Impact of TREM2R47H variant on tau pathology–induced gliosis and neurodegeneration DOI Open Access
Maud Gratuze, Cheryl E. G. Leyns, Andrew D. Sauerbeck

et al.

Journal of Clinical Investigation, Journal Year: 2020, Volume and Issue: 130(9), P. 4954 - 4968

Published: June 16, 2020

Alzheimer's disease (AD) is characterized by plaques containing amyloid-β (Aβ) and neurofibrillary tangles composed of aggregated, hyperphosphorylated tau. Beyond tau Aβ, evidence suggests that microglia play an important role in AD pathogenesis. Rare variants the microglia-expressed triggering receptor expressed on myeloid cells 2 (TREM2) gene increase risk 2- to 4-fold. It likely these TREM2 decreasing response Aβ its local toxicity. However, neocortical pathology occurs many years before AD. Thus, it will be understand context tauopathy. We investigated impact AD-associated variant (R47H) tau-mediated neuropathology PS19 mouse model assessed mice expressing human TREM2CV (common variant) or TREM2R47H. PS19-TREM2R47H had significantly attenuated brain atrophy synapse loss versus PS19-TREM2CV mice. Gene expression analyses CD68 immunostaining revealed microglial reactivity There was also a decrease phagocytosis postsynaptic elements TREM2R47H brains. These findings suggest impaired signaling reduces microglia-mediated neurodegeneration setting

Language: Английский

Synergy between amyloid-β and tau in Alzheimer’s disease DOI
Marc Aurel Busche, Bradley T. Hyman

Nature Neuroscience, Journal Year: 2020, Volume and Issue: 23(10), P. 1183 - 1193

Published: Aug. 10, 2020

Language: Английский

Citations

869
Alzheimer's disease DOI

José Arguedas López,

Hector M. González, Gabriel C. Léger

et al.

Handbook of clinical neurology, Journal Year: 2019, Volume and Issue: unknown, P. 231 - 255

Published: Jan. 1, 2019

Language: Английский

Citations

628
Deep Multilayer Brain Proteomics Identifies Molecular Networks in Alzheimer’s Disease Progression DOI Creative Commons
Bing Bai, Xusheng Wang, Yuxin Li

et al.

Neuron, Journal Year: 2020, Volume and Issue: 105(6), P. 975 - 991.e7

Published: Jan. 8, 2020

Language: Английский

Citations

438
Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets DOI Creative Commons
Chao Gao, Jingwen Jiang, Yuyan Tan

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: Sept. 22, 2023

Abstract Microglia activation is observed in various neurodegenerative diseases. Recent advances single-cell technologies have revealed that these reactive microglia were with high spatial and temporal heterogeneity. Some identified specific states correlate pathological hallmarks are associated functions. both exert protective function by phagocytosing clearing protein aggregates play detrimental roles due to excessive uptake of aggregates, which would lead microglial phagocytic ability impairment, neuroinflammation, eventually neurodegeneration. In addition, peripheral immune cells infiltration shapes into a pro-inflammatory phenotype accelerates disease progression. also act as mobile vehicle propagate aggregates. Extracellular vesicles released from autophagy impairment all contribute progression Thus, enhancing phagocytosis, reducing microglial-mediated inhibiting exosome synthesis secretion, promoting conversion considered be promising strategies for the therapy Here we comprehensively review biology diseases, including Alzheimer’s disease, Parkinson’s multiple system atrophy, amyotrophic lateral sclerosis, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, dementia Lewy bodies Huntington’s disease. We summarize possible microglia-targeted interventions treatments against diseases preclinical clinical evidence cell experiments, animal studies, trials.

Language: Английский

Citations

426
New insights into the immune functions of complement DOI
Edimara S. Reis, Dimitrios C. Mastellos, George Hajishengallis

et al.

Nature reviews. Immunology, Journal Year: 2019, Volume and Issue: 19(8), P. 503 - 516

Published: May 2, 2019

Language: Английский

Citations

391
Complement C3 Is Activated in Human AD Brain and Is Required for Neurodegeneration in Mouse Models of Amyloidosis and Tauopathy DOI Creative Commons
Tiffany Wu, Borislav Dejanovic, Vineela Gandham

et al.

