Drug Discovery

Anti-amyloid

Discovery of Lead Compounds that Block ADDL-mediated Neurotoxicity

Investigator(s): Grant A. Krafft, PhD

Institution(s): Acumen Pharmaceuticals Inc.

Duration: 2003 - 2004

Summary:

Beta amyloid is believed to play a central role in causing Alzheimer’s disease (AD). Dr. Klein and colleagues at Acumen discovered that small peptide aggregates of beta-amyloid, known as ADDLs, are extremely neurotoxic. ADDLs not only kill neurons but rapidly and efficiently inhibit memory and learning in rodent models. It is believed that ADDLs are the most active, disease causing form of beta-amyloid. Furthermore, Dr. Klein and colleagues at Acumen have evidence that ADDLs kill nerve cells by first binding to a cell surface “ toxicity” receptor. Acumen’s therapeutic focus is discovering drugs that inhibit the interaction of ADDLs with this “toxicity” receptor.The overall aim of this program is to screen CNS combinatorial library for compounds that inhibit the ADDLs’ ability to bind their cell surface receptors and thereby block their neurotoxic activity. Acumen is one of the few companies targeting the active, neurotoxic form of beta-amyloid. In addition, they are among the very few companies targeting the amyloid “toxicity” receptor. The interaction of ADDLs with a “toxicity” receptor may be a cause of neuronal death in AD. It is plausible that drugs emerging from this program will have a novel mechanism of action and may be the most direct-acting and straightforward therapeutic means to treat AD.