Microglia and complement mediate early corticostriatal synapse loss and cognitive dysfunction in Huntington’s disease DOI Creative Commons
Daniel K. Wilton, Kevin Mastro,

Molly D. Heller

et al.

Nature Medicine, Journal Year: 2023, Volume and Issue: 29(11), P. 2866 - 2884

Published: Oct. 9, 2023

Abstract Huntington’s disease (HD) is a devastating monogenic neurodegenerative characterized by early, selective pathology in the basal ganglia despite ubiquitous expression of mutant huntingtin. The molecular mechanisms underlying this region-specific neuronal degeneration and how these relate to development early cognitive phenotypes are poorly understood. Here we show that there loss synaptic connections between cortex striatum postmortem tissue from patients with HD associated increased activation localization complement proteins, innate immune molecules, elements. We also found levels secreted molecules elevated cerebrospinal fluid premanifest correlate established measures burden. In preclinical genetic models HD, proteins mediate elimination corticostriatal synapses at an stage pathogenesis, marking them for removal microglia, brain’s resident macrophage population. This process requires huntingtin be expressed both cortical striatal neurons. Inhibition complement-dependent mechanism through administration therapeutically relevant C1q function-blocking antibody or ablation receptor on microglia prevented synapse loss, excitatory input rescued visual discrimination learning flexibility deficits models. Together, our findings implicate cascade selective, presymptomatic HD; they provide new data support as therapeutic target intervention.

Language: Английский

Microglia states and nomenclature: A field at its crossroads DOI Creative Commons
Rosa Chiara Paolicelli, Amanda Sierra, Beth Stevens

et al.

Neuron, Journal Year: 2022, Volume and Issue: 110(21), P. 3458 - 3483

Published: Nov. 1, 2022

Language: Английский

Citations

1065
Multiple sclerosis progression: time for a new mechanism-driven framework DOI
Tanja Kuhlmann, Marcello Moccia, Timothy Coetzee

et al.

The Lancet Neurology, Journal Year: 2022, Volume and Issue: 22(1), P. 78 - 88

Published: Nov. 18, 2022

Language: Английский

Citations

343
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

236
Microglia ferroptosis is regulated by SEC24B and contributes to neurodegeneration DOI Creative Commons
Sean K. Ryan,

Matija Zelic,

Yingnan Han

et al.

Nature Neuroscience, Journal Year: 2022, Volume and Issue: 26(1), P. 12 - 26

Published: Dec. 19, 2022

Iron dysregulation has been implicated in multiple neurodegenerative diseases, including Parkinson's disease (PD). Iron-loaded microglia are frequently found affected brain regions, but how iron accumulation influences physiology and contributes to neurodegeneration is poorly understood. Here we show that human induced pluripotent stem cell-derived grown a tri-culture system highly responsive susceptible ferroptosis, an iron-dependent form of cell death. Furthermore, overload causes marked shift the microglial transcriptional state overlaps with transcriptomic signature PD postmortem microglia. Our data also this response neurodegeneration, as removal from substantially delayed iron-induced neurotoxicity. To elucidate mechanisms regulating microglia, performed genome-wide CRISPR screen identified novel regulators vesicle trafficking gene SEC24B. These suggest critical role for ferroptosis neurodegeneration.

Language: Английский

Citations

214
Multiple sclerosis DOI
Dejan Jakimovski, Stefan Bittner, Robert Zivadinov

et al.

The Lancet, Journal Year: 2023, Volume and Issue: 403(10422), P. 183 - 202

Published: Nov. 7, 2023

Language: Английский

Citations

189
Roles of neuropathology-associated reactive astrocytes: a systematic review DOI Creative Commons
Jill M. Lawrence,

Kayla A. Schardien,

Brian Wigdahl

et al.

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

Published: March 13, 2023

Abstract In the contexts of aging, injury, or neuroinflammation, activated microglia signaling with TNF-α, IL-1α, and C1q induces a neurotoxic astrocytic phenotype, classified as A1, A1-like, neuroinflammatory reactive astrocytes. contrast to typical astrocytes, which promote neuronal survival, support synapses, maintain blood–brain barrier integrity, these astrocytes downregulate supportive functions begin secrete factors, complement components like C3, chemokines CXCL10, may facilitate recruitment immune cells across BBB into CNS. The proportion pro-inflammatory increases age through associated activation, are particularly abundant in neurodegenerative disorders. As identification astrocyte phenotypes progress, their molecular cellular effects characterized growing array neuropathologies.

