A Serine Protease Inhibitor Domain Encoded Within the Alzheimer Disease-Associated Amyloid ß-Protein Precursor Gene
A crucial event in the pathogenesis of AD involves the aggregation of a 4.2 kiloDalton (kd) hydrophobic peptide referred to as the amyloid ß- protein (ABP) into insoluble extracellular proteinaceous fibers. These aggregates take the form of both senile (neuritic) plaques (SP) and cerebrovascular amyloid (CVA) deposits.1 Besides AD, amyloid deposits also occur in Dutch cerebral amyloidosis,2 older patients with Down syndrome (DS; trisomy 21), and to a limited extent in normal aged individuals. The formation of amyloid plaques and blood vessel CVA deposits appears to correlate well, although not perfectly, with the degree of dementia in AD patients.3 Whether amyloidogenesis is a primary or secondary event in AD-related neuropathology is not known. However, given the association between neuronal cell death and the presence of amyloid in AD and DS, multiple laboratories have focused their efforts on delineating the mechanism by which the 40 amino acid peptide, ABP, is generated and subsequently aggregated into insoluble amyloid fibrils. ABP is derived from a much larger precursor protein (APP) encoded by a gene located on chromosome 21.4–7 This precursor protein may consist of 695, 751, or 770 amino acids depending on the alternate splicing of two exons of 168 and 57 basepairs.5’8–10 The larger exon encodes a functional serine protease inhibitor domain in the Kunitz family. The effect of this inhibitor on the proteolytic processing of APP and the generation of amyloid is not yet known.
KeywordsDown Syndrome Trypsin Inhibitory Activity Amyloid Protein Precursor mRNA Kunitz Type Cerebrovascular Amyloid
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