Genetic background modifies neurodegeneration and neuroinflammation driven by misfolded human tau protein in rat model of tauopathy: implication for immunomodulatory approach to Alzheimer's disease

Stozicka, Zuzana; Žilka, Norbert; Novák, Petr; Kováčech, Branislav; Bugos, Ondrej; Novák, Michal

doi:10.1186/1742-2094-7-64

Cited by 40 publications

(54 citation statements)

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“…Substantial basic biomolecular and clinical studies suggest that neuroinflammation, with overexpression of cytokines and inflammatory mediators, is centrally involved in the pathogenesis of AD (124)(125)(126). One notable feature of the pathophysiology of the brains of patients with AD is that oxidative stress can induce an active, self-perpetuating cycle of chronic neuroinflammation, which further promotes oxidative stress and contributes to irreversible neuronal dysfunction and cell death (127).…”

Section: Activated Mao Contributes To the Formation Of Amyloid Plaquesmentioning

confidence: 99%

Monoamine oxidase inhibitors: Promising therapeutic agents for Alzheimer’s disease (Review)

Cai

2014

Molecular Medicine Reports

165

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Abstract. Activated monoamine oxidase (MAO) has a critical role in the pathogenesis of Alzheimer's disease (AD), including the formation of amyloid plaques from amyloid β peptide (Aβ) production and accumulation, formation of neurofibrillary tangles, and cognitive impairment via the destruction of cholinergic neurons and disorder of the cholinergic system. Several studies have indicated that MAO inhibitors improve cognitive deficits and reverse Aβ pathology by modulating proteolytic cleavage of amyloid precursor protein and decreasing Aβ protein fragments. Thus, MAO inhibitors may be considered as promising therapeutic agents for AD.

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Section: Activated Mao Contributes To the Formation Of Amyloid Plaquesmentioning

confidence: 99%

Monoamine oxidase inhibitors: Promising therapeutic agents for Alzheimer’s disease (Review)

Cai

2014

Molecular Medicine Reports

165

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“…The absence of pathology may potentially be a consequence of the insertion of a mutant analogue (P290L rather than P301L) into the murine Tau gene. Beyond these concerns, cross-model comparison is further complicated by variable background strains, which influence phenotypes of emotionality (Podhorna and Brown, 2002;Salomons et al, 2012) cognition (Brooks et al, 2005, and potentially key features such as phosphorylation, inflammation and neurodegeneration (Stozicka et al, 2010;Bailey et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Mutant Tau knock-in mice display frontotemporal dementia relevant behaviour and histopathology

Koss

Robinson

Drever

et al. 2016

Neurobiology of Disease

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Models of Tau pathology related to frontotemporal dementia (FTD) are essential to determine underlying neurodegenerative pathologies and resulting Tauopathy relevant behavioural changes. However, existing models are often limited in their translational value due to Tau overexpression, and the frequent occurrence of motor deficits which prevent comprehensive behavioural assessments. In order to address these limitations, a forebrain-specific (CaMKIIα promoter), human mutated Tau (hTauP301L+R406W) knock-in mouse was generated out of the previously characterised PLB1Triple mouse, and named PLB2Tau. After confirmation of an additional hTau species (~60 kDa) in forebrain samples, we identified age-dependent progressive Tau phosphorylation which coincided with the emergence of FTD relevant behavioural traits. In line with the noncognitive symptomatology of FTD, PLB2Tau mice demonstrated early emerging (~ 6 months) phenotypes of heightened anxiety in the elevated plus maze, depressive/apathetic behaviour in a sucrose preference test and generally reduced exploratory activity in the absence of motor impairments. Investigations of cognitive performance indicated prominent dysfunctions in semantic memory, as assessed by social transmission of food preference, and in behavioural flexibility during spatial reversal learning in a homecage corner-learning task. Spatial learning was only mildly affected and task-specific, with impairments at 12-month of age in the corner learning but not in the water maze task. Electroencephalographic (EEG) investigations indicated a vigilance-stage specific loss of alpha power during wakefulness at both parietal and prefrontal recording sites, and site-specific EEG changes during nonrapid eye movement sleep (prefrontal) and rapid eye movement sleep (parietal). Further investigation of hippocampal electrophysiology conducted in slice preparations indicated a modest reduction in efficacy of synaptic transmission in the absence of altered synaptic plasticity. Together, our data demonstrate that the transgenic PLB2Tau mouse model presents with striking behavioural and physiological face validity relevant for FTD, driven by the low level expression of mutant FTD hTau. AbstractModels of Tau pathology related to frontotemporal dementia (FTD) are essential to determine underlying neurodegenerative pathologies and resulting Tauopathy relevant behavioural changes. However, existing models are often limited in their translational value due to Tau overexpression, and the frequent occurrence of motor deficits which prevent comprehensive behavioural assessments. In order to address these limitations, a forebrain-specific (CaMKIIα promoter), human mutated Tau (hTau P301L+R406W ) knock-in mouse was generated out of the previously characterised PLB1 Triple mouse, and named PLB2 Tau . After confirmation of an additional hTau species (~60 kDa) in forebrain samples, we identified age-dependent progressive Tau phosphorylation which was coincided with the emergence of FTD relevant behavioural traits. In...

