In Alzheimer's disease (AD), the microtubule-associated protein tau is hyperphosphorylated and aggregatesinto paired helical filaments (PHFs), leading to NFT formation. Previously, we described a cascade ofmolecular events associated with NFT formation within cortical neurons in AD. Whether similar or differentevents occur during NFT formation within cholinergic basal forebrain (CBF) projection neurons during theprogression of AD remains unknown. The Program Project entitled 'Neurobiology of Mild CognitiveImpairment in the Elderly' provides an outstanding opportunity to extend these findings to an early stage ofAD, people who have died with a clinical diagnosis of mild cognitive impairment (MCI). Establishment of thiscascade of tau changes is paramount as NFTs provide a window into the tau portion of the neruonaldegnerationn in AD and will allow for in vitro modeling to approach a mechanistic understanding of taupathology and and aggregation. We propose to investigate whether formation of fibrillar pathologies follows adefinable sequence of molecular events that directly impact tau's assembly competency throughphosphorylation and truncation while other events (tau cleavage by Puromycin-Sensitive Aminopeptidaseexpression and non-canonical tau isoform expression) inhibit this process in CBF neurons during the earlystages of AD. We propose to place tau changes in an overall molecular context within affected CBF neuronsby correlating NFT evolutionary states with enzyme and other proteins expression profiles affecting tauassociation and function. Specifically: 1. We will test the hypothesis that CBF neuron NFT formation occursin a linear and orderly fashion assayed and ordered by alterations in phosphorylation and truncation eventsas certain phosphorylation and carboxy-terminal truncation events appear facilitative of NFT formation; 2.We will test for the expression of candidate enzyme genes known to stimulate or inhibit tau's ability to formNFTs defined by specific antibodies to phosphoepitopes, conformational states, and C-terminal truncationsites and, 3. We will test the hypothesis that the expression of small tau isoforms lacking the microtubulebinding repeats and carboxy termini inhibit tau filament (and hence NFT) formation.
These aims will begin todefine the molecular milieu of tau tangle formation and provide insight into regulatory mechanisms involvedin controling and/or inhibiting this phenomenon, which are needed to develop new treatments for AD.
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