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2006 Grant - Lu
Signaling Mechanisms That link APP and Tau
Bingwei Lu, Ph.D.
Palo Alto Institute for Research & Education, Inc.
Palo Alto, California
2007 Investigator-Initiated Research Grant
Tau protein plays a crucial role in maintaining the structural framework and transport system within nerve cells. Tau is normally modified by the attachment of phosphate molecules, a process known as phosphorylation. Yet excessive phosphorylation can lead to the development of harmful structures called tangles, and it can prevent the protein from carrying out normal functions. Such abnormalities are hallmarks of Alzheimer's disease and other brain disorders.
Scientists know little about how excessive phosphorylation of tau occurs and promotes disease. Bingwei Lu, Ph.D., and colleagues have been researching tau using fruit flies engineered to develop Alzheimer-like symptoms. Preliminary test results indicate that amyloid precursor protein (APP) helps initiate a series of molecular events that culminate in aberrant tau phosphorylation. APP is the parent molecule of beta-amyloid, a key suspect in Alzheimer pathology. Investigators found that APP helps activate a tumor suppressor protein called LKB1. This protein, in turn, phosphorylates and helps activate a second protein called protease-activated receptor-1 (PAR-1) kinase. If PAR-1 kinase becomes over-activated, it may trigger another phosphorylation process that generates abnormal tau.
In this proposed study, Dr. Lu's team will focus on three goals: (1) to identify the precise regions of APP that stimulate molecular events leading to irregular tau phosphorylation, (2) to determine the mechanisms behind this activity and (3) to find other molecules that may mediate the effects of APP on tau. The study's results could lead to new ways of diagnosing Alzheimer's disease and other brain disorders at an early stage.