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The presenilin 2 mutation (N141I) linked to familial Alzheimer disease (Volga German families) increases the secretion of amyloid β protein ending at the 42nd (or 43rd) residue

  1. Kunihiko Obata*

    To gain insights into the significance of presenilins (PS) in the pathogenetic mechanisms of early-onset familial Alzheimer disease (FAD), we expressed cDNAs for wild-type PS2 and PS2 with the Volga German (N141I) mutation in cultured cells and then examined the metabolism of the transfected proteins and their effect on the C-terminal properties of secreted amyloid β protein (Aβ). PS2 was identified as a 50- to 55-kDa protein, which was cleaved to produce N-terminal fragments of 35–40 kDa and C-terminal fragments of 19–23 kDa. The Volga German (N141I) mutation did not cause any significant change in the metabolism of PS2. COS-1 cells doubly transfected with cDNAs for N141I mutant PS2 and human β-amyloid precursor protein (βAPP) or a C-terminal fragment thereof, as well as mouse Neuro2a neuroblastoma cells stably transfected with N141I mutant PS2 alone, secreted 1.5- to 10-fold more Aβ ending at residues 42 (or 43) [Aβ42(43)] compared with those expressing the wild-type PS2. These results strongly suggest that the PS2 mutation (N141I) linked to FAD alters the metabolism of Aβ/βAPP to foster the production of the form of Aβ that most readily deposits in amyloid plaques. Thus, mutant PS2 may lead to AD by altering the metabolism of Aβ/βAPP.

    Footnotes

      • ↵ To whom reprint requests should be addressed at: Laboratory of Neurochemistry, National Institute for Physiological Sciences, Myodaiji, Okazaki, Aichi 444, Japan. e-mail: keimaru{at}nips.ac.jp.

      • ↵ To whom reprint requests should be addressed at: Department of Neuropathology and Neuroscience, Faculty of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyoku, Tokyo 113, Japan. e-mail: iwatsubo{at}mol.f.u-tokyo.ac.jp.

      • Setsuro Ebashi, National Institute for Physiological Sciences, Aichi, Japan

    • ABBREVIATIONS

      Aβ,
      amyloid β protein;
      AD,
      Alzheimer disease;
      FAD,
      familial AD;
      βAPP,
      β-amyloid precursor protein;
      N2a,
      mouse Neuro2a neuroblastoma;
      PS,
      presenilin
      • Received September 11, 1996.
      • Accepted December 5, 1996.

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