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Mouse Models Pave the Way for Therapeutic Opportunities

Gérard Emilien, PhD; Jean-Marie Maloteaux, MD, PhD; Konrad Beyreuther, PhD; Colin L. Masters, MD

Arch Neurol. 2000;57:176-181.

Research into the molecular mechanisms of Alzheimer disease (AD) continues to clarify important issues in aberrant protein processing while seeking to identify therapeutic targets. Mutations of genes on chromosomes 1, 14 (presenilins 1 and 2), and 21 (the amyloid- [A] amyloid precursor protein [APP]) cause the familial forms of AD that often begin before age 65. An allelic polymorphism on chromosome 19 (apolipoprotein E ) affects the age of onset of the more common forms of sporadic AD. Multiple studies in transgenic mice provide strong evidence to support the view that A amyloid formation is an early and critical pathogenic event: mice expressing pathogenic human APP mutations develop A deposits; coexpression of mutant presenilin genes accelerates the rate of A deposition; and apolipoprotein E plays a role in this process. Thus, the 3 established genetic causes or risk factors for AD affect A deposition. The fact that elevation of the A42/A40 ratio (differing only in 2 amino acids in length) is also linked to amyloid deposition in the APP mice and is temporally linked to cognitive impairment suggests that A42 may be a principal inducing factor of AD. The exact sequence of events is still unknown, but the transgenic models generated so far have shown their usefulness in clarifying this complex part of the pathology. The continuing progress in elucidation of the molecular pathogenesis of AD suggests a range of rational pharmacological interventions for this disorder. The most promising strategy involves the development of approaches to retard, halt, or prevent A-mediated disease progression, and these can now be tested in transgenic animals.

The Laboratory of Pharmacology (Drs Emilien and Maloteaux) and Department of Neurology (Dr Maloteaux), Université Catholique de Louvain, Cliniques Universitaires Saint Luc, Brussels, Belgium; Zentrum für Molekulare Biologie der Universität Heidelberg, Heidelberg, Germany (Dr Beyreuther); and the Department of Pathology, the University of Melbourne and the Mental Health Research Institute, Parkville, Victoria, Australia (Dr Masters).

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