Inhibition of Glycogen Synthase Kinase-3 Ameliorates β-Amyloid Pathology and Restores Lysosomal Acidification and Mammalian Target of Rapamycin Activity in the Alzheimer Disease Mouse Model

Avrahami, Limor; Farfara, Dorit; Shaham-Kol, Maya; Vassar, Robert; Frenkel, Dan; Eldar-Finkelman, Hagit

doi:10.1074/jbc.m112.409250

Cited by 214 publications

(176 citation statements)

References 83 publications

(109 reference statements)

Supporting

Mentioning

167

Contrasting

Order By: Relevance

“…23 In an AD model, a substrate competitive GSK3 inhibitor, L803-mts, restored the activity of mTOR, inhibited autophagy and ameliorated the Alzheimer's-like pathology. 73 In AβPP swe / PS1 A246E mice, lithium treatment upregulated the inactivated form of phosphorylated GSK3β(S9) and prevented autophagy. 49 These studies indicate that GSK3β is rather an autophagy-positive regulator by upregulating the mTOR pathway.…”

Section: Controversiesmentioning

confidence: 99%

Lithium and Autophagy

Motoi

Shimada

Ishiguro

et al. 2014

ACS Chem. Neurosci.

130

View full text Add to dashboard Cite

Lithium, a drug used to treat bipolar disorders, has a variety of neuroprotective mechanisms, including autophagy regulation, in various neuropsychiatric conditions. In neurodegenerative diseases, lithium enhances degradation of aggregate-prone proteins, including mutated huntingtin, phosphorylated tau, and α-synuclein, and causes damaged mitochondria to degrade, while in a mouse model of cerebral ischemia and Alzheimer's disease autophagy downregulation by lithium is observed. The signaling pathway of lithium as an autophagy enhancer might be associated with the mammalian target of rapamycin (mTOR)-independent pathway, which is involved in myoinositol-1,4,5-trisphosphate (IP 3 ) in Huntington's disease and Parkinson's disease. However, the mTOR-dependent pathway might be involved in inhibiting glycogen synthase kinase-3β (GSK3β) in other diseases. Lithium's autophagy-enhancing property may contribute to the therapeutic benefit of patients with neuropsychiatric disorders.

show abstract

Section: Controversiesmentioning

confidence: 99%

Lithium and Autophagy

Motoi

Shimada

Ishiguro

et al. 2014

ACS Chem. Neurosci.

130

View full text Add to dashboard Cite

show abstract

“…62 Briefly, cells were resuspended in a hypotonic buffer (10 mM KCl, 30 mM Tris, pH 7.5, 5 mM MgOAc, 1 mM b-mercaptoethanol) and dissociated by piston strokes. Homogenates were centrifuged at 1,000 X g to precipitate the nuclei, then the supernatant fractions were collected and centrifuged at 100,000 X g for 1 h at 4 C.…”

Section: Partial Purification Of Lysosomesmentioning

confidence: 99%

Insulin-degrading enzyme secretion from astrocytes is mediated by an autophagy-based unconventional secretory pathway in Alzheimer disease

et al. 2016

View full text Add to dashboard Cite

The secretion of proteins that lack a signal sequence to the extracellular milieu is regulated by their transition through the unconventional secretory pathway. IDE (insulin-degrading enzyme) is one of the major proteases of amyloid beta peptide (Ab), a presumed causative molecule in Alzheimer disease (AD) pathogenesis. IDE acts in the extracellular space despite having no signal sequence, but the underlying mechanism of IDE secretion extracellularly is still unknown. In this study, we found that IDE levels were reduced in the cerebrospinal fluid (CSF) of patients with AD and in pathology-bearing AD-model mice. Since astrocytes are the main cell types for IDE secretion, astrocytes were treated with Ab. Ab increased the IDE levels in a time-and concentration-dependent manner. Moreover, IDE secretion was associated with an autophagy-based unconventional secretory pathway, and depended on the activity of RAB8A and GORASP (Golgi reassembly stacking protein). Finally, mice with global haploinsufficiency of an essential autophagy gene, showed decreased IDE levels in the CSF in response to an intracerebroventricular (i.c.v.) injection of Ab. These results indicate that IDE is secreted from astrocytes through an autophagy-based unconventional secretory pathway in AD conditions, and that the regulation of autophagy is a potential therapeutic target in addressing Ab pathology.

show abstract

“…Research has found wildtype PS-1, but not mutation forms, is crucial for acidification of lysosome by regulating distribution of v-ATPase, and thus contributes to autophagy degradation in a gamma-secretase independent way [38]. Meanwhile, hyper-activation of Glycogen synthase kinase-3 (GSK-3), which is also a high-risk factor for AD, could interfere lysosome acidification via similar mechanism as PS-1 [39]. These investigations suggested that autophagy malfunction is involved in FAD, while the mechanism(s) is still not clear.…”

Section: Autophagy Malfunction In Admentioning

confidence: 99%

The role of autophagy in Alzheimer's disease

Li¹,

Sun²

2017

J Syst Integr Neurosci

View full text Add to dashboard Cite

Autophagy is a key pathway to clear cellular abnormal protein aggregates, and is essential for protein homeostasis and neuronal health. Several studies have shown autophagy deficits may occur in early stage of Alzheimer's disease (AD). Regarding to Alzheimer's disease, autophagy itself plays an important role in generation and metabolism of β-amyloid (Aβ), assembling of tau and thus its dysfunction may lead to the progress or aggravate of AD. By considering all published evidences, autophagy may be considered as a new target for developing AD targeted drugs. So far, a number of mammalian target of rapamycin (mTOR)-dependent and independent autophagy modulators have been identified to have positive effects in AD treatment. In this review, we summarized the latest progress supporting the role for autophagy deficits in AD, and the potential therapeutic effects of autophagy modulators in AD.

show abstract

Inhibition of Glycogen Synthase Kinase-3 Ameliorates β-Amyloid Pathology and Restores Lysosomal Acidification and Mammalian Target of Rapamycin Activity in the Alzheimer Disease Mouse Model

Cited by 214 publications

References 83 publications

Lithium and Autophagy

Lithium and Autophagy

Insulin-degrading enzyme secretion from astrocytes is mediated by an autophagy-based unconventional secretory pathway in Alzheimer disease

The role of autophagy in Alzheimer's disease

Contact Info

Product

Resources

About