Beta amyloid (Abeta) accumulation is critical to the development of Alzheimer's disease (AD), a disease that currently afflicts 4 million Americans and is predicted to affect 22 million people around the world by 2025. In particular an increase in the longer more toxic form of beta amyloid, Abeta1-42, which is proposed to trigger tau hyperphosphorylation and neural degeneration is considered a key etiological feature of AD.

Chicago based researchers Chauhan & Siegel have recently reported on studies designed to investigate the role of NGF in the etiology of AD using the AD mutant transgenic mouse model Tg2576 that develops pre-synaptic molecular changes in hippocampus prior to plaque formation. NGF is critical to neuronal growth and is involved in regulating the processing of the amyloid precursor protein, APP. Now the Chicago group report that early on in the life of Tg2576 mice, the expression of NGF and its low affinity receptor, p75, is dramatically reduced, a finding that mirrors a 21-fold increase in Abeta40/42. Inducing NGF expression through the administration of dietary propentofylline decreased Abeta40/42 by 45/48% by reversing the reduction of sAPPalpha expression, a characteristic of Tg2576 mice. On the other hand increasing p75 expression through the administration of acetyl-L-carnitine decreased Abeta40/42 by 46/26% independently of sAPP expression. The results indicate that NGF expression is reduced early in the Tg2576 brain, that this reduction increases Abeta formation, and that inducing NGF shifts the balance towards secretory processing of APP and away from the alternate pathway that produces beta amyloid. To a lesser extent, p75 decreases the formation of Abeta peptides, possibly via peptidases since sAPPalpha level is not changed.

These data therefore suggest that NGF mimics or molecules that induce the expression of NGF or p75 may be of use in the treatment of AD. Such strategies are already in development. For example, Ceregene is developing a gene therapy for Alzheimer's disease, involving NGF gene transfer to autologous cells ex vivo and transplantation of the NGF-secreting cells. In contrast Enact are developing human NGF. On the other hand Cephalon is developing orally-active stimulants of endogenous NGF expression for the treatment of AD. Further development of approaches such as these are eagerly awaited.

Entry date Monday, May 19, 2003

Adapted from Chauhan & Siegel, Neurochem Int 2003 Aug;43(3):225-33 - Interested in collaborating with this group? Contact LeadDiscovery or the authors direct.

Interested in collaborating with this group? Contact leaddiscovery@bioportfolio.co.uk