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Molecular basis of Alzheimer’s disease

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Abstract

Studies of the molecular mechanisms of Alzheimer’s disease (AD) have led to two major achievements. First, genes with mutations causing AD (PS1 and PS2 presenilin genes and APP) or bearing a risk factor polymorphism (APOE) have been described. Second, a new type of proteases has been identified along with the mechanisms regulating cell differentiation and development via intramembrane proteolysis. These mechanisms are apparently universal for various cell systems and organisms. Presenilin is a catalytic component of the tetraprotein complex (ɛ-/γ-secretase) that cleaves type I transmembrane proteins. Type II transmembrane proteins are cleaved by IMPAS/SPP aspartate proteases, found recently. The processing of transmembrane proteins by intramembrane proteases generates signal peptides, transcription factors, and short hydrophobic proteins (fragments of transmembrane domains), which can play both a physiological role and a key role in pathological events associated with aging (β-amyloid in AD). About 160 PS1 mutations, more than ten PS2 mutations, and 21 APP mutations have been described to date. Preclinical diagnosis has become possible for some early-onset forms of AD. Since early-and late-onset forms of AD are similar in pathogenesis, studies of proteolysis driven by intramembrane aspartate proteases may eventually contribute to the development of drugs directly affecting the processing of transmembrane proteins as a primary mechanism of AD.

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  1. Mental Health Research Center, Russian Academy of Medical Sciences, Moscow, 113152, Russia

    A. P. Grigorenko & E. I. Rogaev

  2. Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, MA, 01604, USA

    A. P. Grigorenko & E. I. Rogaev

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Original Russian Text © A.P. Grigorenko, E.I. Rogaev, 2007, published in Molekulyarnaya Biologiya, 2007, Vol. 41, No. 2, pp. 331–345.

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Grigorenko, A.P., Rogaev, E.I. Molecular basis of Alzheimer’s disease. Mol Biol 41, 294–307 (2007). https://doi.org/10.1134/S0026893307020100

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