Tau seeding and spreading in vivo is supported by both AD-derived fibrillar and oligomeric tau DOI Creative Commons
Anastasie Maté de Gérando, Lindsay A. Welikovitch, Anita Khasnavis

et al.

Acta Neuropathologica, Journal Year: 2023, Volume and Issue: 146(2), P. 191 - 210

Published: June 21, 2023

Insoluble fibrillar tau, the primary constituent of neurofibrillary tangles, has traditionally been thought to be biologically active, toxic form tau mediating neurodegeneration in Alzheimer's disease. More recent studies have implicated soluble oligomeric species, referred as high molecular weight (HMW), due their properties on size-exclusion chromatography, propagation across neural systems. These two forms never directly compared. We prepared sarkosyl-insoluble and HMW from frontal cortex Alzheimer patients compared using a variety biophysical bioactivity assays. Sarkosyl-insoluble comprises abundant paired-helical filaments (PHF) quantified by electron microscopy (EM) is more resistant proteinase K, which mostly an form. are nearly equivalent potency HEK cell assay for seeding aggregates, injection reveals similar local uptake into hippocampal neurons PS19 Tau transgenic mice. However, preparation appears far potent inducing glial response including Clec7a-positive rod microglia absence or synapse loss promotes rapid misfolded distal, anatomically connected regions, such entorhinal perirhinal cortices. data suggest that with regard potential, but may equal even bioactive respect systems activation responses, both relevant tau-related phenotypes.

Language: Английский

Molecular basis of astrocyte diversity and morphology across the CNS in health and disease DOI
Fumito Endo, Atsushi Kasai, Joselyn S. Soto

et al.

Science, Journal Year: 2022, Volume and Issue: 378(6619)

Published: Nov. 3, 2022

Astrocytes, a type of glia, are abundant and morphologically complex cells. Here, we report astrocyte molecular profiles, diversity, morphology across the mouse central nervous system (CNS). We identified shared region-specific astrocytic genes functions explored cellular origins their regional diversity. gene networks correlated with morphology, several which unexpectedly contained Alzheimer’s disease (AD) risk genes. CRISPR/Cas9–mediated reduction candidate reduced morphological complexity resulted in cognitive deficits. The same were down-regulated human AD, an AD model that displayed other brain disorders. thus provide comprehensive data on diversity mechanisms CNS basis health disease.

Language: Английский

Citations

318
Astrocyte contribution to dysfunction, risk and progression in neurodegenerative disorders DOI
Ashley N. Brandebura, Adrien Paumier, Tarik Seref Onur

et al.

Nature reviews. Neuroscience, Journal Year: 2022, Volume and Issue: 24(1), P. 23 - 39

Published: Oct. 31, 2022

Language: Английский

Citations

263
Functional roles of reactive astrocytes in neuroinflammation and neurodegeneration DOI
Rickie Patani, Giles E. Hardingham, Shane A. Liddelow

et al.

Nature Reviews Neurology, Journal Year: 2023, Volume and Issue: 19(7), P. 395 - 409

Published: June 12, 2023

Language: Английский

Citations

242
Astrocyte biomarker signatures of amyloid-β and tau pathologies in Alzheimer’s disease DOI Creative Commons
João Pedro Ferrari‐Souza, Pâmela C.L. Ferreira, Bruna Bellaver

et al.

Molecular Psychiatry, Journal Year: 2022, Volume and Issue: 27(11), P. 4781 - 4789

Published: Aug. 10, 2022

Astrocytes can adopt multiple molecular phenotypes in the brain of Alzheimer's disease (AD) patients. Here, we studied associations cerebrospinal fluid (CSF) glial fibrillary acidic protein (GFAP) and chitinase-3-like 1 (YKL-40) levels with amyloid-β (Aβ) tau pathologies. We assessed 121 individuals across aging AD clinical spectrum positron emission tomography (PET) imaging for Aβ ([

Language: Английский

Citations

85
Transgenic Mouse Models of Alzheimer’s Disease: An Integrative Analysis DOI Open Access
Raquel Sánchez‐Varo, Marina Mejias‐Ortega, Juan José Fernandez-Valenzuela

et al.

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(10), P. 5404 - 5404

Published: May 12, 2022

Alzheimer's disease (AD) constitutes the most prominent form of dementia among elderly individuals worldwide. Disease modeling using murine transgenic mice was first initiated thanks to discovery heritable mutations in amyloid precursor protein (APP) and presenilins (PS) genes. However, due repeated failure translational applications from animal models human patients, along with recent advances genetic susceptibility our current understanding on biology, these have evolved over time an attempt better reproduce complexity this devastating improve their applicability. In review, we provide a comprehensive overview about major pathological elements AD (plaques, tauopathy, synaptic damage, neuronal death, neuroinflammation glial dysfunction), discussing knowledge that available mouse provided mechanisms underlying disease. Moreover, highlight pros cons models, revolution offered by concomitant use omics technologies may lead more rapid improvement present battery.

