BETA-AMYLOID AMPLIFIES PLC ACTIVITY AND CA2-CELLS OF ADULT MICE( SIGNALING IN FULLY DIFFERENTIATED BRAIN)

The beta-amyloid peptide (A beta) has been shown to possess neurotoxic properties, suggesting that the peptide may be involved in neurodegen erative processes occurring during AD. On the other hand, low concentr ations of A beta have been shown to be neurotrophic. Both the neurotro phic as well as the neurotoxic effect of A beta could be related to mo dulation of neuronal calcium homeostasis by the peptide and subsequent influences on Ca2+ dependent processes such as the phosphatidylinosit ol-phospholipas C-protein kinase C (PtdIns-PLC-PKC) cascade. Therefore , we investigated in parallel the role of A beta on the PtdIns-hydroly sis and on the free intracellular calcium concentration ([Ca2+](i)) in mechanically dissociated mouse brain cells of adult mice. Low concent rations (> 50nM) of the A beta fragment 25-35 amplified the depolariza tion (KCl 20mM) induced rise in [Ca2+](i) but did not influence basal [Ca2+](i), whereas higher peptide concentrations induced direct destab ilization of the neuronal Ca2+ homeostasis. The amplifying effect of A beta 25-35 was restricted to submaximal depolarization (KCl <20mM) wi th 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-in duced [H-3]InsP-accumulation. At peptide concentrations > In MAP ampli fied 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 influe nce on maximal activation. The amplifying effect of A beta on [H-3]Ins P-accumulation was also found in presence of A beta 1-28, 1-40 and 1-4 3 whereas the scrambled A beta 25-35 did not influence the [H-3]InsP-a ccumtllation. Moreover A beta 25-35 also amplified carbachol and NMDA (10mM)-induced [H-3]InsP-accumulation. Our findings show that A beta m odulates neuronal signal transduction in brain cells of adult animals and indicate that it enhances PtdIns-hydrolysis by amplifying the depo larization-induced Ca2+ response. This might represent an important me chanism related to physiological and pathophysiological properties of A beta