TFEB enhances astroglial uptake of extracellular tau species and reduces tau spreading

Martini‐Stoica, Heidi; Cole, Allysa L.; Swartzlander, Daniel B.; Chen, Fading; Wan, Ying-Wooi; Bajaj, Lakshya; Bader, David A.; Lee, Virginia M.‐Y.; Trojanowski, John Q.; Liu, Zhandong; Sardiello, Marco; Zheng, Hui

doi:10.1084/jem.20172158

Cited by 173 publications

(182 citation statements)

References 81 publications

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“…The vascular associations for AD and the reported effects of peripheral hypoxia on amyloid clearance from the brain 68 , warrants further investigation of the output of cell-subcluster specific responses to hypoxia. Our analyses also showed that the TFEB gene, which was upregulated in diseased astrocytes 69 , acts upstream of 10 GWAS loci for AD (namely: BIN1, CLDN11, POLN, STK32B, EDIL3, AKAP12, HECW1, WDR5, LEMD2 and DLC1 ), which are also dysregulated in AD astrocytes (Fig. 5c).…”

Section: Resultssupporting

confidence: 59%

A single cell brain atlas in human Alzheimer’s disease

Grubman

Chew

Ouyang

et al. 2019

Preprint

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26Alzheimer's disease (AD) is a heterogeneous disease that is largely dependent on the complex 27 cellular microenvironment in the brain. This complexity impedes our understanding of how 28 individual cell types contribute to disease progression and outcome. To characterize the 29 molecular and functional cell diversity in the human AD brain we utilized single nuclei RNA-30 seq in AD and control patient brains in order to map the landscape of cellular heterogeneity in 31 AD. We detail gene expression changes at the level of cells and cell subclusters, highlighting 32 specific cellular contributions to global gene expression patterns between control and 33 Alzheimer's patient brains. We observed distinct cellular regulation of APOE which was 34 repressed in oligodendrocyte progenitor cells (OPCs) and astrocyte AD subclusters, and highly 35 enriched in a microglial AD subcluster. In addition, oligodendrocyte and microglia AD 36 subclusters show discordant expression of APOE. Integration of transcription factor regulatory 37 modules with downstream GWAS gene targets revealed subcluster-specific control of AD cell 38 fate transitions. For example, this analysis uncovered that astrocyte diversity in AD was under 39 the control of transcription factor EB (TFEB), a master regulator of lysosomal function and 40 which initiated a regulatory cascade containing multiple AD GWAS genes. These results 41 establish functional links between specific cellular sub-populations in AD, and provide new 42 insights into the coordinated control of AD GWAS genes and their cell-type specific 43 contribution to disease susceptibility. Finally, we created an interactive reference web resource 44 which will facilitate brain and AD researchers to explore the molecular architecture of subtype 45 and AD-specific cell identity, molecular and functional diversity at the single cell level. 46Highlights 47 • We generated the first human single cell transcriptome in AD patient brains 48 • Our study unveiled 9 clusters of cell-type specific and common gene expression 49 patterns between control and AD brains, including clusters of genes that present 50 properties of different cell types (i.e. astrocytes and oligodendrocytes) 51 • Our analyses also uncovered functionally specialized sub-cellular clusters: 5 52 microglial clusters, 8 astrocyte clusters, 6 neuronal clusters, 6 oligodendrocyte 53 clusters, 4 OPC and 2 endothelial clusters, each enriched for specific ontological 54 gene categories 55 • Our analyses found manifold AD GWAS genes specifically associated with one 56 cell-type, and sets of AD GWAS genes co-ordinately and differentially regulated 57 between different brain cell-types in AD sub-cellular clusters 58 • We mapped the regulatory landscape driving transcriptional changes in AD brain, 59 and identified transcription factor networks which we predict to control cell fate 60 transitions between control and AD sub-cellular clusters 61 • Finally, we provide an interactive web-resource that allows the user to further 62 visua...

