Alzheimer's disease (AD) is characterized by elevated brain iron levels and accumulation of copper and zinc in cerebral β-amyloid deposits. Both ionic zinc and copper 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 into stable oligomers. Recent reports documented the release of Aβ together with ionic zinc and copper in cortical glutaminergic synapses following excitation, leading to the formation of Aβ oligomers. Excessive accumulation of Aβ oligomers in the synaptic cleft is thought to adversely affect synaptic neurotransmission, and transition metals have been implicated in the misfolding and accumulation of a-synuclein and Huntington protein in Parkinson's and Huntington's diseases (PD and HD), respectively, as well as tau hyperphosphorylation in AD, contributing to disease pathogenesis and progression. The "Metal Hypothesis of Neurodegenerative Diseases" is proposed to describe the underlying, possibly causative, events, leading to the neuropathology that drives AD, PD, and HD. This symposium examines how these findings led to the discovery of small molecules designed to restore the physiologic balance of transition metals in the brain, prevent further accumulation of misfolded proteins, and possibly even have a disease-modifying effect. A review of the early clinical experience of one such compound, PBT2, will be presented.
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