ß/Α4 Amyloid in Alzheimer's Disease 4. Amyloid ß/Α4 Peptide Associated with Alzheimer's Disease and Cerebral Amyloid Angiopathy

We reviewed the recent progress in cerebral amyloid research, especially on the amyloid ß/Α4 (Αß) peptide from results in our laboratory and those reported in the literature. Cerebral amyloid deposition is an extracellular deposition in the brain and brain blood vessels of insoluble aggregates of the Αß peptide. Isolation and sequencing of the peptide from senile plaques and cerebrovascular amyloid deposits has led to the elucidation of the etiology and pathogenesis of Alzheimer's disease (1, 2). The Αß peptide, about 40 amino acids in length (3), is a breakdown product of a much larger protein, the amyloid ß/Α4 protein precursor (APP) (2). APP exists mainly in three isoforms that result from alternative splicing. APP is a glycosylated transmembrane protein with a large extracellular domain, a single transmembrane domain and a small cytoplasmic domain; the Αß fragment composes a part of the transmembrane domain and a short stub of the extracellular domain. First, cerebral amyloid was examined by immunohistochemical staining using an antiserum to synthetic Αß peptide (1-28). The Αß peptide was closely associated with cerebrovascular and senile plaque amyloid deposition (Fig. 1); also, another type of "diffuse plaque", in addition to "classic", "primitive", and "compact (burned-out)" plaques, was demonstrated (4). Diffuse (very primitive) plaques of the cerebral cortex and cerebellum were seen as ill-defined areas of fine fibrillar materials labeled by Αß peptide immunostaining and silver impregnation. Electron and immunogold electron microscopic investigation revealed that the diffuse plaques consist of accumulations of small bundles of amyloid fibrils or nonfibrillar materials (preamyloid) scattered among the normalappearing neurites, including a few altered neurites (5). The Α ß peptide deposits are also seen in the subpial area, subcortical white matter and in some eosinophilic tangles which represent the end stage of neurofibrillary tangles (6). Although Αß peptide has been considered to be deposited only in the brain, Αß peptide deposits have been reported in the skin tissue and intestines of Alzheimer's disease patients and normal elderly humans (7). There are multiple initiating mechanisms (Alzheimer's disease, aging, Down's syndrome, mutation in APP, and trauma) in the production of excess amyloid deposition. Various antisera against synthetic peptides to APP and against recombinant APP (Boehringer) were used to study the immunohistochemical distribution of APP. In normal mice, rats and humans, the immunoreactivities are recognized in almost all neurons and some glia cells of both central and peripheral nervous systems (8). Here, accumulations of APP-positive swollen neurites were seen in the classic and primitive plaques