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Aggregated Beta Amyloid Peptide 1–40 Decreases Ca2+- and Cholinergic Receptor-Mediated Phosphoinositide Degradation by Alteration of Membrane and Cytosolic Phospholipase C in Brain Cortex

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Abstract

The effects of full-length amyloid β protein, Aβ (1–40), on phosphoinositide-specific phospholipase C (PLC) were investigated in synaptic plasma membranes (SPM) and cytosol prepared from the cerebral cortex of adult rats. Moreover, the role of Aβ (1–40) on the activation of lipid peroxidation was evaluated. The activity of phospholipase C (PLC) acting on phosphatidylinositol (PI) and phosphatidylinositol-4, 5-bisphosphate (PIP2) was determined using exogenous labeled substrates. The subcellular fractions were the source of enzyme(s). The radioactivity of lipid messengers derived from degradation of [14C- arachidonoyl] PI was also determined. The stable aggregated form of β-amyloid peptide (1–40) at 25 μM concentration exerted reproducible effects. The aggregated form of Aβ (1–40) inhibited Ca2+-regulated PI and PIP2 degradation by SPM and cytosolic enzymes. Aggregated Aβ also decreased significantly the level of diacylglycerol, the product of PLC. This additionally supports the inhibitory effect of Aβ on membrane-bound and cytosolic PLC. Moreover, Aβ (1–40) significantly decreased the basal activity of the PIP2-PLC in SPM and the enzyme activity regulated through cholinergic receptors. However, in spite of the lower enzyme activity, the percentage distribution of inositol (1,4,5) P3 radioactivity (IP3) in the total pool of inositol metabolites was not significantly changed. The aggregated neurotoxic fragment, Aβ (25–35), mimicked the effect of full-length Aβ (1–40). Aβ (1–40) enhanced the level of malondialdehyde indicating an activation of free radical stimulated membrane lipid peroxidation that may be involved in alteration of phospholipase(s) activity. Our results indicated that aggregated Aβ (1–40) alters Ca2+-dependent phosphoinositide degradation affecting synaptic plasma membrane and cytosolic phospholipase(s) activity. Moreover, this peptide significantly decreased the phosphoinositide-dependent signal transduction mediated by cholinergic receptors. The effect of aggregated Aβ (1–40) is more pronounced than that of the neurotoxic fragment Aβ (25–35). Our study suggests that the deposition of aggregated Aβ may alter phosphoinositide signaling in brain.

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Authors and Affiliations

  1. Medical Research Centre, Department of Cellular Signaling, Polish Academy of Sciences, Poland

    Agata Zambrzycka

  2. Department of Neurophysiology, 5 Pawinski St, 02-106, Warsaw, Poland

    Robert P. Strosznajder

  3. Medical Research Centre, Department of Cellular Signaling, Polish Academy of Sciences, Poland

    Joanna B. Strosznajder

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Zambrzycka, A., Strosznajder, R.P. & Strosznajder, J.B. Aggregated Beta Amyloid Peptide 1–40 Decreases Ca2+- and Cholinergic Receptor-Mediated Phosphoinositide Degradation by Alteration of Membrane and Cytosolic Phospholipase C in Brain Cortex. Neurochem Res 25, 189–196 (2000). https://doi.org/10.1023/A:1007511217525

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