Endoplasmic reticulum stress responses in mouse models of Alzheimer's disease: Overexpression paradigm versus knockin paradigm

Hashimoto, Shoko; Ishii, Ayano; Kamano, Naoko; Watamura, Naoto; Saito, Takashi; Ohshima, Toshio; Yokosuka, Makoto; Saido, Takaomi C.

doi:10.1074/jbc.m117.811315

Cited by 67 publications

(68 citation statements)

References 39 publications

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“…We measured the mRNA and protein level of several markers involved in the UPR branches in human from three different diseases related to tau pathology and found that tau pathology is not associated with UPR activation. This study utilizing human samples is consistent with a growing number of studies that do not report UPR in experimental models of chronic neurodegeneration [18,19].…”

Section: Introductionsupporting

confidence: 88%

“…The UPR involvement in tau-related pathology was previously questioned and investigated and of note, no indication of UPR activation was observed in the transgenic mouse model of tauopathy. No changes in the XBP-1 splicing or the level of p-eIF2a, BiP or CHOP was observed between tau P301S -expressing mice and wild type animals [18]. In our recent study, we confirmed the absence of UPR activation in the rTg4510 mouse model expressing tau P301L and we further expanded the UPR investigation to an in vitro model of tauopathy [19].…”

Section: Discussionsupporting

confidence: 54%

“…However, this concept has been called into question due to the fact that tau is a cytosolic protein that does not form aggregates in the ER compartment and thus it is unclear how tau misfolding would induce a UPR activation [11]. UPR induction has been investigated in transgenic mouse models of tauopathy with opposing results being reported [16][17][18]. We have previously used in vivo and in vitro pre-clinical models of tauopathy and found no indication of UPR activation in response to misfolded tau [19].…”

Section: Introductionmentioning

confidence: 99%

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Human tauopathies are not associated with an activated unfolded protein response

Pitera

Boche

et al. 2019

Preprint

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Tauopathies are the neurodegenerative diseases associated with the accumulation of misfolded tau protein. Despite many years of investigation, the mechanisms underpinning tau dependent proteinopathy remains to be elucidated. A protein quality control pathway within the endoplasmic reticulum (ER), called unfolded protein response (UPR), has been suggested as a possible response implicated in the misfolded tau-mediated neurodegeneration. However, the question arose: how does the cytosolic protein tau that does not enter the ER induce a response stemming from this compartment? In this study we investigated three different human tauopathies to establish whether these diseases are associated with the activation of UPR. We probed for the modulation of several reliable UPR markers in mRNA and proteins extracted from 20 brain samples from Alzheimer's disease (AD) patients, 11 from Pick's disease (PiD) and 10 from Progressive Supranuclear Palsy (PSP) patients coupled to equal numbers of age-matched non-demented controls. This showed that different markers of UPR are not changed in any of the human tauopathies investigated. Interestingly, UPR signatures were often observed in non-demented controls. These data from human tissue further support the emerging evidence that the accumulation of misfolded cytosolic tau does not drive a diseased associated activation of UPR.Acknowledgements Brain tissue was provided by the London Neurodegenerative Diseases Brain Bank (LNDBB), the South West Dementia Brain Bank (SWDBB) and the Oxford Brain Bank (OBB).

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Section: Introductionsupporting

confidence: 88%

Section: Discussionsupporting

confidence: 54%

Section: Introductionmentioning

confidence: 99%

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Human tauopathies are not associated with an activated unfolded protein response

Pitera

Boche

et al. 2019

Preprint

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“…) . Advantages associated with using the App KI strains have been described, with these mouse strains showing fewer artifactual anomalies compared with APP overexpressing mice . However, we did not observe NFT in the App KI mice during their lifespan, suggesting that the mice might also be useful as preclinical AD mouse models to investigate the pathological role of amyloidosis and amyloid‐associated neuroinflammation.…”

Section: Animal Models For Ad and Neuroinflammationmentioning

confidence: 66%

Neuroinflammation in mouse models of Alzheimer's disease

Saito

Saido

2018

Clinical & Exp Neuroim

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Alzheimer's disease (AD) is the most common type of neurocognitive disorder. Although both amyloid β peptide deposition and neurofibrillary tangle formation in the AD brain have been established as pathological hallmarks of the disease, many other factors contribute in a complex manner to the pathogenesis of AD before clinical symptoms of the disease become apparent. Longitudinal pathophysiological processes cause patients’ brains to exist in a state of chronic neuroinflammation, with glial cells acting as key regulators of the neuroinflammatory state. However, the detailed molecular and cellular mechanisms of glial function underlying AD pathogenesis remain elusive. Furthermore, recent studies have shown that peripheral inflammatory conditions affect glial cells in the brain through a process of neuroimmune communication. Such disease complexities make it difficult for the pathogenesis of AD to be understood, and impede the development of effective therapeutic strategies to combat the disease. Relevant AD animal models are thus likely to serve as a key resource to overcome many of these issues. Furthermore, as the pathogenesis of AD might be linked to conditions both within the brain as well as peripherally, it might become necessary for AD to be studied as a whole‐body disorder. The present review aimed to summarize insights regarding current AD research, and share perspectives for understanding glial function in the context of the pathogenesis of AD.

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“…Additionally, enrichment of cholesterol in mitochondrial membranes is reported in AD pathology.Mitochondria from a mouse model of cholesterol overload exhibit increased susceptibility to Aβ-induced oxidative stress and consequent cytochrome c release(Fernandez, Llacuna, Fernandez-Checa, & Colell, 2009). Coupled with this observation, loading of mChol is increased in a mouse model of AD(Fernandez, Llacuna, Fernandez- Checa, & Colell, 2009), accompanied by an overexpression of the steroidogenic acute regulatory (StAR) protein(Barbero-Camps et al, 2014;Hashimoto et al, 2018). StAR is a lipoprotein that transports cholesterol from the ER to mitochondria, regulating the intra-organelle distribution of the lipid.…”

mentioning

confidence: 96%

Exploring mitochondrial cholesterol signalling for therapeutic intervention in neurological conditions

Desai

Campanella

2019

British J Pharmacology

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The pharmacological targeting of cholesterol levels continues to generate interest due to the undoubted success of therapeutic agents, such as statins, in extending life expectancy by modifying the prognosis of diseases associated with the impairment of lipid metabolism. Advances in our understanding of mitochondrial dysfunction in chronic age‐related diseases of the brain have disclosed an emerging role for mitochondrial cholesterol in their pathophysiology, thus delineating an opportunity to provide mechanistic insights and explore strategies of intervention. This review draws attention to novel signalling mechanisms in conditions linked with impaired metabolism associated with impaired handling of cholesterol and its oxidized forms (oxysterols) by mitochondria. By emphasizing the role of mitochondrial cholesterol in neurological diseases, we here call for novel approaches and new means of assessment. Linked Articles This article is part of a themed section on Mitochondrial Pharmacology: Featured Mechanisms and Approaches for Therapy Translation. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.22/issuetoc

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Endoplasmic reticulum stress responses in mouse models of Alzheimer's disease: Overexpression paradigm versus knockin paradigm

Abstract: Endoplasmic reticulum (ER)stressWe conclude that the role of ER stress in AD pathogenesis needs to be carefully addressed in future studies.

Cited by 67 publications

References 39 publications

Human tauopathies are not associated with an activated unfolded protein response

Human tauopathies are not associated with an activated unfolded protein response

Neuroinflammation in mouse models of Alzheimer's disease

Exploring mitochondrial cholesterol signalling for therapeutic intervention in neurological conditions

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