Synaptic dysfunction in Alzheimer's disease.

ABSTRACT

Generation of amyloid peptide (Aß) is at the beginning of a cascade that leads to Alzheimer's disease (AD). Amyloid precursor protein (APP), as well as ß- and γ-secretases, is the principal player involved in Aß production, while α-secretase cleavage on APP prevents Aß deposition. Recent studies suggested that soluble assembly states of Aß peptides can cause cognitive problems by disrupting synaptic function in the absence of significant neurodegeneration. Therefore, current research investigates the relative importance of these various soluble Aß assemblies in causing synaptic dysfunction and cognitive deficits. Several Aß oligomers targets and cellular mechanisms responsible of Aß-induced synaptic failure have been identified. The first and most important mechanism impugns a toxic gain of function for Aß which results due to self-association and attainment of new structures capable of novel interactions that lead to impaired plasticity. Other scenarios predicate that Aß has a normal physiological role. On the one hand, insufficient Aß could lead to a loss of normal function, whereas excess Aß may precipitate dysfunction. How this occurs and which the main target/s is/are for the synaptic action of Aß remains to be fully understood and would certainly represent one of the main challenges to future AD research.