The cell cycle hypothesis of Alzheimer's disease: Suggestions for drug development

Abstract

The cell cycle of hypothesis of neural dysfunction in chronic neurodegenerative conditions such as Alzheimer's disease (AD) offers a unified approach to understanding both existing and novel strategies for drug development. At the present time, a ligand based approach is a pragmatic solution for identifying new chemical leads on which to base future discovery and optimisation. We have pursued a ligand based approach on the basis of public domain data to identify existing compounds capable of abrogating the cell cycle at the G0-G1 interface. Selected on this basis, irrespective of the tissue under study, we identified several classes of compounds as potential chemical leads. Of these compounds, at least ten have already been shown to be neuroprotective in animal models of acute neurodegeneration. Such compounds could form the basis of a screening exercise after development of suitable screening tools. Progressing of chemical leads through such an approach will be more efficient if future leads display relevant "drug-like" properties. Further, drug development in this arena should take account of the special concerns raised by targeting an elderly population. This will involve accounting for frequent polypharmacy in the aging population, and age-related alterations in physiology.

The Neuronal Expression of MYC Causes a Neurodegenerative Phenotype in a Novel Transgenic Mouse

“…The establishment of this model provides a working platform to test genetic and pharmacological approaches to block cell cycle re-entry. 34 …”

Iron: The Redox-active Center of Oxidative Stress in Alzheimer Disease

“…Therefore, not surprisingly, progress in AD treatment based on lesion-centered hypotheses continues in a Brownian-like motion. A fundamental reorganization of the concepts related to etiology, pathogenesis, and treatment of AD seems warranted (e.g., [3]). In this review, we discuss the role of iron in AD pathogenesis as a potential therapeutic target.…”

Tumorigenesis and neurodegeneration: two sides of the same coin?

“…(44) These and related observations have made the G 0 -G 1 and G 1 -S transitions attractive therapeutic targets for Alzheimer disease and possibly other neurodegenerative conditions. (45) The challenge is to find compounds that arrest neurons at these stages and allow them to ''reset'' G 0 without triggering apoptosis, in contrast to traditional chemotherapeutics that induce both cell-cycle arrest and apoptosis. Many compounds with this restricted activity show a marked neuroprotective effect in animal models of acute neurodegeneration, especially the rat stroke model.…”