Metals in neurobiology: modulation of amyloidogenic peptides and NGF activity by transition metal ions

Transition metal ions are emerging as crucial for neurophysiology and neuropathology, in addition to the well-known participation of alkali and alkaline-earth metals (Na+, K+, Ca2+) in the neurotransmission and other neuronal functions. It was recently seen that Cu2+ and Zn2+ are released at the glutamatergic synapses in the hippocampus, brain area involved in learning and memory and the place of early occurrence of Aß amyloid plaques in Alzheimer’s disease. Moreover, the brain areas in which Zn2+ and Cu2+ dyshomeostasis is observed in pathological conditions overlap with those where amyloid plaque appears and where NGF performs its activity. Indeed, the hippocampus is innervated by neurons that are protected by NGF against age-related atrophy and insults. Interestingly we also observed that amylin, the insulin’s partner hormone, shares the same toxicity pathway of Aß upon metal-related mysfolding, and can likely cross the BBB causing brain derangement. We demonstrate that conformational changes, due to Cu2+ and Zn2+ binding, can alter the biological activities of NGF and amyloidogenic peptides, giving clues to the molecular mechanisms in which metal ions are involved in the CNS.