Cellular demise and inflammatory microglial activation during β-amyloid toxicity are governed by Wnt1 and canonical signaling pathways

Abstract

Initially described as a modulator of embryogenesis for a number of organ systems, Wnt1 has recently been linked to the development of several neurodegenerative disorders, none being of greater significance than Alzheimer's disease. We therefore examined the ability of Wnt1 to oversee vital pathways responsible for cell survival during β-amyloid (Aβ 1-42 )exposure. Here we show that Wnt1 is critical for protection in the SH-SY5Y neuronal cell line against genomic DNA degradation, membrane phosphatidylserine (PS) exposure, and microglial activation, since these neuroprotective attributes of Wnt1 are lost during gene silencing of Wnt1 protein expression. Intimately tied to Wnt1 protection is the presence and activation of Akt1. Pharmacological inhibition of the PI 3-K pathway or gene silencing of Akt1 expression can abrogate the protective capacity of Wnt1. Closely aligned with Wnt1 and Akt1 are the integrated canonical pathways of synthase kinase-3β (GSK-3β) and β-catenin. Through Akt1 dependent pathways, Wnt1 phosphorylates GSK-3β and maintains β-catenin integrity to insure its translocation from the cytoplasm to the nucleus to block apoptosis. Our work outlines a highly novel role for Wnt1 and its integration with Akt1, GSK-3β, and β-catenin to foster neuronal cell survival and repress inflammatory microglial activation that can identify new avenues of therapy against neurodegenerative disorders.

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“…Reduction in tissue injury through Wnt signaling during pressure overload cardiac hypertrophy is linked to Akt activation [182] and the benefits of cardiac ischemic preconditioning appear to rely upon Akt [181]. In the neuronal system, Wnt over-expression can independently increase the phosphorylation and the activation of Akt to promote neuronal protection [149]. Inhibition of the phosphatidylinositol 3-kinase (PI 3-K) pathway or gene silencing of Akt expression prevents Wnt from blocking apoptotic injury and microglial activation [149].…”

“…In the neuronal system, Wnt over-expression can independently increase the phosphorylation and the activation of Akt to promote neuronal protection [149]. Inhibition of the phosphatidylinositol 3-kinase (PI 3-K) pathway or gene silencing of Akt expression prevents Wnt from blocking apoptotic injury and microglial activation [149].…”

“…In mature tissues, the Wnt-FZD pathway is involved in the self-renewal of pluripotent embryonic stem cells [169], bone formation [170], and may be responsible for the maintenance of many normal tissues [171][172][173][174] as well as cellular senescence [175]. Other studies have revealed that dysfunction of the Wnt-FZD pathway can lead to neurodegenerative disorders, such as Alzheimer's disease [149,[176][177][178][179] and heart failure [44,[180][181][182].…”

“…Interestingly, Wnt also can protect cells during oxidative stress [152] and other toxic injuries such as β-amyloid toxicity [152] through the modulation of glycogen synthase kinase-3β (GSK-3β) and β-catenin [149]. Inhibition of GSK-3β activity can increase cell survival during oxidative stress and, as a result, GSK-3β is considered to be a therapeutic target for some neurodegenerative disorders [10,179,199,200].…”

“…Wnt proteins are secreted cysteine-rich glycosylated proteins that can be dependent upon Akt signaling and oversee embryonic cell proliferation, differentiation, survival, and death [44,[149][150][151]. More than eighty target genes of Wnt signaling pathways have been demonstrated in human, mouse, Drosophila, Xenopus, and zebrafish.…”