Therapeutics for Alzheimer's Disease Based on the Metal Hypothesis

Alzheimer's disease is the most common form of dementia in the elderly, and it is characterized by elevated brain iron levels and accumulation of copper and zinc in cerebral β-amyloid deposits (e.g., senile plaques). Both ionic zinc and copper are able to accelerate the aggregation of Aβ, the principle component of β-amyloid deposits. Copper (and iron) can also promote the neurotoxic redox activity of Aβ and induce oxidative cross-linking of the peptide into stable oligomers. Recent reports have documented the release of Aβ together with ionic zinc and copper in cortical glutamatergic synapses after excitation. This, in turn, leads to the formation of Aβ oligomers, which, in turn, modulates long-term potentiation by controlling synaptic levels of the NMDA receptor. The excessive accumulation of Aβ oligomers in the synaptic cleft would then be predicted to adversely affect synaptic neurotransmission. Based on these findings, we have proposed the “Metal Hypothesis of Alzheimer's Disease,” which stipulates that the neuropathogenic effects of Aβ in Alzheimer's disease are promoted by (and possibly even dependent on) Aβ-metal interactions. Increasingly sophisticated pharmaceutical approaches are now being implemented to attenuate abnormal Aβ-metal interactions without causing systemic disturbance of essential metals. Small molecules targeting Aβ-metal interactions (e.g., PBT2) are currently advancing through clinical trials and show increasing promise as disease-modifying agents for Alzheimer's disease based on the “metal hypothesis.”