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Section: Resultssupporting

confidence: 59%

A single cell brain atlas in human Alzheimer’s disease

Grubman

Chew

Ouyang

et al. 2019

Preprint

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“…Accumulating evidence has suggested that targeting TFEB to regulate ALP is a promising approach to developing new drugs to treat neurodegenerative disorders including AD (Chandra, Jana, & Pahan, 2018;Chauhan et al, 2015;Martini-Stoica et al, 2018;Polito et al, 2014;Wang et al, 2016;Xiao et al, 2014Xiao et al, , 2015. However, most of these studies were at the stage of proof-of-concept by exogenously overexpressing TFEB.…”

Section: Discussionmentioning

confidence: 99%

“…Exogenous TFEB expression mediated by AAV injection in hippocampal astrocytes and neurons of APP/PS1 mice reportedly promotes the degradation of APP and APP C‐terminal fragments (CTFs) and reduces Aβ generation (Xiao et al, , ). In tauopathy mice, TFEB overexpression mediated by AAV delivery or transgene targeted hyperphosphorylated and misfolded MAPT for degradation (Polito et al, ), reversed learning deficits (Wang, Wang, Carrera, Xu, & Lakshmana, ) and reduced MAPT spreading (Martini‐Stoica et al, ). These findings indicate that TFEB is a promising drug target for AD treatment.…”

Section: Introductionmentioning

confidence: 99%

A small molecule transcription factor EB activator ameliorates beta‐amyloid precursor protein and Tau pathology in Alzheimer's disease models

et al. 2019

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Accumulating studies have suggested that targeting transcription factor EB (TFEB), an essential regulator of autophagy‐lysosomal pathway (ALP), is promising for the treatment of neurodegenerative disorders, including Alzheimer's disease (AD). However, potent and specific small molecule TFEB activators are not available at present. Previously, we identified a novel TFEB activator named curcumin analog C1 which directly binds to and activates TFEB. In this study, we systematically investigated the efficacy of curcumin analog C1 in three AD animal models that represent beta‐amyloid precursor protein (APP) pathology (5xFAD mice), tauopathy (P301S mice) and the APP/Tau combined pathology (3xTg‐AD mice). We found that C1 efficiently activated TFEB, enhanced autophagy and lysosomal activity, and reduced APP, APP C‐terminal fragments (CTF‐β/α), β‐amyloid peptides and Tau aggregates in these models accompanied by improved synaptic and cognitive function. Knockdown of TFEB and inhibition of lysosomal activity significantly inhibited the effects of C1 on APP and Tau degradation in vitro. In summary, curcumin analog C1 is a potent TFEB activator with promise for the prevention or treatment of AD.

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“…Furthermore, depletion of microglia strongly suppressed propagation of tau pathology in human tau(P301S) expressing transgenic mice [147]. Additionally, astrocytes are also able to internalize both fibrillar and monomeric tau, implicating a possible role for other glial cells in the process of spreading the pathology [224,225].…”

Section: Further Considerations For Understanding Propagation Of Tau mentioning

confidence: 97%

Mechanisms of secretion and spreading of pathological tau protein

Brunello

Merezhko

Uronen

et al. 2019

Cell. Mol. Life Sci.

193

180

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Accumulation of misfolded and aggregated forms of tau protein in the brain is a neuropathological hallmark of tauopathies, such as Alzheimer's disease and frontotemporal lobar degeneration. Tau aggregates have the ability to transfer from one cell to another and to induce templated misfolding and aggregation of healthy tau molecules in previously healthy cells, thereby propagating tau pathology across different brain areas in a prion-like manner. The molecular mechanisms involved in cell-tocell transfer of tau aggregates are diverse, not mutually exclusive and only partially understood. Intracellular accumulation of misfolded tau induces several mechanisms that aim to reduce the cellular burden of aggregated proteins and also promote secretion of tau aggregates. However, tau may also be released from cells physiologically unrelated to protein aggregation. Tau secretion involves multiple vesicular and non-vesicle-mediated pathways, including secretion directly through the plasma membrane. Consequently, extracellular tau can be found in various forms, both as a free protein and in vesicles, such as exosomes and ectosomes. Once in the extracellular space, tau aggregates can be internalized by neighboring cells, both neurons and glial cells, via endocytic, pinocytic and phagocytic mechanisms. Importantly, accumulating evidence suggests that prion-like propagation of misfolding protein pathology could provide a general mechanism for disease progression in tauopathies and other related neurodegenerative diseases. Here, we review the recent literature on cellular mechanisms involved in cell-to-cell transfer of tau, with a particular focus in tau secretion.

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TFEB enhances astroglial uptake of extracellular tau species and reduces tau spreading

Cited by 173 publications

References 81 publications

A single cell brain atlas in human Alzheimer’s disease

A single cell brain atlas in human Alzheimer’s disease

A small molecule transcription factor EB activator ameliorates beta‐amyloid precursor protein and Tau pathology in Alzheimer's disease models

Mechanisms of secretion and spreading of pathological tau protein

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