Neuroprotective Strategies in Alzheimer's Disease

In addition to strategies designed to decrease amyloid beta (Aβ) 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 Aβ and other toxic stimuli. Strategies include creating small molecules that block Aβ 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. © 2004 The American Society for Experimental NeuroTherapeutics, Inc.