As overviewed in our current "Target of the Month" 4 million Americans currently suffer from Alzheimer's disease (AD), and experts estimate that 22 million people around the world will be so afflicted by 2025. The current AD market is dominated by acetylcholinestase inhibitors which contribute to the $1.2 billion AD market (2001 figures). This figure will increase with the recent launch of the NMDA antagonist, Ebixa, and eventually with the development of molecules that are able to modify the course of the disease rather than treating symptoms. One hypothesis on the etiopathogenesis of AD proposes that the aggregates of Aß trigger tau hyperphosphorylation and neuronal degeneration. Neurotoxicity is thought to be due to altered calcium regulation, mitochondrial damage and/or immune stimulation. "Target of the Month" focuses on the central role that glycogen synthase kinase-3 plays in the development of AD. Here we highlight research emerging from the University of Washington describing a role for clusterin. Studies have shown that clusterin (also called apolipoprotein J) can influence the structure and toxicity of Aß in vitro. To determine whether endogenous clusterin plays a role in influencing Aß deposition, structure, and toxicity in vivo, this group bred PDAPP mice, a transgenic mouse model of Alzheimer's disease, with clusterin(-/-) mice. By 12 months of age, PDAPP, clusterin(-/-) mice had similar levels of brain Aß deposition as did PDAPP, clusterin(+/+) mice. Although Aß deposition was similar, PDAPP, clusterin(-/-) mice had significantly fewer fibrillar Aß (amyloid) deposits than PDAPP mice expressing clusterin. In the absence of clusterin, neuritic dystrophy associated with the deposited amyloid was markedly reduced, resulting in dissociation between fibrillar amyloid formation and neuritic dystrophy. These findings demonstrate that clusterin markedly influences Aß structure and neuritic toxicity in vivo and is likely to play an important role in Alzheimer's disease pathogenesis. Of interest OncoGenex have developed OGX-011, which is an antisense oligonucleotide inhibitor of clusterin expected to enter phase I trials for the treatment of cancer. Examining the therapeutic benefit of this and similar molecules in models of AD would therefore be of immense interest.

Entry date October, 2002

Adapted from DeMattos et al, Proc Natl Acad Sci U S A 2002 Aug 6;99(16):10843-8

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