AGING AND BETA-AMYLOID PEPTIDES DECREASE CHOLINERGIC RECEPTOR-MEDIATED CALCIUM INCREASE IN BRAIN CORTEX SYNAPTONEUROSOMES

In this study, the muscarinic cholinergic receptor (MAChR)-evoked inos itol 1,4,5-trisphosphate (IP3)-mediated increase of cytosolic calcium concentration ([Ca](i)) in synaptoneurosomes from brain cortex of adul t 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-in duced increase of [Ca](i) in brain cortex synaptoneurosomes of adult r ats was evaluated. Release of IP3 was measured after prelabeling of sy naptoneurosomal phosphoinositides with myo-[2-H-3]inositol. Changes in [Ca](i) were monitored by using fura-2 indicator. The effect of A bet a peptides was evaluated following their preincubation with synaptoneu rosomal protein for 1, 5, 30 and 60 min. It was observed that in brain cortex synaptoneurosomes from aged rats, Ca2+-dependent and MAChR-med iated IP3 production was not changed in comparison with that estimated in adult brain, over 60 min of incubation. Activation of MAChR in syn aptoneurosomes from brain cortex of adult rats for 10 min increased [C a](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 detecta ble change in resting [Ca](i) (165 nM) due to MAChR stimulation. The 2 5-35 A beta peptide caused a time-dependent significant increase of re sting [Ca](i) in synaptoneurosomes from brain cortex of adult rats, wh ich was almost five-fold after 60 min. In the same conditions, the act ion of 1-28 A beta peptide was statistically insignificant up to 30 mi n, then a rapid increase of resting [Ca](i) by two-fold was observed u p to 60 min. Both A beta peptides decreased markedly the MAChR-depende nt elevation of [Ca](i) in respect to control (resting [Ca](i)) in syn aptoneurosomes from brain cortex of adult rats. These results indicate that beta-amyloid 1-28 and 25-35 peptides may be involved in alterati on of muscarinic receptor-mediated signal transduction during brain ag ing.