The presenilin hypothesis of Alzheimer's disease: Evidence for a loss-of-function pathogenic mechanism

Jie Shen*,^†,^‡ and
Raymond J. KelleherIII^†,^‡,^§

*Center for Neurologic Diseases, Brigham and Women's Hospital,
^§Center for Human Genetic Research and Harvard-Partners Center for Genetics and Genomics, Massachusetts General Hospital, and
^†Program in Neuroscience and Department of Neurology, Harvard Medical School, Boston, MA 02115

Edited by Thomas C. Südhof, University of Texas Southwestern Medical Center, Dallas, TX, and approved November 17, 2006 (received for review October 5, 2006)

Abstract

Dominantly inherited mutations in the genes encoding presenilins (PS) and the amyloid precursor protein (APP) are the major causes of familial Alzheimer's disease (AD). The prevailing view of AD pathogenesis posits that accumulation of β-amyloid (Aβ) peptides, particularly Aβ42, is the central event triggering neurodegeneration. Emerging evidence, however, suggests that loss of essential functions of PS could better explain dementia and neurodegeneration in AD. First, conditional inactivation of PS in the adult mouse brain causes progressive memory loss and neurodegeneration resembling AD, whereas mouse models based on overproduction of Aβ have failed to produce neurodegeneration. Second, whereas pathogenic PS mutations enhance Aβ42 production, they typically reduce Aβ40 generation and impair other PS-dependent activities. Third, γ-secretase inhibitors can enhance the production of Aβ42 while blocking other γ-secretase activities, thus mimicking the effects of PS mutations. Finally, PS mutations have been identified in frontotemporal dementia, which lacks amyloid pathology. Based on these and other observations, we propose that partial loss of PS function may underlie memory impairment and neurodegeneration in the pathogenesis of AD. We also speculate that Aβ42 may act primarily to antagonize PS-dependent functions, possibly by operating as an active site-directed inhibitor of γ-secretase.

Footnotes

^‡To whom correspondence may be addressed. E-mail: jshen{at}rics.bwh.harvard.edu or kelleher{at}helix.mgh.harvard.edu
Author contributions: J.S. and R.J.K. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS direct submission.
Abbreviations:

AD,

Alzheimer's disease;

Aβ,

β-amyloid;

FAD,

familial AD;

FTD,

frontotemporal dementia;

LBD,

Lewy body dementia;

NFT,

neurofibrillary tangle;

APP,

amyloid precursor protein;

PS,

presenilin;

NICD,

Notch intracellular domain;

AICD,

APP intracellular domain;

SEL12,

suppressor/enhancer of LIN12;

cDKO,

conditional double knockout.