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“…Microglial activation also correlates with t burden in other human tauopathies such as tangle-predominant dementia, Guamanian parkinsonism-dementia, progressive supranuclear palsy, and corticobasal degeneration (33)(34)(35). Moreover, activation of microglia linked to t deposition has been documented in mice transgenic for human mutant t protein P301S (36,37), R406W (38), or P301L (39) and in transgenic rats expressing human nonmutated truncated t (40,41). Notwithstanding these findings, the mechanism underlying t-mediated microglial activation has not been identified.…”

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confidence: 99%

Misfolded Truncated Protein τ Induces Innate Immune Response via MAPK Pathway

Kováč

Žilka

Kazmerova

et al. 2011

The Journal of Immunology

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Neuroinflammation plays a key role in the pathogenesis of Alzheimer’s disease and related tauopathies. We have previously shown that expression of nonmutated human truncated τ (151-391, 4R), derived from sporadic Alzheimer's disease, induced neurofibrillary degeneration accompanied by microglial and astroglial activation in the brain of transgenic rats. The aim of the current study was to determine the molecular mechanism underlying innate immune response induced by misfolded truncated τ. We found that purified recombinant truncated τ induced morphological transformation of microglia from resting into the reactive phenotype. Simultaneously, truncated τ caused the release of NO, proinflammatory cytokines (IL-1β, IL-6, TNF-α), and tissue inhibitor of metalloproteinase-1 from the mixed glial cultures. Notably, when the pure microglial culture was activated with truncated τ, it displayed significantly higher levels of the proinflammatory cytokines, suggesting a key role of microglia in the τ-mediated inflammatory response. Molecular analysis showed that truncated τ increased the mRNA levels of three MAPKs (JNK, ERK1, p38β) and transcription factors AP-1 and NF-κB that ultimately resulted in enhanced mRNA expression of IL-1β, IL-6, TNF-α, and NO. Our results showed for the first time, to our knowledge, that misfolded truncated protein τ is able to induce innate immune response via a MAPK pathway. Consequently, we suggest that misfolded truncated protein τ represents a viable target for immunotherapy of Alzheimer’s disease.

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Genetic background modifies neurodegeneration and neuroinflammation driven by misfolded human tau protein in rat model of tauopathy: implication for immunomodulatory approach to Alzheimer's disease

Cited by 40 publications

References 54 publications

Monoamine oxidase inhibitors: Promising therapeutic agents for Alzheimer’s disease (Review)

Monoamine oxidase inhibitors: Promising therapeutic agents for Alzheimer’s disease (Review)

Mutant Tau knock-in mice display frontotemporal dementia relevant behaviour and histopathology

Misfolded Truncated Protein τ Induces Innate Immune Response via MAPK Pathway

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