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

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

^*Laboratory of Neurochemistry, National Institute for Physiological Sciences, Okazaki 444, Japan; ^†Department of Neuropathology and Neuroscience, Faculty of Pharmaceutical Sciences, University of Tokyo, Tokyo 113, Japan; ^§Department of Molecular Biology, Tokyo Metropolitan Institute of Medical Sciences, Tokyo 113, Japan; and ^¶Department of Molecular Biology, Central Institute of Mental Health, Mannheim 68159, Germany

Abstract

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