Protein kinase C inhibits amyloid β‐peptide neurotoxicity by acting on members of the Wnt pathway

Abstract

Current evidence supports the notion that the amyloid beta-peptide (Abeta) plays a major role in the neurotoxicity observed in the brain in Alzheimer's disease. However, the signal transduction mechanisms involved still remain unknown. In the present work, we analyzed the effect of protein kinase C (PKC) on some members of the Wnt signaling pathway and its implications for Abeta neurotoxicity. Activation of PKC by phorbol 12-myristate 13-acetate protected rat hippocampal neurons from Abeta toxicity. This effect was accomplished by inhibition of glycogen synthase kinase-3beta (GSK-3beta) activity, which led to the accumulation of cytoplasmic beta-catenin and transcriptional activation via beta-catenin/T-cell factor/lymphoid enhancer factor-1 (TCF/LEF-1) of Wnt target genes, which in the present study were engrailed-1 (en-1) and cyclin D1 (cycD1,). In contrast, inhibition of Ca2+-dependent PKC isoforms activated GSK-3beta and offered no protection from Ab neurotoxicity. Wnt-3a and lithium salts, classical activators of the Wnt pathway, mimicked PKC activation. Our results suggest that regulation of members of the Wnt signaling pathway by Ca2+-dependent PKC isoforms may be important in controlling the neurotoxic process induced by Ab.

P2X7 Nucleotide Receptor is Coupled to GSK-3 Inhibition and Neuroprotection in Cerebellar Granule Neurons

“…Indeed, several PKC isoforms have been shown to phosphorylate and inactivate GSK-3 both ''in vivo '' and ''in vitro'' (Goode et al 1992;Fang et al 2002). In hippocampal neurons, direct PKC activators, such as phorbol esters, were reported to induce GSK-3 phosphorylation in Ser-9 and stabilisation of b-catenin, implying that several members of the Wnt signalling pathway are regulated by PKCs (Garrido et al 2002). In addition, different extracellular signals have been reported to use the PKC/GSK-3 signalling, such as LPA in Swiss 3T3 cells (Fang et al 2002), and muscarinic and PDGF receptors, which cooperate to regulate airway myocyte proliferation (Gosens et al 2007).…”

Activation of Wnt signaling by lithium and rosiglitazone reduced spatial memory impairment and neurodegeneration in brains of an APPswe/PSEN1ΔE9 mouse model of Alzheimer's disease

“…5,12,31,[47][48][49][50] Considering that lithium is a pharmacological activator of the Wnt signaling pathway and rosiglitazone is a PPARg agonist that activates Wnt signaling by cross talk, 5,17 we wanted to confirm that under our experimental conditions, Wnt signaling was in fact activated. The expression of Wnt key proteins was analyzed by western blotting.…”

Huperzine A Activates Wnt/β-Catenin Signaling and Enhances the Nonamyloidogenic Pathway in an Alzheimer Transgenic Mouse Model

“…Recent studies have shown that Wnt signaling is involved in neurodegenerative diseases, especially in acetylcholinesterase (AChE) and Ab-mediated neurotoxicity (Inestrosa et al, 2000;Garrido et al, 2002;De Ferrari et al, 2003). First, AChE is present in neuritic plaques in the AD brain (Geula and Mesulam, 1995;Guillozet et al, 1997), and can enhance Ab aggregation and plaque formation and may form AChE-Ab complexes (Alvarez et al, 1997).…”