Presence of tau astrogliopathy in frontotemporal dementia caused by a novel Grn nonsense (Trp2*) mutation

Gómez‐Tortosa, Estrella; Baradaran-Heravi, Yalda; Alvarez, Valentina González; Sainz, María José; Prieto-Jurczynska, Cristina; Guerrero, Rosa; Agüero, Pablo; Broeckhoven, Christine Van; Zee, Julie van der; Gutiérrez, Alberto Rábano

doi:10.1016/j.neurobiolaging.2018.11.010

Cited by 9 publications

(5 citation statements)

References 19 publications

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“…Indeed, neuronal-specific knockdown of LRP1 decreased transsynaptic tau propagation, but increased tau accumulation in astrocytes ( Rauch et al, 2020 ). Furthermore, tau accumulation in astrocytes effectively induces neuronal dysfunction and memory deficits in mice ( Richetin et al, 2020 ), and astrocytic tau accumulation was also observed in the brain of patients with tauopathies ( Chin and Goldman, 1996 ; Gomez-Tortosa et al, 2019 ; Kovacs, 2020 ; Kovacs et al, 2016 , 2017b ; Nolan et al, 2019 ), suggesting tau accumulation in astrocytes might contribute to dementia in patients with tauopathies. Importantly, astrocytes are very sensitive to senescence-inducing stimuli ( Bitto et al, 2010 ), indicating that astrocyte senescence is more abundant in the brain ( Bitto et al, 2010 ; Bussian et al, 2018 ; Chinta et al, 2018 ; Cohen and Torres, 2019 ; Han et al, 2020 ; Limbad et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Tau oligomer induced HMGB1 release contributes to cellular senescence and neuropathology linked to Alzheimer’s disease and frontotemporal dementia

et al. 2021

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Tau oligomer induced HMGB1 release contributes to cellular senescence and neuropathology linked to Alzheimer's disease and frontotemporal dementia Graphical abstract Highlights d Postmortem AD and FTD brain tissues exhibit TauOassociated senescent astrocytes d Direct exposure of TauO triggers cellular senescence in cultured astrocytes d HMGB1 release is a crucial event during TauO-induced cellular senescence d HMGB1 released by senescent cells may contribute to the progression of tauopathies

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Section: Discussionmentioning

confidence: 99%

Tau oligomer induced HMGB1 release contributes to cellular senescence and neuropathology linked to Alzheimer’s disease and frontotemporal dementia

et al. 2021

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“…Further studies are needed to shed light on novel genetic aspects involved in common pathogenic events. Indeed, widespread TSAs and GFAs have also been described in a novel GRN nonsense mutation associated with TDP‐43 pathology, 42 a mixture of bushy and tufted astrocytes in a TARDBP mutation, 43 and astrocytic plaques and ARTAG in 17q21.31 duplication 44,45 …”

Section: Discussionmentioning

confidence: 99%

Multiple system aging‐related tau astrogliopathy with complex proteinopathy in an oligosymptomatic octogenarian

Klotz

Fischer²,

Hinterberger³

et al. 2020

Neuropathology

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The combination of multiple neurodegenerative proteinopathies is increasingly recognized. Together they can potentiate neuronal dysfunction and contribute to complex neurological symptoms. We report an octogenarian female case of multiple extraneural metastases of a rectal carcinoma. She attempted suicide, which ultimately led to cardiorespiratory failure nine days after hospital admission. Apart from the suicide attempt and late‐onset depression, other psychiatric or neurological symptoms were not reported. Unexpectedly, histopathologic examination revealed prominent aging‐related tau astrogliopathy (ARTAG) of all five types (subpial, subependymal, grey and white matter, and perivascular) affecting cortical and subcortical brain regions. This pathology was associated with intermediate Alzheimer's disease neuropathologic change (A2B2C2 score), cerebral amyloid angiopathy, Lewy body‐type α‐synuclein proteinopathy (Braak stage 4), and a multiple system transactivation response DNA‐binding protein of 43 kDa (TDP‐43) proteinopathy also involving the astroglia. In summary, we report a complex and extensive combination of multiple proteinopathies with widespread ARTAG of all five types in a patient who had attempted suicide. Although longitudinal psychometric tests and neuropsychological evaluations were not performed, this report poses the question of thresholds of cognition and pathology load, describes ARTAG affecting unusually widespread brain regions, and supports the notion that complex proteinopathies should be regarded as a frequent condition in the elderly.

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“…Further, a case was identified with GBE1 mutations leading to both ARTAG-like and TDP-43 pathologies ( 100 ). Another FTLD-linked GRN mutation also was correlated with both ARTAG-like and TDP-43 pathologies ( 101 ). In a larger autopsy series, ARTAG was relatively common in brains affected by FTLD-TDP ( 63 ).…”

Section: Late-nc and Comorbidities That Are Enriched In Brains With L...mentioning

confidence: 99%

Limbic-predominant age-related TDP-43 encephalopathy (LATE-NC): Co-pathologies and genetic risk factors provide clues about pathogenesis

Nelson,

Fardo,

et al. 2024

Journal of Neuropathology &Amp; Experimental Neurology

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Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is detectable at autopsy in more than one-third of people beyond age 85 years and is robustly associated with dementia independent of other pathologies. Although LATE-NC has a large impact on public health, there remain uncertainties about the underlying biologic mechanisms. Here, we review the literature from human studies that may shed light on pathogenetic mechanisms. It is increasingly clear that certain combinations of pathologic changes tend to coexist in aging brains. Although “pure” LATE-NC is not rare, LATE-NC often coexists in the same brains with Alzheimer disease neuropathologic change, brain arteriolosclerosis, hippocampal sclerosis of aging, and/or age-related tau astrogliopathy (ARTAG). The patterns of pathologic comorbidities provide circumstantial evidence of mechanistic interactions (“synergies”) between the pathologies, and also suggest common upstream influences. As to primary mediators of vulnerability to neuropathologic changes, genetics may play key roles. Genes associated with LATE-NC include TMEM106B, GRN, APOE, SORL1, ABCC9, and others. Although the anatomic distribution of TDP-43 pathology defines the condition, important cofactors for LATE-NC may include Tau pathology, endolysosomal pathways, and blood-brain barrier dysfunction. A review of the human phenomenology offers insights into disease-driving mechanisms, and may provide clues for diagnostic and therapeutic targets.

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Presence of tau astrogliopathy in frontotemporal dementia caused by a novel Grn nonsense (Trp2*) mutation

Cited by 9 publications

References 19 publications

Tau oligomer induced HMGB1 release contributes to cellular senescence and neuropathology linked to Alzheimer’s disease and frontotemporal dementia

Tau oligomer induced HMGB1 release contributes to cellular senescence and neuropathology linked to Alzheimer’s disease and frontotemporal dementia

Multiple system aging‐related tau astrogliopathy with complex proteinopathy in an oligosymptomatic octogenarian

Limbic-predominant age-related TDP-43 encephalopathy (LATE-NC): Co-pathologies and genetic risk factors provide clues about pathogenesis

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