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Vol. 4, No. 5, 2007
Issue release date: July 2007
Section title: Review
Neurodegenerative Dis 2007;4:349–365
(DOI:10.1159/000105156)

Current Insights into Molecular Mechanisms of Alzheimer Disease and Their Implications for Therapeutic Approaches

Van Broeck B. · Van Broeckhoven C. · Kumar-Singh S.
Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB; Laboratory of Neurogenetics, Institute Born-Bunge; University of Antwerp, Antwerp, Belgium

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Article / Publication Details

First-Page Preview
Abstract of Review

Received: 9/7/2006
Accepted: 4/12/2006
Published online: 7/6/2007

Number of Print Pages: 17
Number of Figures: 4
Number of Tables: 2

ISSN: 1660-2854 (Print)
eISSN: 1660-2862 (Online)

For additional information: http://www.karger.com/NDD

Abstract

During the last 10 years, a lot of progress has been made in unraveling the pathogenic cascade leading to Alzheimer disease (AD). According to the most widely accepted hypothesis, production and aggregation of the amyloid β (Aβ) peptide plays a key role in AD, and thus therapeutic interference with these processes is the subject of intense research. However, some important aspects of the disease mechanism are not yet fully understood. There is no consensus as yet on whether the disease acts through a loss- (LOF) or a gain-of-function (GOF) mechanism. While for many years, an increased production of Aβ42 was considered to be the prime culprit for the initiation of the disease process, and accordingly Aβ42 is elevated by AD-related presenilin(PS) mutations, recent data strongly suggest that PS mutations also lead to a LOF of PS towards a plethora of its substrates including amyloid precursor protein. How this PS LOF, especially decreased Aβ40 secretion due to mutant PS, impacts on the disease pathogenesis is yet to be elucidated. Secondly, vascular abnormalities – frequently observed to co-occur with AD – might also play a critical role in the initiation and aggravation of AD pathology given that the elimination of Aβ through a vascular route is an important brain Aβ clearance mechanism and its failure leads to formation of vascular amyloidosis and dense-core plaques. In this review, we will first focus on the important issue of a LOF versus a GOF mechanism for AD due to mutant PS, as well as on the possible role of vascular damage and reduced perfusion in AD. Special emphasis will be given to some of the AD mouse models that have helped to gain insights into the disease mechanism. Secondly, considering these mechanistic insights, we will discuss some therapeutic strategies which are currently in clinical or preclinical trials for AD.


  

Author Contacts

Samir Kumar-Singh, MD, PhD
VIB, Department of Molecular Genetics, Neurodegenerative Brain Diseases Group
University of Antwerp, Universiteitsplein 1
BE–2610 Antwerp (Belgium)
Tel. +32 3265 1002, Fax +32 3265 1012, E-Mail samir.kumarsingh@ua.ac.be

  

Article Information

Received: September 7, 2006
Accepted after revision: December 12, 2006
Published online: July 6, 2007
Number of Print Pages : 17
Number of Figures : 4, Number of Tables : 2, Number of References : 98

  

Publication Details

Neurodegenerative Diseases

Vol. 4, No. 5, Year 2007 (Cover Date: July 2007)

Journal Editor: Nitsch, R.M. (Zürich)
ISSN: 1660–2854 (print), 1660–2862 (Online)

For additional information: http://www.karger.com/NDD


Article / Publication Details

First-Page Preview
Abstract of Review

Received: 9/7/2006
Accepted: 4/12/2006
Published online: 7/6/2007

Number of Print Pages: 17
Number of Figures: 4
Number of Tables: 2

ISSN: 1660-2854 (Print)
eISSN: 1660-2862 (Online)

For additional information: http://www.karger.com/NDD


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