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

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Abstract
The β-amyloid peptide (Aβ) 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 Aβ have been shown to be neurotrophic. Both the neurotrophic as well as the neurotoxic effect of Aβ 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 (Ptdlns-PLC-PKC) cascade. Therefore, we investigated in parallel the role of Aβ on the Ptdlns-hydrolysis and on the free intracellular calcium concentration ([Ca2+];) in mechanically dissociated mouse brain cells of adult mice. Low concentrations (> 50nM) of the Aβ fragment 25–35 amplified the depolarization(KCl 20mM) induced rise in [Ca2+]. but did not influence basal [Ca2+]i, whereas higher peptide concentrations induced direct de-stabilization of the neuronal Ca2+ homeostasis. The amplifying effect of Aβ25–35 was restricted to submaximal de-polarization (KCl 1 nM Aβ amplified the [3H]InsP-accumulation with no effect on the basal [3H]InsP formation. Higher peptide concentrations (> 1mM) activated basal [3H]InsP formation directly. Again, the amplifying effect of Aβ25–35 was restricted to submaximal depolarization (< 10mM KCl) with no influence on maximal activation. The amplifying effectof Aβ on [3H]InsP-accumulation was also found in presence of Aβ 1–28, 1–40 and 1–43 whereas the scrambled Aβ25–35 did not influence the [3H]InsP-accumulation. Moreover, Aβ25–35 also amplified carbachol and NMDA (10mM)-induced [3H]InsP-accumulation. Our findings show that Aβ modulates neuronal signal transduction in brain cells of adult animals and indicate that it enhances Ptdlns-hydrolysis by amplifying the depolarization-induced Ca2+ response. This might represent an important mechanism related to physiological and pathophysiological properties of Aβ