IngentaConnect BACE1 Deficient Mice: Their Role in Drug Target Validation and Im...

Author: Vassar R.

Source: Current Medicinal Chemistry - Immunology, Endocrine & Metabolic Agents, Volume 3, Number 1, March 2003 , pp. 47-55(9)

Publisher: Bentham Science Publishers

Abstract:

A large (and still growing) body of evidence suggests that the bgr -amyloid peptide (A bgr ) is central to the pathophysiology of Alzheimer's Disease (AD) and may in fact initiate disease processes that lead to this intractable neurodegenerative disorder. Amyloid plaques composed of A bgr progressively develop in the brains of AD patients, and mutations in three genes (amyloid precursor protein, presenilin1, presenilin2) cause early on-set familial AD by increasing synthesis of the toxic A bgr 42 peptide. Given the strong correlation between A bgr and AD, therapeutic strategies to lower A bgr levels in the brain should prove beneficial for the treatment of AD. A bgr is derived from the amyloid precursor protein via cleavage by two proteases, bgr - and ggr -secretase. bgr -secretase was identified as the novel aspartic protease BACE1, and it initiates the formation of A bgr . Consequently, BACE1 in principle is an excellent therapeutic target for reducing the production of A bgr in AD. However, the discovery of the homologue BACE2 raised the question of whether it too may be a bgr -secretase. To settle this issue, our group and others have used gene targeting to generate BACE1 deficient (knockout) mice. These BACE1 knockout mice have been instrumental in validating BACE1 as the authentic bgr -secretase in vivo . Here, I review the recent studies of the BACE1 knockouts and discuss the implications of these studies for therapeutic approaches that target BACE1 for the treatment of AD.

Keywords: secretase; bace; alzheimer disease; peptide; app processing

Language: English

Document Type: Review article

DOI: 10.2174/1568013033358770

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BACE1 Deficient Mice: Their Role in Drug Target Validation and Implications for Alzheimer's Disease Therapies