Cell Reports, Journal Year: 2019, Volume and Issue: 28(8), P. 2111 - 2123.e6

Published: Aug. 1, 2019

Complement pathway overactivation can lead to neuronal damage in various neurological diseases. Although Alzheimer's disease (AD) is characterized by β-amyloid plaques and tau tangles, previous work examining complement has largely focused on amyloidosis models. We find that glial cells show increased expression of classical components the central component C3 mouse models (PS2APP) more extensively tauopathy (TauP301S). Blocking function deleting rescues plaque-associated synapse loss PS2APP mice ameliorates neuron brain atrophy TauP301S mice, improving neurophysiological behavioral measurements. In addition, protein elevated AD patient brains, including at synapses, levels processing are CSF correlate with tau. These results demonstrate activation contributes neurodegeneration caused pathology suggest blocking might be protective other tauopathies.

Language: Английский

Citations

362
Gamma Entrainment Binds Higher-Order Brain Regions and Offers Neuroprotection DOI Creative Commons
Chinnakkaruppan Adaikkan, Steven J. Middleton,

Asaf Marco

et al.

Neuron, Journal Year: 2019, Volume and Issue: 102(5), P. 929 - 943.e8

Published: May 8, 2019

Language: Английский

Citations

349
Microglia modulate neurodegeneration in Alzheimer’s and Parkinson’s diseases DOI
Tim Bartels, Sebastiaan De Schepper, Soyon Hong

et al.

Science, Journal Year: 2020, Volume and Issue: 370(6512), P. 66 - 69

Published: Oct. 2, 2020

Dementia is a rapidly rising global health crisis that silently disables families and ends lives livelihoods around the world. To date, however, no early biomarkers or effective therapies exist. It now clear brain microglia are more than mere bystanders amyloid phagocytes; they can act as governors of neuronal function homeostasis in adult brain. Here, we highlight fundamental role tissue-resident macrophages health. Then, suggest how chronic impairment microglia-neuron cross-talk may secure permanence failure synaptic Alzheimer's Parkinson's diseases. Understanding to assess modulate interactions critical for will be key developing dementia.

Language: Английский

Citations

312
Local externalization of phosphatidylserine mediates developmental synaptic pruning by microglia DOI Creative Commons
Nicole Scott‐Hewitt, Fabio Perrucci, Raffaella Morini

et al.

The EMBO Journal, Journal Year: 2020, Volume and Issue: 39(16)

Published: July 13, 2020

Neuronal circuit assembly requires the fine balance between synapse formation and elimination. Microglia, through elimination of supernumerary synapses, have an established role in this process. While microglial receptor TREM2 soluble complement proteins C1q C3 are recognized as key players, neuronal molecular components that specify synapses to be eliminated still undefined. Here, we show exposed phosphatidylserine (PS) represents a "eat-me" signal involved microglial-mediated pruning. In hippocampal neuron microglia co-cultures, can partially prevented by blocking accessibility PS using Annexin V or loss TREM2. vivo, exposure at both retinogeniculate engulfment PS-labeled material occurs during developmental periods Mice deficient C1q, which fail properly refine connections, elevated presynaptic reduced microglia. These data provide mechanistic insight into pruning identify novel developmentally regulated is common among developing brain structures.

Language: Английский

Citations

306
Neuron-Glia Signaling in Synapse Elimination DOI Open Access
Daniel K. Wilton,

Lasse Dissing‐Olesen,

Beth Stevens

et al.

Annual Review of Neuroscience, Journal Year: 2019, Volume and Issue: 42(1), P. 107 - 127

Published: July 8, 2019

Maturation of neuronal circuits requires selective elimination synaptic connections. Although neuron-intrinsic mechanisms are important in this process, it is increasingly recognized that glial cells also play a critical role. Without proper functioning these cells, the number, morphology, and function contacts profoundly altered, resulting abnormal connectivity behavioral abnormalities. In addition to their role refinement, have been implicated pathological synapse loss dysfunction following injury or nervous system degeneration adults. regulating glia-mediated still being uncovered, clear complex process involves many cues promote inhibit removal specific Gaining greater understanding signals contribution different cell types will not only provide insight into biological event but be instrumental advancing knowledge brain development neural disease.

Language: Английский

Citations

299