A lymphocyte–microglia–astrocyte axis in chronic active multiple sclerosis

Nature, Journal Year: 2021, Volume and Issue: 597(7878), P. 709 - 714

Published: Sept. 8, 2021

Language: Английский

---

Trem2 restrains the enhancement of tau accumulation and neurodegeneration by β-amyloid pathology

Neuron, Journal Year: 2021, Volume and Issue: 109(8), P. 1283 - 1301.e6

Published: March 7, 2021

Language: Английский

---

The biology of TREM receptors

Nature reviews. Immunology, Journal Year: 2023, Volume and Issue: 23(9), P. 580 - 594

Published: Feb. 7, 2023

Language: Английский

---

SYK coordinates neuroprotective microglial responses in neurodegenerative disease

Cell, Journal Year: 2022, Volume and Issue: 185(22), P. 4135 - 4152.e22

Published: Oct. 1, 2022

Recent studies have begun to reveal critical roles for the brain's professional phagocytes, microglia, and their receptors in control of neurotoxic amyloid beta (Aβ) myelin debris accumulation neurodegenerative disease. However, intracellular molecules that orchestrate neuroprotective functions microglia remain poorly understood. In our studies, we find targeted deletion SYK leads exacerbated Aβ deposition, aggravated neuropathology, cognitive defects 5xFAD mouse model Alzheimer's disease (AD). Disruption signaling this AD was further shown impede development disease-associated (DAM), alter AKT/GSK3β-signaling, restrict phagocytosis by microglia. Conversely, receptor-mediated activation limits load. We also found critically regulates microglial DAM acquisition demyelinating Collectively, these results broaden understanding key innate immune instruct beneficial response material.

Language: Английский

---

Emerging Microglia Biology Defines Novel Therapeutic Approaches for Alzheimer’s Disease

Neuron, Journal Year: 2020, Volume and Issue: 108(5), P. 801 - 821

Published: Oct. 23, 2020

Language: Английский

---

Dopamine, Immunity, and Disease

Pharmacological Reviews, Journal Year: 2022, Volume and Issue: 75(1), P. 62 - 158

Published: Dec. 8, 2022

The neurotransmitter dopamine is a key factor in central nervous system (CNS) function, regulating many processes including reward, movement, and cognition. Dopamine also regulates critical functions peripheral organs, such as blood pressure, renal activity, intestinal motility. Beyond these functions, growing body of evidence indicates that an important immunoregulatory factor. Most types immune cells express receptors other dopaminergic proteins, take up, produce, store, and/or release dopamine, suggesting immunomodulation for function. Targeting pathways could be promising avenue the treatment inflammation disease, but despite increasing research this area, data on specific effects disease remain inconsistent poorly understood. Therefore, review integrates current knowledge role cell function inflammatory signaling across systems. We discuss understanding regulation CNS tissues, highlighting diseases Parkinson’s several neuropsychiatric conditions, neurologic human immunodeficiency virus, bowel rheumatoid arthritis, others. Careful consideration given to influence experimental design results, we note number areas need further research. Overall, our immunology at cellular, tissue, level prompts development therapeutics strategies targeted toward ameliorating through immunity.

Significance Statement

Canonically, recognized involved cognition, reward. However, acts modulator periphery. This comprehensively assesses pathogenesis cellular tissue level. will provide broad access information fields, identify investigation, drive therapeutic strategies.

Language: Английский

---

Identifying disease-critical cell types and cellular processes by integrating single-cell RNA-sequencing and human genetics

Nature Genetics, Journal Year: 2022, Volume and Issue: 54(10), P. 1479 - 1492

Published: Sept. 29, 2022

Language: Английский

---

APOE in the bullseye of neurodegenerative diseases: impact of the APOE genotype in Alzheimer’s disease pathology and brain diseases

Molecular Neurodegeneration, Journal Year: 2022, Volume and Issue: 17(1)

Published: Sept. 24, 2022

Abstract ApoE is the major lipid and cholesterol carrier in CNS. There are three human polymorphisms, apoE2, apoE3, apoE4, genetic expression of APOE4 one most influential risk factors for development late-onset Alzheimer's disease (AD). Neuroinflammation has become third hallmark AD, together with Amyloid-β plaques neurofibrillary tangles hyperphosphorylated aggregated tau protein. This review aims to broadly extensively describe differential aspects concerning apoE. Starting from evolution apoE how APOE's single-nucleotide polymorphisms affect its structure, function, involvement during health disease. reflects on impact critical AD pathology, such as neuroinflammatory response, particularly effect APOE astrocytic microglial function dynamics, synaptic amyloid-β load, autophagy, cell–cell communication. We discuss affecting pathology combined genotype, sex, age, diet, physical exercise, current therapies clinical trials field. The genotype other neurodegenerative diseases characterized by overt inflammation, e.g., alpha- synucleinopathies Parkinson's disease, traumatic brain injury, stroke, amyotrophic lateral sclerosis, multiple also addressed. Therefore, this gathers relevant findings related up date implications CNS pathologies provide a deeper understanding knowledge

Language: Английский

---

A TREM2-activating antibody with a blood–brain barrier transport vehicle enhances microglial metabolism in Alzheimer’s disease models

Nature Neuroscience, Journal Year: 2023, Volume and Issue: unknown

Published: Jan. 12, 2023

Abstract Loss-of-function variants of TREM2 are associated with increased risk Alzheimer’s disease (AD), suggesting that activation this innate immune receptor may be a useful therapeutic strategy. Here we describe high-affinity human TREM2-activating antibody engineered monovalent transferrin (TfR) binding site, termed transport vehicle (ATV), to facilitate blood–brain barrier transcytosis. Upon peripheral delivery in mice, ATV:TREM2 showed improved brain biodistribution and enhanced signaling compared standard anti-TREM2 antibody. In induced pluripotent stem cell (iPSC)-derived microglia, proliferation mitochondrial metabolism. Single-cell RNA sequencing morphometry revealed shifted microglia metabolically responsive states, which were distinct from those by amyloid pathology. an AD mouse model, boosted microglial activity glucose Thus, represents promising approach improve function treat hypometabolism found patients AD.

Language: Английский

---

Oligodendrocyte death and myelin loss in the cuprizone model: an updated overview of the intrinsic and extrinsic causes of cuprizone demyelination

Molecular Neurodegeneration, Journal Year: 2022, Volume and Issue: 17(1)

Published: May 7, 2022

Abstract Background The dietary consumption of cuprizone – a copper chelator has long been known to induce demyelination specific brain structures and is widely used as model multiple sclerosis. Despite the extensive use cuprizone, mechanism by which it induces are still unknown. With this review we provide an updated understanding model, showcasing two distinct yet overlapping modes action for cuprizone-induced demyelination; 1) damage originating from within oligodendrocyte, caused mitochondrial dysfunction or reduced myelin protein synthesis. We term mode ‘intrinsic cell damage’. And 2) oligodendrocyte exerted inflammatory molecules, resident cells, such oligodendrocytes, astrocytes, microglia peripheral immune cells neutrophils T-cells. ‘extrinsic cellular Lastly, summarize recent developments in research on different forms death induced could add valuable insights into mechanisms toxicity. hope modern understand causes behind MS.

Language: Английский

---