Hyperphosphorylation of Tau at Ser396 occurs in the much earlier stage than appearance of learning and memory disorders in 5XFAD mice

Kanno, Takeshi; Tsuchiya, Ayako; Nishizaki, Tomoyuki

doi:10.1016/j.bbr.2014.08.034

Cited by 55 publications

(34 citation statements)

References 14 publications

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“…We also found there was no amyloid pathology at 1 month old in 5XFAD mice. In addition, the concentrations of synaptophysin in the whole brain decrease from 4 months and Ser396 tau phosphorylation is significantly higher than wild‐type mice at age ranging from 2 to 6 months in 5XFAD mice . However, we found that spatial memory retrieval is impaired in one‐month‐old mice prior to the emergence of classical pathological markers for AD (amyloid deposition, tau pathologies, and degeneration of synapses).…”

Section: Discussionsupporting

confidence: 90%

“…In addition, the concentrations of synaptophysin in the whole brain decrease from 4 months 29 and Ser396 tau phosphorylation is significantly higher than wild-type mice at age ranging from 2 to 6 months in 5XFAD mice. 34 However, we found that spatial memory retrieval is impaired in one-month-old mice prior to the emergence of classical pathological markers for AD (amyloid deposition, tau pathologies, and degeneration of synapses). Impairment of learning ability in acquisition trials emerged from 3 months of age, which was later than memorial impairments.…”

Section: Discussionmentioning

confidence: 69%

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LINGO‐1 antibody ameliorates myelin impairment and spatial memory deficits in the early stage of 5XFAD mice

Xiang

et al. 2018

CNS Neurosci Ther

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Our results demonstrated that myelin injury was an early event in 5XFAD mice even prior to emergence of deposition of Aβ. Intervention with the LINGO-1 antibody could attenuate impaired spatial memory deficits by remyelination, which suggested that myelin injury was involved in spatial memory deficits and remyelination may be a potential therapeutic strategy in early stage of AD or mild cognitive impairments.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 69%

LINGO‐1 antibody ameliorates myelin impairment and spatial memory deficits in the early stage of 5XFAD mice

Xiang

et al. 2018

CNS Neurosci Ther

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“…To assess the role of gut microbiota alteration in AD pathogenesis, we used the 5XFAD transgenic (Tg) mouse model, which is widely used in AD study for faithfully recapitulating AD-associated pathological features including the severely accelerated cognitive impairment, amyloid deposition in the 2 nd postnatal month, synaptic degeneration in the 4 th postnatal month, and behavioural changes in the 6 th month. [20][21][22][23] Consistent with these reports, [24][25][26][27] we observed rapid accumulation of Aβ plaque deposition in the cortex and hippocampus beginning from the 3 rd postnatal month in Tg mice compared to the age-paired wild-type (WT) mice (Supplementary information, Fig. S1a).…”

Section: Ad Progression Is Associated With the Alteration Of Gut Micrsupporting

confidence: 88%

Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer’s disease progression

Wang¹,

et al. 2019

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Recently, increasing evidence has suggested the association between gut dysbiosis and Alzheimer's disease (AD) progression, yet the role of gut microbiota in AD pathogenesis remains obscure. Herein, we provide a potential mechanistic link between gut microbiota dysbiosis and neuroinflammation in AD progression. Using AD mouse models, we discovered that, during AD progression, the alteration of gut microbiota composition leads to the peripheral accumulation of phenylalanine and isoleucine, which stimulates the differentiation and proliferation of pro-inflammatory T helper 1 (Th1) cells. The brain-infiltrated peripheral Th1 immune cells are associated with the M1 microglia activation, contributing to AD-associated neuroinflammation. Importantly, the elevation of phenylalanine and isoleucine concentrations and the increase of Th1 cell frequency in the blood were also observed in two small independent cohorts of patients with mild cognitive impairment (MCI) due to AD. Furthermore, GV-971, a sodium oligomannate that has demonstrated solid and consistent cognition improvement in a phase 3 clinical trial in China, suppresses gut dysbiosis and the associated phenylalanine/isoleucine accumulation, harnesses neuroinflammation and reverses the cognition impairment. Together, our findings highlight the role of gut dysbiosis-promoted neuroinflammation in AD progression and suggest a novel strategy for AD therapy by remodelling the gut microbiota.

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“…Figure 4. C, D), however; due to weak correlation with AD dementia in 5XFAD mice, co-localization with Tau signal is likely less reliable than that with Aβ plaques [31]. Our ndings suggest that TXNIP is early expressed in the hippocampus of 5XFAD mice.…”

Section: Txnip Expression Is Co-localized With Aβ Plaques In the Cortmentioning

confidence: 62%

TXNIP regulates age-associated neuroinflammation: Implication in Alzheimer’s disease

Ismael¹,

Nasoohi²,

Yoo³

et al. 2020

Preprint

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Background Immune system hypersensitivity with aging is believed to contribute to mental frailty in elderlies. This is postulated to arise from accumulation of oxidative molecular patterns. Solid evidences delineates thioredoxin interacting protein (TXNIP), an inducible protein involved in oxidative stress, is essential for NOD-like receptor pyrin domain containing-3 (NLRP3)-inflammasome activation which intimately connects “inflammaging” to senile cognitive decline. This study aims to fundamentally explore the plausible involvement of TXNIP/NLRP3 inflammasome pathway in senile dementia and the typical Alzhemier’s disease. Methods In experimental studies cerebral samples from gender-matched mice were compared for TXNIP/NLRP3 inflammasome activation and klotho depletion, through immunoblotting and immunostaining in different life span points. In aged males, genetic or pharmacological ablation of TXNIP were then used to determine effects on cognitive decline and sensorimotor frailty in morris water maze, novel object recognition test and gait control analysis. Immunoblotting/staining experiments were also performed on human postmortem aged hippocampal specimens and 5XFAD transgenic mice, to ultimately address Alzheimer’s disease (AD) as the most age related dementia. Results According to our preclinical studies, cerebral TXNIP was significantly upregulated in aged animals, paralleled by the NLRP3-inflammasome over-activity in both sexes, and closely associated klotho depletion in aged males. TXNIP knock-out reversed age-related NLRP3-hyperactivity and enhanced thioredoxin (TRX) levels in aged brains. Further, pharmacological TXNIP inhibition replicated the TXNIP/NLRP3-inflammasome downregulation in aged animals, with FOXO-1 and mTOR upregulation. These alterations concurred with substantial improvements in both cognitive and sensorimotor abilities. Moreover, our immunostaining shows a significant increase of TXNIP in transgenic 5XFAD mice brain and TXNIP/NLRP3-inflammasome activity in AD human postmortem hippocampal specimens, in proximity of p-tau tangles and β-amyloid plaques. Conclusion Together, these findings substantiate the pivotal role of TXNIP to drive inflammging in parallel with klotho depletion and functional decline. TXNIP co-localization with hallmarks of AD pathology is further supportive of potential mechanistic links between TXNIP and AD. Unraveling new information on upstream pathways, these data support modulating thioredoxin system as a potential approach to decelerate senile frailty.

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Hyperphosphorylation of Tau at Ser396 occurs in the much earlier stage than appearance of learning and memory disorders in 5XFAD mice

Cited by 55 publications

References 14 publications

LINGO‐1 antibody ameliorates myelin impairment and spatial memory deficits in the early stage of 5XFAD mice

LINGO‐1 antibody ameliorates myelin impairment and spatial memory deficits in the early stage of 5XFAD mice

Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer’s disease progression

TXNIP regulates age-associated neuroinflammation: Implication in Alzheimer’s disease

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