Language: Английский

Citations

84
A molecular switch for neuroprotective astrocyte reactivity DOI
Evan G. Cameron, Michael Nahmou, Anna B. Toth

et al.

Nature, Journal Year: 2023, Volume and Issue: 626(7999), P. 574 - 582

Published: Dec. 12, 2023

Language: Английский

Citations

49
An astrocyte BMAL1-BAG3 axis protects against alpha-synuclein and tau pathology DOI Creative Commons
Patrick W. Sheehan, Collin J. Nadarajah,

Michael F. Kanan

et al.

Neuron, Journal Year: 2023, Volume and Issue: 111(15), P. 2383 - 2398.e7

Published: June 13, 2023

Language: Английский

Citations

48
Astrocyte-targeting therapy rescues cognitive impairment caused by neuroinflammation via the Nrf2 pathway DOI Creative Commons

Akiko Nakano-Kobayashi,

Andrés Canela,

Toru Yoshihara

et al.

Proceedings of the National Academy of Sciences, Journal Year: 2023, Volume and Issue: 120(33)

Published: Aug. 7, 2023

Neuroinflammation is a common feature of neurodegenerative disorders such as Alzheimer's disease (AD). induced by dysregulated glial activation, and astrocytes, the most abundant cells, become reactive upon neuroinflammatory cytokines released from microglia actively contribute to neuronal loss. Therefore, blocking astrocyte functions viable strategy manage disorders. However, factors or therapeutics directly regulating subtypes remain unexplored. Here, we identified transcription factor NF-E2-related 2 (Nrf2) therapeutic target in neurotoxic astrocytes neuroinflammation. We found that absence Nrf2 promoted activation brain tissue samples obtained AD model 5xFAD mice, whereas enhanced expression blocked induction gene counteracting NF-κB subunit p65 recruitment. Neuroinflammatory robustly up-regulated genes associated with type I interferon antigen-presenting pathway, which were suppressed pathway activation. Moreover, impaired cognitive behaviors observed mice rescued ALGERNON2 treatment, potentiated reduced astrocytes. Thus, highlight potential astrocyte-targeting therapy promoting signaling for neuroinflammation-triggered neurodegeneration.

Language: Английский

Citations

46
Human Alzheimer’s disease reactive astrocytes exhibit a loss of homeostastic gene expression DOI Creative Commons
David Dai, Mingyao Li, Edward B. Lee

et al.

Acta Neuropathologica Communications, Journal Year: 2023, Volume and Issue: 11(1)

Published: Aug. 2, 2023

Astrocytes are one of the brain's major cell types and responsible for maintaining neuronal homeostasis via regulating extracellular environment, providing metabolic support, modulating synaptic activity. In neurodegenerative diseases, such as Alzheimer's disease, astrocytes can take on a hypertrophic appearance. These reactive canonically associated with increases in cytoskeletal proteins, glial fibrillary acidic protein vimentin. However, molecular alterations that characterize human disease tissues have not been extensively studied single resolution. Using nucleus RNA sequencing data from normal, pathologic aging, brains, we identified transcriptomic changes astrocytes. Deep learning-based clustering algorithms denoised expression 17,012 genes clustered 15,529 astrocyte nuclei, identifying protoplasmic, gray matter fibrous, white clusters. trajectory analyses revealed spectrum reactivity within protoplasmic characterized by modest increase marked decrease homeostatic genes. Amyloid but tau pathology correlated reactivity. To identify reactivity-associated genes, linear regressions gene versus were used to top 52 upregulated 144 downregulated Gene Ontology analysis cellular growth, responses metal ions, inflammation, proteostasis. Downregulated involved interactions, development, ERBB signaling, synapse regulation. Transcription factors significantly enriched among co-immunofluorescence staining brain tissues, confirmed downregulation ERBB4 transcription factor NFIA Our findings reveal exist is strong loss normal function.

Language: Английский

Citations

43
Cellular and pathological functions of tau DOI
C Bravo, Sarah Naguib, Li Gan

et al.

Nature Reviews Molecular Cell Biology, Journal Year: 2024, Volume and Issue: 25(11), P. 845 - 864

Published: July 16, 2024

Language: Английский

Citations

40