STAT1 Negatively Regulates Spatial Memory Formation and Mediates the Memory-Impairing Effect of Aβ

Hsu, Wei‐Lun; Ma, Yun‐Li; Hsieh, Ding-You; Liu, Yen-Chen; Lee, Eminy H.Y.

doi:10.1038/npp.2013.263

Cited by 42 publications

(35 citation statements)

References 33 publications

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“…This is of particular importance, since STAT1 has recently been linked to cognitive function. Mice lacking STAT1 show enhanced memory performance and are resistant to memory impairment induced by Aβ peptides injected into the hippocampus (96).…”

Section: Discussionmentioning

confidence: 99%

HDAC inhibitor–dependent transcriptome and memory reinstatement in cognitive decline models

Benito

Urbanke

Ramachandran

et al. 2015

Journal of Clinical Investigation

158

137

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Section: Discussionmentioning

confidence: 99%

HDAC inhibitor–dependent transcriptome and memory reinstatement in cognitive decline models

Benito

Urbanke

Ramachandran

et al. 2015

Journal of Clinical Investigation

158

137

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“…Herein, we focused on STAT1 which has been implicated in cognitive functions [28,29]. We demonstrated that overexpressing hTau remarkably increased the activation-dependent phosphorylation of STAT1 at Tyr701 (pY-STAT1) in both cell lysates (Fig 1C and D) and the nuclear fraction ( Fig 1E and F) with an enhanced nuclear translocation ( Fig 1G) and dimerization ( Fig 1H) of STAT1 measured by Western blotting and immunofluorescence imaging.…”

Section: Intracellular Htau Accumulation Induces Activation Of Stat1mentioning

confidence: 93%

Tau accumulation triggers STAT 1‐dependent memory deficits by suppressing NMDA receptor expression

Hong

Wang

et al. 2019

EMBO Reports

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Intracellular tau accumulation forming neurofibrillary tangles is hallmark pathology of Alzheimer's disease (AD), but how tau accumulation induces synapse impairment is elusive. By overexpressing human full‐length wild‐type tau (termed hTau) to mimic tau abnormality as seen in the brain of sporadic AD patients, we find that hTau accumulation activates JAK2 to phosphorylate STAT1 (signal transducer and activator of transcription 1) at Tyr701 leading to STAT1 dimerization, nuclear translocation, and its activation. STAT1 activation suppresses expression of N‐methyl‐D‐aspartate receptors (NMDARs) through direct binding to the specific GAS element of GluN1, GluN2A, and GluN2B promoters, while knockdown of STAT1 by AAV‐Cre in STAT1flox/flox mice or expressing dominant negative Y701F‐STAT1 efficiently rescues hTau‐induced suppression of NMDAR expression with amelioration of synaptic functions and memory performance. These findings indicate that hTau accumulation impairs synaptic plasticity through JAK2/STAT1‐induced suppression of NMDAR expression, revealing a novel mechanism for hTau‐associated synapse and memory deficits.

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“…9, 10 More recently, we have found that A β induces the expression of activated signal transducer and activator of transcription-1 (STAT1) and A β induction of STAT1 mediates the memory-impairing effect of A β . 11 On the other hand, it is conceivable that when A β produces its toxicity, neurons would develop defense mechanisms to cope with A β toxicity. For example, a non-amyloidogenic neurotrophic peptide sAPP α is shown to activate neuroprotectin D1 and promote cell survival.…”

mentioning

confidence: 99%

Epigenetic regulation of HDAC1 SUMOylation as an endogenous neuroprotection against Aβ toxicity in a mouse model of Alzheimer’s disease

Tao

Hsu

et al. 2017

Cell Death Differ

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Amyloid-β (Aβ) produces neurotoxicity in the brain and causes neuronal death, but the endogenous defense mechanism that is activated on Aβ insult is less well known. Here we found that acute Aβ increases the expression of PIAS1 and Mcl-1 via activation of MAPK/ERK, and Aβ induction of PIAS1 enhances HDAC1 SUMOylation in rat hippocampus. Knockdown of PIAS1 decreases endogenous HDAC1 SUMOylation and blocks Aβ induction of Mcl-1. Sumoylated HDAC1 reduces it association with CREB, increases CREB binding to the Mcl-1 promoter and mediates Aβ induction of Mcl-1 expression. Transduction of SUMO-modified lenti-HDAC1 vector to the hippocampus of APP/PS1 mice rescues spatial learning and memory deficit and long-term potentiation impairment in APP/PS1 mice. It also reduces the amount of amyloid plaque and the number of apoptotic cells in CA1 area of APP/PS1 mice. Meanwhile, HDAC1 SUMOylation decreases HDAC1 binding to the neprilysin promoter. These results together reveal an important role of HDAC1 SUMOylation as a naturally occurring defense mechanism protecting against Aβ toxicity and provide an alternative therapeutic strategy against AD. Cell Death and Differentiation (2017) 24, 597-614; doi:10.1038/cdd.2016.161; published online 10 February 2017The brain of Alzheimer's disease (AD) patient is characterized by the accumulation of senile plaques, and amyloid-β peptides (Aβ 1-40 and Aβ 1-42 ) are the major components of these senile plaques. Aβ is known to cause lipid peroxidation, free radical production, caspase 3 activation and DNA damage that eventually lead to neuronal death. [1][2][3] In addition, the Aβ peptide or overexpression of Aβ causes cognitive impairment in animals. 4,5 This cognitive impairment correlates with amyloid plaque formation 4,6 or precedes it. 7,8 Further, naturally secreted Aβ or the Aβ peptide also inhibits longterm potentiation (LTP) in the hippocampus in vivo and disrupts synaptic and network function. 9,10 More recently, we have found that Aβ induces the expression of activated signal transducer and activator of transcription-1 (STAT1) and Aβ induction of STAT1 mediates the memory-impairing effect of Aβ. 11 On the other hand, it is conceivable that when Aβ produces its toxicity, neurons would develop defense mechanisms to cope with Aβ toxicity. For example, a nonamyloidogenic neurotrophic peptide sAPPα is shown to activate neuroprotectin D1 and promote cell survival. 12 In addition, we have found that Aβ activates the MAPK/ERK-SGK (serum-and glucocorticoid-inducible kinase) signaling pathway for neuroprotection against Aβ insult. 13 However, with the role and mechanism of Aβ-induced toxicity been studied extensively, the endogenous protection mechanism induced by Aβ is less well known.Histone acetylation is one kind of epigenetic regulations that has an important role in a wide range of brain functions and disorders, and histone deacetylases (HDACs) regulate the homeostasis of histone acetylation. The HDAC family contains 18 HDAC proteins that belong to different classifications. Inhibitio...

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STAT1 Negatively Regulates Spatial Memory Formation and Mediates the Memory-Impairing Effect of Aβ

Cited by 42 publications

References 33 publications

HDAC inhibitor–dependent transcriptome and memory reinstatement in cognitive decline models

HDAC inhibitor–dependent transcriptome and memory reinstatement in cognitive decline models

Tau accumulation triggers STAT 1‐dependent memory deficits by suppressing NMDA receptor expression

Epigenetic regulation of HDAC1 SUMOylation as an endogenous neuroprotection against Aβ toxicity in a mouse model of Alzheimer’s disease

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