TRANSGENIC MOUSE MODEL FOR ALZHEIMER'S DISEASE

IT IS PLANNED TO DEVELOP A TRANSGENIC MOUSE MODEL FOR ALZHEIMER'S DISEASE (AD), A DEVASTATING DEGENERATIVE DISORDER OF THE BRAIN THAT IS THE LEADING CAUSE OF DEMENTIA AMONG THE ELDERLY. AD IS CHARACTERIZED BY CEREBROVASCULAR AMYLOID DEPOSITS, ENDOCORTICAL PLAQUES, AND NEUROFIBRILLARY TANGLES. THE PREDOMINANT COMPONENT OF THESESTRUCTURES IS BETA-AMYLOID PROTEIN (BETA AP). THIS IS ENCODED BY PART OF A LARGER GENE FOR AMYLOID PRECURSOR PROTEIN (APP), WHICH HAS BEEN CLONED, MAPPED, AND PARTIALLY CHARACTERIZED. RECENT DATA SUGGEST THAT IN AD, BETAAP IS CLEAVED FROM APP AND DEPOSITED IN AMYLOID PLAQUES AS A RESULT OF ABNORMAL PRECURSOR PROCESSING. INCREASING THE APP GENE DOSAGE IN CULTURED CELLS BY TRANSFECTING THE HUMAN APP GENE INDUCES OVERPRODUCTION OF PROTEIN DETERMINANTS INCLUDING BETAAP. ALTHOUGH INCREASED GENE DOSAGE OF APP IS NOT FOUND IN AD, ITMAY BE SUFFICIENT FOR AMYLOID PLAQUE FORMATION. THEREFORE, THE TRANSFER OF HUMAN APP INTO MICE MAY CONFER AN EFFECTIVE INCREASE IN GENE DOSAGE THAT PREDISPOSES THEM TO AMYLOID PLAQUE DEPOSITS. THESE MICE MAY BE USED TO STUDY THE RELATIONSHIP BETWEEN APP EXPRESSION, AMYLOID PROCESSING, AND PLAQUE FORMATION. SUCH MICE WOULD BE A VALUABLE MODEL FOR EXPLORING BOTH PATHOPHYSIOLOGY AND POTENTIAL PALLIATIVE TREATMENTS FOR THE HUMAN DISORDER.