DESCRIPTION (provided by applicant): Deposition of beta-amyloid peptide (Aß) within neuritic plaques is a hallmark pathology of Alzheimer's disease (AD). Processing of the Amyloid Precursor Protein (APP) by ß and ?-secretases results in the generation of Aß peptides. Excess Aß is believed to be a main contributor to the dysfunction and degeneration of neurons that underlies AD. As such, preventing Aß deposition or clearing excess pathogenic Aß remains an important therapeutic target in AD. APP internalization is required for Aß production and there is evidence that general endocytic dysregulations underlie sporadic AD and AD- like pathophysiologies. Therefore a better understanding of the mechanisms that regulate APP internalization would guide more selective strategies for developing AD therapies. In this proposal we will use biochemical, cell biology and imaging analysis of primary neuronal cultures to test the hypothesis that the novel APP adaptor AIDA-1 regulates Aß production by promoting APP internalization. To determine if AIDA-1 regulates APP metabolism in vivo we will quantify APP proteolytic fragments in newly generated AIDA-1 knockout mice, and determine if loss of AIDA-1 can rescue AD-like phenotypes in mouse models of AD. Moreover we will evaluate the therapeutic potential of cell-permeable peptides that block AIDA-1/APP interactions by determining their effects on excess Aß production in AD mouse models. We will also determine how loss of AIDA-1 affects synaptic function in cell cultures and in acute hippocampal slices from AIDA-1 knockout mice and determine if loss of AIDA-1 can revert the synaptic deficits observed in AD mouse models. With the tools developed here, we will be able to address the chronic and acute effects of loss of AIDA-1 and endogenous Aß production on neurotransmission. This is important given AD has been increasingly viewed as a synaptic dysfunction caused by excess Aß production.
|Effective start/end date||8/1/11 → 5/31/17|
- Clinical Neurology
- Cell Biology
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