Neuroprotective strategies in Alzheimer's disease

Abstract

In addition to strategies designed to decrease amyloid beta (A beta) levels, it is likely that successful Alzheimer's disease (AD) therapeutic regimens will require the concomitant application of neuroprotective agents. Elucidation of pathophysiological processes occurring in AD and identification of the molecular targets mediating these processes point to potential high-yield neuroprotective strategies. Candidate neuroprotective agents include those that interact specifically with neuronal targets to inhibit deleterious intraneuronal mechanisms triggered by A beta and other toxic stimuli. Strategies include creating small molecules that block A beta interactions with cell surface and intracellular targets, down-regulate stress kinase signaling cascades, block activation of caspases and expression of pro-apoptotic proteins, and inhibit enzymes mediating excessive tau protein phosphorylation. Additional potential neuroprotective compounds include those that counteract loss of cholinergic function, promote the trophic state and plasticity of neurons, inhibit accumulation of reactive oxygen species, and block excitotoxicity. Certain categories of compounds, such as neurotrophins or neurotrophin small molecule mimetics, have the potential to alter neuronal signaling patterns such that several of these target actions might be achieved by a single agent.

FIG. 1.

Overview of pathophysiological processes occurring in AD. A perspective emphasizing the many mutually reinforcing pathological processes in AD suggests that neuroprotective strategies, inhibiting as many of these process as possible, will likely be required for successful therapy in AD in parallel to therapies reducing Aβ accumulation.

FIG. 2.

Aβ binding targets and candidate associated neurodegenerative mechanisms. Extracellular Aβ interacts with a number of neuronal and glial cell surface receptors. Evidence suggests that many of these interactions promote stress kinase and other signaling triggering neurodegenerative processes. Intracellular Aβ is also likely to bind to one or more targets to contribute to neurodegenerative signaling.