Studies of the cellular and molecular mechanisms underlying the sequential cleavage of theamyloid precursor protein (APP) to p-amyloid (Ap) by p- and y-secretases have afforded greatnsight into the etiology of Alzheimer's Disease (AD). Understanding the mechanisms that regulateAp generation may enable the development of pharmacologically active compounds that targetAp formation. Our work supported by this Program Project Grant has identified the serine/threonineprotein kinase CK1 as an important regulator of APP processing. CK1 has been implicated in everal important neuronal processes, including dopamine signaling in striatum, circadian rhythm,brain receptor signaling, and AD. Notably, CK15 mRNA is up-regulated in brain tissue from ADpatients, and CK1 may phosphorylate and regulate a number of proteins that likely play animportant role in AD, for example, p- and y-secretases. CK1 has also been implicated in tau hyper-phosphorylation and aggregation, another hallmark of AD pathogenesis. The long-term objective ofProject 3 is to study the molecular mechanisms underlying CK1-dependent increases in Approduction.
In Aim I, we will investigate the cellular process(es) responsible for the effects of CK1and in Aim II we will identify the protein targets (eg BACE, presenilin) that mediate the effects ofCK1. Little is known about regulation of CK1, but it is known from our studies to be regulated inneurons by metabotropic glutamate receptors.
In Aim III we will investigate the molecular basis forthe regulation of CK1 by neurotransmitters such as glutamate, and in Aim IV we will investigate therole of several new proteins that we have found to interact with CK1. In these studies, we willcollaborate with other Projects in the Program Project Grant in our studies of the role of CK1 in APPprocessing (Project 2), and synaptic structure and function (Project 1). We will also utilize keyreagents and cell-based assay systems generated by Core B. These studies will lead to greaterknowledge of mechanisms involved in the production of Ap in the brains of AD patients and willhopefully identify novel proteins that can be targeted by therapeutic agents.
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