AD) that develops both plaques and tangles. The goal of the studies proposed for the mentored phase is to elucidate the temporal relationship between Aft and tau in the 3xTg-AD mice. Two specific aims are proposed: Aim 1 will determine if active A¿ immunization prevents or delays the development of NFTs. Our earlier results indicate that passive A¿ immunotherapy suffices to remove early but not late hyperphosphorylated tau lesions. Here we propose to determine if the temporal development of the tau pathology is altered by actively immunizing young, pre- pathological 3xTg-AD mice. Aim 2 will determine if genetically shifting A¿ production from predominantly A¿ 42 to Ap40 impacts the plaque burden and tau load and cognitive deficits. In this aim, we will use a genetic approach to lower A¿ 42 production to determine the consequences of reducing A¿ 42 production on the onset and progression of A¿ and tau pathology and cognitive deficits in the 3xTg-AD mice. The main focus of the independent phase will be to identify molecular mechanisms underlying the A¿ -induced cognitive decline. In particular two additional aims are proposed: Aim 3 will elucidate the role of AKT/CREB in the A¿-induced learning deficits. This aim follows up on our preliminary data showing that 4-month old 3xTg-AD mice have significantly reduced CREB activation compared to age- and gender-matched NonTg mice, following training in the MWM. Thus, we hypothesize that A¿ 42 blocks CREB activation by directly or indirectly interfering with AKT activity. To test this hypothesis, we will use a genetic and immunological approach to block AP accumulation and determine if CREB and AKT activation deficits are restored following learning. In addition, we will directly increase CREB function to determine if cognitive deficits can be restored in the presence of A¿. Aim 4 uses a candidate approach to determine other molecular pathways underlying A¿-induced cognitive decline, and is part of our efforts to define the molecular pathways that link A¿ to cognitive decline. Combined the proposed aims will help to elucidate the underlying molecular pathways linking A¿ to cognition. The identification of pathways leading to cognitive decline may point to new therapeutic targets.