Effects of beta amyloid on alpha7 receptor function

LASALA M; CORRADI J; BOUZAT C

Sierra de la Ventana

Congreso; XLIII Reunión Annual de la Sociedad Argentina de Biofísica (SAB).; 2014

SAB

Alzheimer?s disease (AD)is the most common form of dementia in elderly people that produces a severe impairment in mentalfunction, with profound effects on learning and memory. The beta amyloid peptide (bA) plays an important role in AD development. Several studies have shown that bA can affect cholinergic signaling in the brain but the specific mechanism is still obscure. Of the nicotinic acetylcholine receptors at risk, the most critical may be those containing the alpha7 subunit, because they are widespread, have a high relative permeability to calcium, and regulate numerous cellular events in the nervous system. Here we explore the effect of bA1-40 on the human alpha7 nicotinic receptors at the single-channel level. We observe that nanomolar concentrations of beta amyloid peptides block human alpha7 receptors. In the presence of 100M ACh combined with the positive allosteric modulator PNU, single-channel episodes appear as openings of 200 ms grouped in long clusters of 3s and high open probability (>0.9). In the presence of bA there is a clear reduction in open- and cluster-duration (4-fold and 2-fold, respectively at 500 nM of bA).Our results demonstrate that bA antagonizes the human alpha7 receptor by at least two different mechanisms, one that produces reduction in the open duration, probably acting as an open channel blocker, and another that reduces cluster duration, which is compatible with slow block or increased desensitization. Understanding the actual mechanism that leads to the neuronal damage would help to design more effective and specific treatments for AD patients.