Alzheimer disease: Amyloidogenesis, the presenilins and animal models

Alzheimer's disease is the most prevalent form of dementia. Neuropathogenesis is proposed to be a result of the accumulation of amyloid beta peptides in the brain together with oxidative stress mechanisms and neuroinflammation. The presenilin proteins are central to the gamma-secretase cleavage of the amyloid prescursor protein (APP), releasing the amyloid beta peptide. Point mutations in the presenilin genes lead to cases of familial Alzheimer's disease by increasing APP cleavage resulting in excess amyloid beta formation. This review discusses the molecular mechanism of Alzheimer's disease with a focus on the presenilin genes. Alternative splicing of transcripts from these genes and how these may function in several disease states is discussed. There is an emphasis on the importance of animal models in elucidating the molecular mechanisms behind the development of Alzheimer's disease and how the zebrafish, Dania rerio, can be used as a model organism for analysis of presenilin function and Alzheimer's disease pathogenesis. (c) 2006 Elsevier B.V. All rights reserved.