Alzheimer's disease causes dementia in many elderly people and in some individuals with Down syndrome who survive to age 50. Alzheimer's is characterized by various pathological markers in the brain--large numbers of amyloid plaques surrounded by neurons containing neurofibrillary tangles , vascular damage from extensive plaque deposition , and neuronal cell loss . Because it is not known if the amyloid plaques or the neurofibrillary tangles are the earliest lesion in the disease process, the role of these markers in the etiology of the disease is controversial.
Our hypothesis is that deposition of amyloid [Beta] protein (A [Beta] P), the main component of the  plaques, is the causative agent of Alzheimer's pathology and that the neurofibrillary tangles, cell loss, vascular damage, and dementia follow as a direct result of this deposition. A [Beta] P is a peptide produce of the larger amyloid precursor protein (APP) . Because Down syndrome is caused by trisomy of the region of chromosome 21 that contains the APP gene, deposition of A [Beta] P is likely to be an early event in the disease . The A [Beta] P molecule is a 39- to 42-amino acid peptide [4, 6], part of which forms the hydrophobic transmembrane domain in the COOH-terminal portion of APP (Fig. 1). A [Beta] P is one of a diverse group of "amyloid" (starch-like) proteins that forms insoluble extracellular deposits. The APP gene undergoes alternative RNA splicing to produce several protein isoforms; the predominant variant in brain lacks a serine protease inhibitor domain that is present in APP molecules in other tissues .
We now know something about how APP proteolysis leads to A [Beta] P deposition. APP is inserted into the cytoplasmic membrane and then cleaved at residues 15 to 17 within the A [Beta] P sequence by the APP "secretase"  (Fig. 1). This cleavage event therefore produces fragments that do not contain intact A [Beta] P and so cannot result in amyloid deposition. These fragments include secreted [NH.sub.2] -terminal derivatives that can be detected in brain and cerebrospinal fluid . The APP secretase that cuts within the A [Beta] P region has an extraordinarily broad sequence specificity and recognizes the secondary structure of APP, cleaving at a defined distance from the membrane . Several recent studies suggest that APP can also be processed by the endosomal-lysosomal pathway, after recycling of membrane-bound APP ad possibly via an intracellular metabolic route [11, 13]. Carboxyl-terminal fragments containing the entire A [Beta] P sequence can be derived from this alternate normal processing of APP [12, 14] and may eventually lead to amyloid deposition [12, 14] (Fig. 1).
Mutations in the COOH-terminal portion of APP cause hereditary, early onset Alzheimer's disease [15, 16] and hereditary cerebral hemorrhage with amyloidosis (Dutch-type) . The APP mutation that causes massive A [Beta] P deposition in the Dutch amyloidopathy is a glutamic acid to glutamine substitution at codon 693 [with reference to the longest form of APP, APP-770 ] (Fig. 1), located only six residues away from...
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