Aging and beta-amyloid peptides decrease cholinergic receptor-mediated calcium increase in brain cortex...

In this study, the muscarinic cholinergic receptor (MAChR)-evoked inositol 1,4,5-trisphosphate (IP3)-mediated increase of cytosolic calcium concentration ([Ca]i) in synaptoneurosomes from brain cortex of adult and aged rats was investigated. In addition, the effect of two beta-amyloid (A beta) peptides, 1-28 and 25-35, on the resting and MAChR-induced increase of [Ca]i in brain cortex synaptoneurosomes of adult rats was evaluated. Release of IP3 was measured after prelabeling of synaptoneurosomal phosphoinositides with myo-[2-3H]inositol. Changes in [Ca]i were monitored by using fura-2 indicator. The effect of A beta peptides was evaluated following their preincubation with synaptoneurosomal protein for 1, 5, 30 and 60 min. It was observed that in brain cortex synaptoneurosomes from aged rats, Ca(2+)-dependent and MAChR-mediated IP3 production was not changed in comparison with that estimated in adult brain, over 60 min of incubation. Activation of MAChR in synaptoneurosomes from brain cortex of adult rats for 10 min increased [Ca]i by about 60% over its resting level (240 nM). This increase was completely blocked by muscarinic antagonists, atropine and pirenzepine, as well as by the antagonist of IP3 receptor, 8-(diethylamino)-octyl-3,4,5-trimethoxybenzoate (TMB-8). In aged brain, there was no detectable change in resting [Ca]i (165 nM) due to MAChR stimulation. The 25-35 A beta peptide caused a time-dependent significant increase of resting [Ca]i in synaptoneurosomes from brain cortex of adult rats, which was almost five-fold after 60 min. In the same conditions, the action of 1-28 A beta peptide was statistically insignificant up to 30 min, then a rapid increase of resting [Ca]i by two-fold was observed up to 60 min. Both A beta peptides decreased markedly the MAChR-dependent elevation of [Ca]i in respect to control (resting [Ca]i) in synaptoneurosomes from brain cortex of adult rats. These results indicate that beta-amyloid 1-28 and 25-35 peptides may be involved in alteration of muscarinic receptor-mediated signal transduction during brain aging.