TSI proposes 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 these structures is b-amyloid protein (bAP). 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, BAP is cleaved from APP and deposited in amyloid plaques as a result of abnormal precursor processing (Tanzi et al., 1989). Increasing the APP gene dosage in cultured cells by transfecting the human APP gene induces overproduction of protein determinants including bAP (Marotta et al., 1989). Although increased gene dosage of APP is not found in AD, it may 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 plaques deposits. These mice may be used to study the relationship between APP expression, amyloid processing, and plaque formation. Such mice would be valuable model for exploring both pathophysiology and potential palliative treatments for the human disorder.
