Astrocytic 4R tau expression drives astrocyte reactivity and dysfunction

Ezerskiy, Lubov; Schoch, Kathleen M.; Sato, Chihiro; Beltcheva, Mariana; Horie, Kazuyuki; Rigo, Frank; Martynowicz, Ryan; Karch, Celeste M.; Bateman, Randall J.; Miller, Timothy M.

doi:10.1172/jci.insight.152012

Cited by 25 publications

(19 citation statements)

References 70 publications

(105 reference statements)

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“…However, this finding is based on bulk transcriptomic data from wild-derived mouse strains. An increasing amount of work is currently going into identifying disease- and context-specific glial states (Keren-Shaul et al, 2017, Paolicelli et al, 2022, Ezerskiy et al, 2022). Single cell RNA sequencing will be necessary to better understand which microglia cell types are involved in this phenotype.…”

Section: Discussionmentioning

confidence: 99%

Network analysis reveals strain-dependent response to misfolded tau aggregates

Acri

You

Tate

et al. 2023

Preprint

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Mouse genetic backgrounds have been shown to modulate amyloid accumulation and propagation of tau aggregates. Previous research into these effects has highlighted the importance of studying the impact of genetic heterogeneity on modeling Alzheimer's disease. However, it is unknown what mechanisms underly these effects of genetic background on modeling Alzheimer's disease, specifically tau aggregate-driven pathogenicity. In this study, we induced tau aggregation in wild-derived mice by expressing MAPT (P301L). To investigate the effect of genetic background on the action of tau aggregates, we performed RNA sequencing with brains of 6-month-old C57BL/6J, CAST/EiJ, PWK/PhJ, and WSB/EiJ mice (n=64). We also measured tau seeding activity in the cortex of these mice. We identified three gene signatures: core transcriptional signature, unique signature for each wild-derived genetic background, and tau seeding-associated signature. Our data suggest that microglial response to tau seeds is elevated in CAST/EiJ and PWK/PhJ mice. Together, our study provides the first evidence that mouse genetic context influences the seeding of tau.

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Section: Discussionmentioning

confidence: 99%

Network analysis reveals strain-dependent response to misfolded tau aggregates

Acri

You

Tate

et al. 2023

Preprint

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“…to acquire neuroprotective and deleterious signatures in response to tau in PS19 mice and Aβ pathology in APP/PS1 mice [86]. Tau induced reactive astrocytes and loss of their neurosupportive functions in mouse models, including PS19, Thy-Tau22, hTau and rTgTauEC mice [52,[103][104][105][106][107][108]. Astrogliosis in turn could increase tau hyperphosphorylation and aggregation [109].…”

Section: Discussionmentioning

confidence: 99%

Aquaporin 4 is differentially increased and depolarized in association with tau and amyloid-beta

Kecheliev

Boss

Maheshwari

et al. 2022

Preprint

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Neurovascular-glymphatic dysfunction plays an important role in Alzheimer’s disease and has been analyzed mainly in association with amyloid-beta (Aβ) pathology. The neurovascular-glymphatic link with tauopathies has not been well elucidated. Here, we aimed to investigate the alterations in the neurovasculature and map the aquaporin 4 (AQP4) distribution and depolarization associated with tau and Aβ. Perfusion, susceptibility weighted imaging and structural magnetic resonance imaging (MRI) were performed in the pR5 P301L mouse model of 4-repeat tau and the arcAβ mouse model of amyloidosis. Immunofluorescence staining was performed using antibodies against AQP4, CD31, astroglia (GFAP, s100β), phospho-tau (AT-8) and Aβ (6E10) in brain tissue slices from P301L, arcAβ and nontransgenic mice. P301L mice showed regional atrophy, preserved cerebral blood flow and reduced cerebral vessel density compared to nontransgenic mice, while arcAβ mice showed cerebral microbleeds and reduced cerebral vessel density. AQP4 depolarization and peri-tau enrichment in the hippocampus and increased AQP4 levels in the forebrain and hippocampus were detected in P301L mice compared to nontransgenic mice. In comparison, cortical AQP4 depolarization and cortical/hippocampal peri-plaque increases were observed in arcAβ mice. Increased s100β-GFAP fluorescence intensities indicative of reactive astrocytes were detected surrounding tau inclusions in P301L mice and Aβ plaques in arcAβ mice. In conclusion, we observed a divergent region-specific AQP4 increase and association with phospho-tau and Aβ pathologies.

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“… 39 , 74 Interestingly, a recently published study demonstrated that the manipulation of tau splicing toward more 4R tau promotes a neurotoxic astrocyte phenotype characterized by the upregulation of C3 levels. 19 Conversely, under certain stimuli, astrocytes can upregulate the expression of many neurotrophic factors that promote the survival and growth of neurons and thrombospondins, which promote synapse repair. 75 Thus, subtypes of astrocytes might have beneficial or reparative functions.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have revealed that lowering tau levels in 4R tau-expressing iPSC-derived astrocytes improves neuronal survival. 19 Thus, we aimed to determine if the deletion of astrocytic tau protects synapses against the toxic effects of Aβ oligomers.…”

Section: Introductionmentioning

confidence: 99%

The reduction of astrocytic tau prevents amyloid-β-induced synaptotoxicity

Cisternas

Taylor

Martínez

et al. 2022

Brain Communications

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Alzheimer’s disease is a neurological disorder characterized by the overproduction and aggregation of amyloid-beta (Aβ) and the phosphorylation and intraneuronal accumulation of tau. These events promote synaptic dysfunction and loss, leading to neurodegeneration and cognitive deficits. Astrocytes are intimately associated with synapses and become activated under pathological conditions, becoming neurotoxic and detrimentally affecting synapses. Although it has been established that reducing neuronal tau expression prevents Aβ−induced toxicity, the role of astrocytic tau in this setting remains understudied. Herein, we performed a series of astrocytic and neuronal primary cultures to evaluate the effects of decreasing astrocytic tau levels on astrocyte-mediated Aβ-induced synaptic degeneration. Our results suggest that the downregulation of tau in astrocytes mitigates the loss of synapses triggered by their exposure to Aβ. Additionally, the absence of tau from astrocytes promotes the upregulation of several synaptoprotective genes, followed by increased production of the neuroprotective factor Pentraxin 3 (PTX3). These results expand our understanding of the contribution of astrocytic tau to the neurodegenerative process induced by Aβ-stimulation and how reducing astrocytic tau could improve astrocyte function by stimulating the expression of synaptoprotective factors. Reducing endogenous astrocytic tau expression could be a potential strategy to prevent synaptic damage in Alzheimer's disease and other neurological conditions.

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Astrocytic 4R tau expression drives astrocyte reactivity and dysfunction

Cited by 25 publications

References 70 publications

Network analysis reveals strain-dependent response to misfolded tau aggregates

Network analysis reveals strain-dependent response to misfolded tau aggregates

Aquaporin 4 is differentially increased and depolarized in association with tau and amyloid-beta

The reduction of astrocytic tau prevents amyloid-β-induced synaptotoxicity

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