Unusual phenotypic alteration of β amyloid precursor protein (βAPP) maturation by a new Val-715 → Met βAPP-770 mutation responsible for probable early-onset Alzheimer’s disease

Unusual phenotypic alteration of β amyloid precursor protein (βAPP) maturation by a new Val-715 → Met βAPP-770 mutation responsible for probable early-onset Alzheimer’s disease

^*Institut de Pharmacologie Moléculaire et Cellulaire du Centre National de la Recherche Scientifique, UPR 411, 660 Route des Lucioles, Sophia Antipolis, 06560 Valbonne, France; ^‡INSERM EMI-U9906, Faculté de Médecine et de Pharmacie, IFRMP, Rouen, France; ^§Hopital Universitaire, Strasbourg, France; and ^¶Centre Hospitalier Universitaire Pitié-Salpêtrière, Institut National de la Santé et de la Recherche Médicale U289, Paris, France

Edited by Stanley B. Prusiner, University of California, San Francisco, CA, and approved February 2, 1999 (received for review November 13, 1998)

Abstract

We have identified a novel β amyloid precursor protein (βAPP) mutation (V715M-βAPP770) that cosegregates with early-onset Alzheimer’s disease (AD) in a pedigree. Unlike other familial AD-linked βAPP mutations reported to date, overexpression of V715M-βAPP in human HEK293 cells and murine neurons reduces total Aβ production and increases the recovery of the physiologically secreted product, APPα. V715M-βAPP significantly reduces Aβ40 secretion without affecting Aβ42 production in HEK293 cells. However, a marked increase in N-terminally truncated Aβ ending at position 42 (x-42Aβ) is observed, whereas its counterpart x-40Aβ is not affected. These results suggest that, in some cases, familial AD may be associated with a reduction in the overall production of Aβ but may be caused by increased production of truncated forms of Aβ ending at the 42 position.

Footnotes

↵ † K.A. and C.D. contributed equally to this work.
↵ ‖ To whom reprint requests should be addressed. e-mail: checler{at}ipmc.cnrs.fr.
This paper was submitted directly (Track II) to the Proceedings Office.
ABBREVIATIONS:

AD,

Alzheimer’s disease;

FAD,

familial AD;

wt,

wild type;

βAPP,

β amyloid precursor protein