Amyloidosis is characterized by the deposition of abnormal fibrillar proteins in extracellular and intracellular spaces. The amyloid beta protein (A-beta) deposited in the brain parenchyma and vessel walls of patients with Alzheimer disease (AD) is a fragment of an amyloid precursor protein (APP) expressed in all tissues tested. Diseases involving A-beta deposition, which include AD, familial AD, and Down syndrome, seem to be heterogeneous in etiology and clinical presentation. A rare autosomal dominant form of early onset familial AD is hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D). In HCHWA-D the amyloid is mainly localized in cerebral vessel walls resulting in recurrent intracerebral hemorrhages leading to death when an individual is in his/her 50s or 60s. HCHWA-D was the first disorder in which an APP gene mutation was found. APP gene mutations and their segregation with the disease suggest that, at least in some cases, such loci may participate in amyloidogenesis. We use HCHWA-D to examine the common features of diseases involving A-beta deposition, including the mechanisms of APP processing, fibril formation, and tissue origin of the A-beta.
However, in most patients the APP gene is normal, suggesting the possible role of other factors in the pathogenesis. We are searching for proteins that bind to A-beta or APP in the brain, assuming that either disruption of normal binding or the formation of abnormal association with a specific protein may lead to the formation of amyloid fibrils.
Associate Professor, Department of Psychiatry
Associate Professor, Department of Biochemistry and Molecular Pharmacology
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