Activation of glycogen synthase kinase-3 induces Alzheimer-like tau hyperphosphorylation in rat hippocampus slices in culture

Li, X.; Lu, Fanghong; Tian, Qing; Yang, Yan; Wang, Q.; Wang, J.-Z.

doi:10.1007/s00702-005-0303-7

Cited by 61 publications

(56 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…To date, several studies have shown that the Wnt signaling components b-catenin and GSK3b form multiprotein complexes with the early-onset familial AD-linked presenilin proteins (Zhou et al, 1997;Takashima et al, 1998b;Kang et al, 2002). 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).…”

Section: Alzheimer's Disease Apolipoprotein E and Wnt Signalingmentioning

confidence: 99%

The ups and downs of Wnt signaling in prevalent neurological disorders

2006

View full text Add to dashboard Cite

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.

show abstract

Section: Alzheimer's Disease Apolipoprotein E and Wnt Signalingmentioning

confidence: 99%

The ups and downs of Wnt signaling in prevalent neurological disorders

2006

View full text Add to dashboard Cite

show abstract

“…Tau hyperphosphorylation at site Ser 199 is directly linked with AD. 32) Our study found that tau phosphorylation increased in a high glucose environment, but that ghrelin attenuated this change. Ghrelin improved insulin-stimulated neuronal tau phosphorylation (Fig.…”

Section: Discussionmentioning

confidence: 45%

Ghrelin Modulates Insulin Sensitivity and Tau Phosphorylation in High Glucose-Induced Hippocampal Neurons

Chen

Cao

et al. 2010

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

Ghrelin is a 28-amino acid brain-gut peptide isolated from rat and human stomach, which is the first endogenous ligand of growth hormone secretagogue receptor 1a (GHSR-1a). 1)Ghrelin exists in the body in two forms: n-octanoyl-ghrelin (ghrelin), which contains an n-octanoyl modification at serine-3 and forms ghrelin's mark structure, and unacylated ghrelin (des-ghrelin). Acylated ghrelin is required for GHSR1a, whereas the unacylated form does not bind to GHSR1a. 2,3) GHSR-1a is widely expressed in peripheral and central tissues, including the hypothalamus, hippocampus and cortex. 4,5) Although ghrelin is predominantly produced in the X/A-like cells of the stomach in rodents, it is expressed in many other peripheral tissues and in the central nervous system 6) ; therefore, ghrelin has extensive biological action, such as stimulating food intake, regulating the secretion of gastric acid, gastric motility, 7) simulating insulin secretion, 8) modulating cell proliferation and survival, 5,9,10) immunological regulation and an anti-inflammatory effect, 11) as well as improving learning and memory, 12) the impairment of which is an Alzheimer's Disease (AD) phaenotype.AD, a devastating neurodegenerative condition, has become the fourth most fatal disease, following heart disease, cancer and stroke. AD has two pathological hallmarks: bamyloid (Ab) deposition and neurofibrillary tangles, which contain hyperphosphorylated tau protein and have a positive relation with cognitive dysfunction. In the process of tau phosphorylation, glycogen synthase kinase-3b (GSK-3b) plays an important role. Schubert demonstrated that disturbance of the insulin signaling system results in phosphorylation, whereas phosphatidylinositol 3-kinase (PI3-K)/Akt signaling pathway dysfunction, which causes GSK-3b activity increase and leads to tau hyperphosphorylation. 13) Recently, some studies have indicated that AD is related to a brain insulin-resistant state that results in glucose utilization abnormalities.14) However, insulin resistance is a critical mechanism associated with type 2 diabetes and AD. Diabetic patients with insulin resistant type 2 diabetes have a 30-65% increased risk for developing AD. Type 2 diabetes is an independent risk factor for the disease. De la Monte and Wands indicated that Alzheimer's Disease could be a "type 3 diabetes." 15) Hyperglycemia, a fundamental biochemistry characteristic in diabetics, has an important role in diabetes. Hyperglycemia in type 2 diabetes is not only a secondary manifestation of insulin resistance, but could also be responsible for directly inducing insulin resistance in the target tissue. 16)However, whether a neuron is an insulin-sensitive cell is still a matter of controversy. [17][18][19] Studies have shown that hyperglycemia is a primary cause of nervous system impairment. 20) Evidence indicates that ghrelin may modulate insulin sensitivity, stimulate insulin-induced glucose uptake, 21) and modulate memory.12) Therefore, we hypothesized that ghrelin may promote hippocampal neuronal glu...

show abstract

“…Much evidence has suggested that GSK-3β is physically complexed with tau in the brain and phosphorylates tau in vitro and in vivo [14,15], and plays an important role on the phosphorylation of tau through the activation of phosphatidylinositol 3-kinase (PI3K) [16,17]. To clarify the role of leptin signaling on the activation of Akt and GSK-3β, we determined the effects of LA on the phosphorylation of Akt at ser-473 site and GSK-3β at ser-9 site in rat primary cultured cortical neurons.…”

Section: Effect Of Leptin Signaling On Geniposide-regulated Gsk-3β Anmentioning

confidence: 99%

Leptin signaling plays a critical role in the geniposide-induced decrease of tau phosphorylation

Liu

Zhang

et al. 2015

ABBS

View full text Add to dashboard Cite

We have previously demonstrated that geniposide attenuates the production of Aβ 1-42 both in vitro and in vivo via enhancing leptin receptor signaling. But the role played by geniposide in the phosphorylation of tau and its underlying molecular mechanisms remain unclear. In this study, we investigated the effect of geniposide on the phosphorylation of tau and the role of leptin signaling in this process. Our data suggested that, accompanied by the up-regulation of leptin receptor expression, geniposide significantly decreased the phosphorylation of tau in rat primary cultured cortical neurons and in APP/PS1 transgenic mice, and this geniposide-induced decrease of tau phosphorylation could be prevented by leptin antagonist (LA). Furthermore, LA also prevented the phosphorylation of Akt at Ser-473 site and GSK-3β at Ser-9 site induced by geniposide. All these results indicate that geniposide may regulate tau phosphorylation through leptin signaling, and geniposide may be a promising therapeutic compound for the treatment of Alzheimer's disease in the future.

show abstract

Activation of glycogen synthase kinase-3 induces Alzheimer-like tau hyperphosphorylation in rat hippocampus slices in culture

Cited by 61 publications

References 32 publications

The ups and downs of Wnt signaling in prevalent neurological disorders

The ups and downs of Wnt signaling in prevalent neurological disorders

Ghrelin Modulates Insulin Sensitivity and Tau Phosphorylation in High Glucose-Induced Hippocampal Neurons

Leptin signaling plays a critical role in the geniposide-induced decrease of tau phosphorylation

Contact Info

Product

Resources

About