Therapeutics for Alzheimer's disease based on the metal hypothesis.
Lahoz E, Pisacane A, Iannaccone M, Palumbo D, Capparelli R
Neurotherapeutics 2008 Jul; 5(3):421-32.
Alzheimer's disease is the most common form of dementia in the
elderly, and it is characterized by elevated brain iron levels and
ac***ulation of copper and zinc in cerebral beta-amyloid deposits
(e.g., senile plaques). Both ionic zinc and copper are able to
accelerate the aggregation of Abeta, the principle component of beta-
amyloid deposits. Copper (and iron) can also promote the neurotoxic
redox activity of Abeta and induce oxidative cross-linking of the
peptide into stable oligomers. Recent re****ts have do***ented the
release of Abeta together with ionic zinc and copper in cortical
glutamatergic synapses after excitation. This, in turn, leads to the
formation of Abeta oligomers, which, in turn, modulates long-term
potentiation by controlling synaptic levels of the NMDA receptor. The
excessive ac***ulation of Abeta 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 Abeta in Alzheimer's disease are promoted by (and possibly
even dependent on) Abeta-metal interactions. Increasingly
sophisticated pharmaceutical approaches are now being implemented to
attenuate abnormal Abeta-metal interactions without causing systemic
disturbance of essential metals. Small molecules targeting Abeta-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."
Neurotherapeutics : the journal of the American Society for
Experimental NeuroTherapeutics [Neurotherapeutics]
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