Alzheimer's Disease (AD) is an age-associated dementia for which there is currently no cure. AD is characterized by memory deficits, loss of CNS neurons, and eventually death. One of the prominent events in AD is the CNS presence of plaques that are mostly formed by large macromolecular aggregates of insoluble fibrillar amyloid beta (Aj3), a 40 or 42 aminoacid-Iong peptide resulting from atypical cleavage of the larger amyloid precursor protein (APP). However, mouse models of AD have shown that memory deficits occur in the absence of neuronal loss and long before plaque deposition;furthermore in humans, total CNS levels of Aj3, rather than number of amyloid plaques, correlate with the degree of disease severity, thus suggesting that soluble, non plaque associated, small forms of Aj3 may be the principal offender in the AD brain. Indeed, recent evidence has shown that specific oligomeric forms of Aj3 perturb synaptic plasticity, depress long term potentiation (L TP) and induce transient memory deficits in rodents. On this basis, there is consensus that preventing oligomeric Aj3 toxicity would be a significant therapeutic step to reverse cognitive deficits and hopefully prevent later neurodegeneration in AD. Thus, understanding the yet unclear cellular mechanisms mediating oligomeric Aj3-promoted memory deficits, the overall goal of this research, is important for the development of future therapies for AD. The central hypothesis of this project is that a key mechanism mediating oligomeric Aft neurotoxicity is the aberrant activation of the phosphatase calcineurin (CaN), a signaling element abundant in the CNS that plays a fundamental role in memory function. This hypothesis has been formulated based on preliminary data and published results showing that CaN is up-regulated in the CNS of APP transgenic mice (Tg2576), coincident with the appearance of oligomeric Aj3 and memory impairments, and that acute inhibition of CaN reverses memory deficits in these mice. The objective of this project is therefore to determine the role played by CaN in mediating the cognitive effects of oligomeric Aj3. This objective will be achieved by pursuing the following specific aim: test the hypothesis that there exist a causal link between the occurrence of oligomeric Aj3 and increased CaN activity in the CNS of ageing Tg2576 APP transgenic mice as a function of age, deteriorating cognitive performance and appearance of amyloid plaques. Once completed, this project will have identified CaN as a crucial element mediating the cognitive outcomes of oligomeric Aj3. Acquiring this new knowledge is important for the future development of effective therapies for AD.
The presence of the atypical amyloid beta (A?) protein in the brain is thought to play a key role in the onset and progression of Alzheimer's Disease (AD), a terminal age-associated neurodegenerative disease affecting millions of elderly Americans;there is currently no effective treatment for AD, but there is great hope that blocking the effects of A? on neurons should decrease or reverse the mental impairment typical of AD patients. A? This project will characterize one putative mechanism mediating the detrimental effects of specifically testing the hypothesis that calcineurin (an enzyme in the brain that is involved in modulation of memory and cell death) mediates the cellular and cognitive outcomes of oligomeric A?, the most neurotoxic form of A?. If successful, these studies will therefore illustrate calcineurin as a potential new therapeutic target for counteracting cognitive deficits and neurodegeneration in AD.
