Impairment of the activity of the plasma membrane Ca2+-ATPase in Alzheimer's disease

AD (Alzheimer's disease) is an age-associated neurodegenerative disorder where the accumulation of neurotoxic A beta (amyloid beta-peptide) in senile plaques is a typical feature. Recent studies point out a relationship between A beta neurotoxicity and Ca2+ dyshomoeostasis, but the molecular mechanisms involved are still under discussion. The PMCAs (plasma membrane Ca2+-ATPases) are a multi-isoform family of proteins highly expressed in brain that is implicated in the maintenance of low intraneural Ca2+ concentration. Therefore the malfunction of this pump may also be responsible for Ca2+ homoeostasis failure in AD. We have found that the Ca2+-dependence of PMCA activity is affected in human brains diagnosed with AD, being related to the enrichment of A beta. The peptide produces an inhibitory effect on the activity of PMCA which is isoform-specific, with the greatest inhibition of PMCA4. Besides, cholesterol blocked the inhibitory effect of A beta, which is consistent with the lack of any A beta effect on PMCA4 found in cholesterol-enriched lipid rafts isolated from pig brain. These observations suggest that PMCAs are a functional component of the machinery that leads to Ca2+ dysregulation in AD and propose cholesterol enrichment in rafts as a protector of the A beta-mediated inhibition on PMCA.