Structure-function implications in Alzheimer's disease:: Effect of a oligomers Aβ central synapses

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease in the growing population of elderly people. A characteristic of AD is the accumulation of plaques in the brain of AD patients, and theses plaques mainly consist of aggregates of amyloid beta-peptide (A beta). All converging lines of evidence suggest that progressive accumulation of the A beta plays a central role in the genesis of Alzheimer's disease and it was long understood that A beta had to be assembled into extracellular amyloid fibrils to exert its cytotoxic effects. This process could be modulated by molecular chaperones which inhibit or accelerate the amyloid formation. The enzyme Acetylcholinesterase (AChE) induces A beta fibrils formation, forming a stable complex highly neurotoxic. On the other hand, laminin inhibit the A beta fibrils formation and depolymerizate A beta fibrils also. Over the past decade, data have emerged from the use of several sources of A beta ( synthetic, cell culture, transgenic mice and human brain) to suggest that intermediate species called A beta oligomers are also injurious. Accumulating evidence suggests that soluble forms of A beta are indeed the proximate effectors of synapse loss and neuronal injury. On the other hand, the member of the Wnt signaling pathway, catenin was markedly reduced in AD patients carrying autosomal dominant PS-1. Also, neurons incubated with A beta revealed a significant dose-dependent decrease in the levels of cytosolic catenin an effect which was reversed in cells co-incubated with increasing concentrations of lithium, an activator of Wnt signaling pathway. Wnt signaling blocks the behavioural impairments induced by hippocampal injection of A beta therefore the activation of Wnt signaling protects agains the A beta neurotoxicity. Here we review recent progress about A beta structure and function, from the formation of amyloid fibrils and some molecular chaperones which modulate the amyloidogenesic process to synaptic damage induce by A beta oligomers.