GSK-3α regulates production of Alzheimer's disease amyloid-β peptides

Phiel, Christopher J.; Wilson, Christopher; Lee, Virginia M.‐Y.; Klein, Peter S.

doi:10.1038/nature01640

Cited by 1,106 publications

(930 citation statements)

References 30 publications

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“…Inhibition of GSK-3β activity through its phosphorylation can prevent apoptotic cell death and potentially block amyloid toxicity and neurodegenerative disease [10,41,42]. We demonstrate that neuronal protection by Wnt1 may require integration of the GSK-3β pathway that involves phosphorylation and inhibition of GSK-3β activity via Akt1.…”

Section: Discussionmentioning

confidence: 82%

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

Chong

Maiese

2007

Cellular Signalling

164

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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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Section: Discussionmentioning

confidence: 82%

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

Chong

Maiese

2007

Cellular Signalling

164

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“…b-Catenin levels are significantly reduced in AD individuals bearing presenilin mutations (Zhang et al, 1998) and active GSK3b accumulates in vivo in AD brains (Pei et al, 1999), where it has a key role in the hyperphosphorylation of the microtubule-associated protein tau (Hanger et al, 1992;Lovestone et al, 1994;Lucas et al, 2001;Sato et al, 2002;Li et al, 2006). Moreover, Wnt signaling may also have an essential role in the processing of the amyloid precursor protein (Mudher et al, 2001;Sun et al, 2002;Phiel et al, 2003), as well as in the neurotoxicity of its derivative the amyloid b-peptide (Ab) (Takashima et al, 1998a;Alvarez et al, 2002;De Ferrari et al, 2003;Alvarez et al, 2004;Caricasole et al, 2004). Remarkably, it has been reported that Ab neurotoxicity induces the expression of Dickkopf 1 (Dkk1) (Caricasole et al, 2004), which may further antagonize Wnt presentation to its complex receptor.…”

Section: Alzheimer's Disease Apolipoprotein E and Wnt Signalingmentioning

confidence: 99%

The ups and downs of Wnt signaling in prevalent neurological disorders

2006

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In order to function properly, the brain must be wired correctly during critical periods in early development. Mistakes in this process are hypothesized to occur in disorders like autism and schizophrenia. Later in life, signaling pathways are essential in maintaining proper communication between neuronal and non-neuronal cells, and disrupting this balance may result in disorders like Alzheimer's disease. The Wnt/b-catenin pathway has a well-established role in cancer. Here, we review recent evidence showing the involvement of Wnt/b-catenin signaling in neurodevelopment as well as in neurodegenerative diseases. We suggest that the onset/development of such pathological conditions may involve the additive effect of genetic variation within Wnt signaling components and of molecules that modulate the activity of this signaling cascade.

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“…Anti-amyloid activities include modulation of secretase activities via membrane "fluidity"/protein mobility changes or Akt > GSK regulation of ␥-secretase [25] and induction of anti-amyloidogenic transthyretin [26]. Like fish oil, DHA from algal sources can be safely taken as a supplement at high doses.…”

Section: Omega-3 Fatty Acidsmentioning

confidence: 99%

Prevention of Alzheimer's disease: Omega-3 fatty acid and phenolic anti-oxidant interventions

Cole

Lim

Yang

et al. 2005

Neurobiology of Aging

201

123

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Alzheimer's disease (AD) and cardiovascular disease (CVD) are syndromes of aging that share analogous lesions and risk factors, involving lipoproteins, oxidative damage and inflammation. Unlike in CVD, in AD, sensitive biomarkers are unknown, and high-risk groups are understudied. To identify potential prevention strategies in AD, we have focused on pre-clinical models (transgenic and amyloid infusion models), testing dietary/lifestyle factors strongly implicated in reducing risk in epidemiological studies. Initially, we reported the impact of non-steroidal anti-inflammatory drugs (NSAIDs), notably ibuprofen, which reduced amyloid accumulation, but suppressed few inflammatory markers and without reducing oxidative damage. Safety concerns with chronic NSAIDs led to a screen of alternative NSAIDs and identification of the phenolic anti-inflammatory/anti-oxidant compound curcumin, the yellow pigment in turmeric that we found targeted multiple AD pathogenic cascades. The dietary omega-3 fatty acid, docosahexaenoic acid (DHA), also limited amyloid, oxidative damage and synaptic and cognitive deficits in a transgenic mouse model. Both DHA and curcumin have favorable safety profiles, epidemiology and efficacy, and may exert general anti-aging benefits (anti-cancer and cardioprotective.)

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GSK-3α regulates production of Alzheimer's disease amyloid-β peptides

Cited by 1,106 publications

References 30 publications

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

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

The ups and downs of Wnt signaling in prevalent neurological disorders

Prevention of Alzheimer's disease: Omega-3 fatty acid and phenolic anti-oxidant interventions

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