The metabolism of the amyloid precursor protein and its relevance to Alzheimer's disease


The pathology of Alzheimer's disease is primarily characterized by the deposition of β-amyloid/Aβ peptide as the major component of senile or neuritic plaques. The Aβ peptide is produced as a result of proteolytic cleavage of the transmembrane protein precursor, APP, during its normal cellular metabolism. The free amino terminus of the Aβ peptide is generated by an endopeptidic cleavage between Met671-Asp672 by a protease termed β-secretase. Increased cleavage at this site takes place in a rare, inherited double mutation (Lys670-Met671 to Asn670-Leu671), leading to increased Aβ production and consequent development of Alzheimer's disease on an accelerated time scale in the affected individuals, underscoring the pathological importance of β-secretase activity. Cellular studies provide direct evidence that inhibition of β-secretase activity would appear to be effective in inhibiting Aβ production as a rational approach to developing therapeutics for the disease.

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Sinha, S. The metabolism of the amyloid precursor protein and its relevance to Alzheimer's disease. Perspectives in Drug Discovery and Design 2, 363–369 (1995).

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Key words

  • APP metabolism
  • Aβ production
  • β-Secretase