54 Mechanisms and treatment of Aβ-induced neuronal dysfunction

Abstract

Amyloid(A ) peptides are widely thought to cause Alzheimer’s disease (AD), but the mechanisms remain to be elucidated. Among the diverse assembly states in which A can exist, soluble A oligomers appear to have the greatest functional impact. They cause an intriguing combination of synaptic depression and aberrant excitatory neuronal activity. If these processes are linked in a causal chain or result through parallel processes from the same trigger mechanism is unknown. Both could contribute to AD-related cognitive decline. Indeed, deficits in hippocampus-dependent cognitive functions in human amyloid precursor (hAPP) transgenic mice can be reversed by normalizing neuronal expression of the receptor tyrosine kinase EphB2, which regulates the function of synaptic NMDAtype glutamate receptors. A oligomers bind directly to EphB2, promoting EphB2 degradation in the proteasome. Blocking aberrant excitatory neuronal activity in hAPP mice can also prevent or reverse their synaptic and cognitive deficits. The most effective strategies in this regard include reduction of the microtubule-associated protein tau, which appears to be involved in the intracellular transport of factors that regulate synaptic functions; reduction of group IVA phospholipase A2, which may regulate the transport of glutamate receptors through release of arachidonic acid metabolites; reduction of the tyrosine kinase Fyn, which directly regulates the activity of specific glutamate receptors; and treatment with specific antiepileptic drugs that are able to block A -induced neuronal hypersynchrony or overexcitation, possibly by preventing overactivation of extrasynaptic NMDA receptors. Ongoing studies aim to determine whether the beneficial effects of these distinct manipulations involve convergent mechanisms, with the ultimate goal of preventing and ameliorating AD-related cognitive dysfunction.