Amyloid precursor protein (APP) over-expression and amyloid deposition are implicated in many neurodegenerative disorders. Down syndrome patients carry an extra copy of the APP gene (located on chromosome 21) and show Aâ deposition as early as age 12. There are enhanced levels of soluble APP in the sera of autistic and Fragile X syndrome (FXS) children. Families with early-onset Alzheimer's disease (AD) carry mutations in the APP and presenilin genes that result in over-production of Aâ. All of these neurological disorders are associated with cognitive deficits. Behavioral and memory/information processing problems are often the first substantive symptoms of early AD suggesting that APP and Aâ could damage dendrites as a proximal cause of incipient dementia. APP mRNA and protein are found in dendrites and the postsynaptic density (PSD). APP has been implicated in synaptogenesis during development and aged APP transgenic mice show deficiencies in learning, memory and LTP. In addition, there is growing evidence that synaptic disease may cause neuronal degeneration, suggesting that therapies directed at this phase of AD pathobiology may be beneficial in slowing the onset of disease severity. We have demonstrated that activation of group 1 mGluR5 signaling increases APP translation by modulating the binding of fragile X mental retardation protein (FMRP) to APP mRNA. Therefore, mGluR5 and FMRP appear to play an important role in the regulation and hence accumulation of APP at synapses thus providing plausible targets for therapeutic intervention to prevent amyloid accumulation. We propose to study the effect of prolonged mGluR5 inhibition on APP and amyloid accumulation in a well-established AD mouse model, PDAPP. We expect to observe decreased APP and âsecretase cleavage products in mGluR5 antagonist-treated mice and to be able to correlate these molecular differences with cognitive phenotypes. mGluR5 antagonists may prove to be an attractive and safe alternative to immunotherapy to reduce soluble Aâ levels and hence plaque accumulation with aging. These studies will strongly support the testing of mGluR5 antagonists in human clinical trials for early AD as well as developmental neurological disorders involving the over-production of APP or one its proteolytic products.
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