Neuron, Год журнала: 2022, Номер 111(1), С. 15 - 29.e8
Опубликована: Ноя. 10, 2022
Язык: Английский
Nature Aging, Год журнала: 2022, Номер 2(9), С. 837 - 850
Опубликована: Сен. 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.
Язык: Английский
Процитировано
161
Molecular Neurodegeneration, Год журнала: 2022, Номер 17(1)
Опубликована: Сен. 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
Язык: Английский
Процитировано
153
International Journal of Molecular Sciences, Год журнала: 2021, Номер 22(12), С. 6355 - 6355
Опубликована: Июнь 14, 2021
A large body of clinical and nonclinical evidence supports the role neurotoxic soluble beta amyloid (amyloid, Aβ) oligomers as upstream pathogenic drivers Alzheimer’s disease (AD). Recent late-stage trials in AD that have evaluated agents targeting distinct species Aβ provide compelling inhibition oligomer toxicity represents an effective approach to slow or stop progression: (1) only target show efficacy patients; (2) clearance plaque does not correlate with improvements; (3) predominantly monomers failed effects; (4) positive trials, is greater carriers ε4 allele apolipoprotein E (APOE4), who are known higher brain concentrations oligomers. These also inhibiting neurotoxicity leads a reduction tau pathology, suggesting sequence events where drives increase formation deposition. The biomarker data include four antibodies engage (aducanumab, lecanemab, gantenerumab, donanemab) ALZ-801, oral agent fully blocks at dose.
Язык: Английский
Процитировано
147
Immunity, Год журнала: 2022, Номер 55(5), С. 879 - 894.e6
Опубликована: Апрель 19, 2022
Язык: Английский
Процитировано
136
Free Radical Biology and Medicine, Год журнала: 2022, Номер 193, С. 134 - 157
Опубликована: Окт. 4, 2022
Язык: Английский
Процитировано
131
Nature reviews. Neuroscience, Год журнала: 2022, Номер 23(4), С. 215 - 230
Опубликована: Фев. 28, 2022
Язык: Английский
Процитировано
127
The Lancet Neurology, Год журнала: 2022, Номер 21(4), С. 329 - 341
Опубликована: Март 16, 2022
Therapeutic modulation of TREM2-dependent microglial function might provide an additional strategy to slow the progression Alzheimer's disease. Although studies in animal models suggest that TREM2 is protective against pathology, its effect on tau pathology and potential beneficial role people with disease still unclear. Our aim was study associations between dynamics soluble TREM2, as a biomarker signalling, amyloid β (Aβ) deposition, tau-related neuroimaging markers, cognitive decline, during autosomal dominant
Язык: Английский
Процитировано
124
Frontiers in Immunology, Год журнала: 2021, Номер 12
Опубликована: Сен. 16, 2021
Neuroinflammation play an important role in Alzheimer’s disease pathogenesis. Advances molecular imaging using positron emission tomography have provided insights into the time course of neuroinflammation and its relation with central pathologies patients animal models. Recent single-cell sequencing transcriptomics indicate dynamic disease-associated microglia astrocyte profiles disease. Mitochondrial 18-kDa translocator protein is most widely investigated target for imaging. New generation tracers improved performance been developed evaluated along tau amyloid assessing progression continuum. Given that not exclusively expressed glia, alternative targets are under rapid development, such as monoamine oxidase B, matrix metalloproteinases, colony-stimulating factor 1 receptor, imidazoline-2 binding sites, cyclooxygenase, cannabinoid-2 purinergic P2X7 P2Y12 fractalkine triggering receptor on myeloid cells 2, advanced glycation end products. Promising should demonstrate a higher specificity cellular locations exclusive expression or activation status (pro- anti-inflammatory) highly specific ligand to enable vivo brain In this review, we summarised recent advances development outlook promising future.
Язык: Английский
Процитировано
119
International Journal of Molecular Sciences, Год журнала: 2022, Номер 23(21), С. 12990 - 12990
Опубликована: Окт. 27, 2022
There is a huge need for novel therapeutic and preventative approaches to Alzheimer’s disease (AD) neuroinflammation seems be one of the most fascinating solutions. The primary cell type that performs immunosurveillance helps clear out unwanted chemicals from brain microglia. Microglia work reestablish efficiency stop further degeneration in early stages AD but mainly fail illness’s later phases. This may caused by number reasons, e.g., protracted exposure cytokines induce inflammation an inappropriate accumulation amyloid beta (Aβ) peptide. Extracellular and/or intraneuronal phosphorylated tau can both activate activation TLRs scavenger receptors, inducing numerous inflammatory pathways, including NF-kB, JAK-STAT, NLRP3 inflammasome, facilitates microglial phagocytosis response these mediators. Aβ/tau are taken up microglia, their removal extracellular space also have protective effects, if illness worsens, environment constantly inflamed overexposed oxidative might encourage continuous activation, which lead neuroinflammation, stress, iron overload, neurotoxicity. complexity diversity roles microglia play health necessitate urgent development new biomarkers identify activity different It imperative comprehend intricate mechanisms result impairment develop immunomodulating therapies primarily attempt recover physiological role allowing them carry core function protection.
Язык: Английский
Процитировано
118
CNS Neuroscience & Therapeutics, Год журнала: 2022, Номер 28(9), С. 1279 - 1293
Опубликована: Июнь 25, 2022
Phagocytosis is the cellular digestion of extracellular particles, such as pathogens and dying cells, a key element in evolution central nervous system (CNS) disorders. Microglia macrophages are professional phagocytes CNS. By clearing toxic debris reshaping matrix, microglia/macrophages help pilot brain repair functional recovery process. However, CNS resident invading immune cells can also magnify tissue damage by igniting runaway inflammation phagocytosing stressed-but viable-neurons.
Язык: Английский
Процитировано
113