Language: Английский

Citations

183
Transforming the understanding of brain immunity DOI
Giulia Castellani, Tommaso Croese, Javier María Peralta Ramos

et al.

Science, Journal Year: 2023, Volume and Issue: 380(6640)

Published: April 6, 2023

Contemporary studies have completely changed the view of brain immunity from envisioning as isolated and inaccessible to peripheral immune cells an organ in close physical functional communication with system for its maintenance, function, repair. Circulating reside special niches brain's borders, choroid plexus, meninges, perivascular spaces, which they patrol sense a remote manner. These niches, together meningeal lymphatic skull microchannels, provide multiple routes interaction between system, addition blood vasculature. In this Review, we describe current ideas about their implications aging, diseases, immune-based therapeutic approaches.

Language: Английский

Citations

179
Complement C1q-dependent excitatory and inhibitory synapse elimination by astrocytes and microglia in Alzheimer’s disease mouse models DOI Creative Commons
Borislav Dejanovic, Tiffany Wu, Ming‐Chi Tsai

et al.

Nature Aging, Journal Year: 2022, Volume and Issue: 2(9), P. 837 - 850

Published: Sept. 20, 2022

Abstract Microglia and complement can mediate neurodegeneration in Alzheimer’s disease (AD). By integrative multi-omics analysis, here we show that astrocytic microglial proteins are increased Tau P301S synapse fractions with age a C1q-dependent manner. In addition to microglia, identified astrocytes contribute substantially elimination hippocampi. Notably, found relatively more excitatory marker lysosomes, whereas lysosomes contained inhibitory material. C1q deletion reduced astrocyte–synapse association decreased synapses engulfment mice rescued density. Finally, an AD mouse model combines β-amyloid pathologies, of the risk gene Trem2 impaired phagocytosis synapses, engulfed around plaques. Together, our data reveal contact eliminate manner thereby pathological loss compensate for dysfunction.

Language: Английский

Citations

159
Astrocytes in human central nervous system diseases: a frontier for new therapies DOI Creative Commons
Alexei Verkhratsky, Arthur M. Butt, Baoman Li

et al.

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

Published: Oct. 13, 2023

Astroglia are a broad class of neural parenchymal cells primarily dedicated to homoeostasis and defence the central nervous system (CNS). contribute pathophysiology all neurological neuropsychiatric disorders in ways that can be either beneficial or detrimental disorder outcome. Pathophysiological changes astroglia primary secondary result gain loss functions. respond external, non-cell autonomous signals associated with any form CNS pathology by undergoing complex variable their structure, molecular expression, function. In addition, internally driven, cell astroglial innate properties lead pathologies. Astroglial is complex, different pathophysiological states phenotypes context-specific vary disorder, disorder-stage, comorbidities, age, sex. Here, we classify into (i) reactive astrogliosis, (ii) atrophy function, (iii) degeneration death, (iv) astrocytopathies characterised aberrant forms drive disease. We review across spectrum human diseases disorders, including neurotrauma, stroke, neuroinfection, autoimmune attack epilepsy, as well neurodevelopmental, neurodegenerative, metabolic disorders. Characterising cellular mechanisms represents new frontier identify novel therapeutic strategies.

Language: Английский

Citations

159
Perivascular cells induce microglial phagocytic states and synaptic engulfment via SPP1 in mouse models of Alzheimer’s disease DOI Creative Commons
Sebastiaan De Schepper,

Judy Z. Ge,

Gerard Crowley

et al.

Nature Neuroscience, Journal Year: 2023, Volume and Issue: 26(3), P. 406 - 415

Published: Feb. 6, 2023

Alzheimer's disease (AD) is characterized by synaptic loss, which can result from dysfunctional microglial phagocytosis and complement activation. However, what signals drive aberrant microglia-mediated engulfment of synapses in AD unclear. Here we report that secreted phosphoprotein 1 (SPP1/osteopontin) upregulated predominantly perivascular macrophages and, to a lesser extent, fibroblasts. Perivascular SPP1 required for microglia engulf upregulate phagocytic markers including C1qa, Grn Ctsb presence amyloid-β oligomers. Absence Spp1 expression mouse models results prevention loss. Furthermore, single-cell RNA sequencing putative cell-cell interaction analyses reveal induces states the hippocampus model AD. Altogether, suggest functional role cells-to-microglia crosstalk, whereby modulates

Language: Английский

Citations

150