beta-amyloid amplifies PLC activity and Ca2+ signalling in fully differentiated brain cells of adult mice

The beta-amyloid peptide (A beta) has been shown to possess neurotoxic properties, suggesting that the peptide may be involved in neurodegenerative processes occurring during AD. On the other hand, low concentrations of A beta have been shown to be neurotrophic. Both the neurotrophic as well as the neurotoxic effect of A beta could be related to modulation of neuronal calcium homeostasis by the peptide and subsequent influences on Ca2+ dependent processes such as the phosphatidylinositol-phospholipas C-protein kinase C (PtdIns-PLC-PKC) cascade. Therefore, we investigated in parallel the role of A beta on the PtdIns-hydrolysis and on the free intracellular calcium concentration ([Ca2+](i)) in mechanically dissociated mouse brain cells of adult mice. Low concentrations (> 50nM) of the A beta fragment 25-35 amplified the depolarization (KCl 20mM) induced rise in [Ca2+](i) but did not influence basal [Ca2+](i), whereas higher peptide concentrations induced direct destabilization of the neuronal Ca2+ homeostasis. The amplifying effect of A beta 25-35 was restricted to submaximal depolarization (KCl <20mM) with no influence on the maximal rise in [Ca2+](i) induced by 80mM KCl. Comparable effects of A beta 25-35 were found on the depolarization-induced [H-3]InsP-accumulation. At peptide concentrations > In MAP amplified the [H-3]InsP-accumulation with no effect on the basal [H-3]InsP-formation. Higher peptide concentrations (> 1mM) activated basal [H-3]InsP-formation directly. Again, the amplifying effect of A beta 25-35 was restricted to submaximal depolarization (<10mM KCl) with no influence on maximal activation. The amplifying effect of A beta on [H-3]InsP-accumulation was also found in presence of A beta 1-28, 1-40 and 1-43 whereas the scrambled A beta 25-35 did not influence the [H-3]InsP-accumtllation. Moreover A beta 25-35 also amplified carbachol and NMDA (10mM)-induced [H-3]InsP-accumulation. Our findings show that A beta modulates neuronal signal transduction in brain cells of adult animals and indicate that it enhances PtdIns-hydrolysis by amplifying the depolarization-induced Ca2+ response. This might represent an important mechanism related to physiological and pathophysiological properties of A beta