Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Июнь 30, 2023

Abstract Amyloid β protein (Aβ) is the main component of neuritic plaques in Alzheimer’s disease (AD), and its accumulation has been considered as molecular driver pathogenesis progression. Aβ prime target for development AD therapy. However, repeated failures Aβ-targeted clinical trials have cast considerable doubt on amyloid cascade hypothesis whether drug followed correct course. recent successes targeted assuaged those doubts. In this review, we discussed evolution over last 30 years summarized application diagnosis modification. particular, extensively pitfalls, promises important unanswered questions regarding current anti-Aβ therapy, well strategies further study more feasible approaches optimization prevention treatment.

Язык: Английский

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Bidirectional Microglia–Neuron Communication in Health and Disease

Frontiers in Cellular Neuroscience, Год журнала: 2018, Номер 12

Опубликована: Сен. 27, 2018

Microglia are ramified cells that exhibit highly motile processes, which continuously survey the brain parenchyma and react to any insult CNS homeostasis. Although microglia have long been recognized as a crucial player in generating maintaining inflammatory responses CNS, now it has become clear, their function much more diverse, particularly healthy brain. The innate immune response phagocytosis represent only little segment of functional repertoire also includes maintenance biochemical homeostasis, neuronal circuit maturation during development experience- dependent remodeling circuits adult Being equipped by numerous receptors cell surface molecules can perform bidirectional interactions with other types CNS. There is accumulating evidence showing neurons inform about status thus capable controlling microglial activation motility while modulate activities. This review addresses topic: how communicate brain, including fractalkine signaling, secreted soluble factors extracellular vesicles. We summarize current state knowledge physiological role mature further highlight contribution pathologies such Alzheimer's Parkinson's disease, ischemia, traumatic injury, tumour well neuropsychiatric diseases (depression, bipolar disorder schizophrenia).

Язык: Английский

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Astrocyte morphology: Diversity, plasticity, and role in neurological diseases

CNS Neuroscience & Therapeutics, Год журнала: 2019, Номер 25(6), С. 665 - 673

Опубликована: Март 30, 2019

Summary Astrocytes are the most abundant glial cells in central nervous system (CNS) and participate synaptic, circuit, behavioral functions. The well‐developed protoplasmic astrocytes contain numerous processes forming well‐delineated bushy territories that overlap by as little 5% at their boundaries. This highly complex morphology, with up to approximately 80% of cell's membrane constituted fine dimensions on tens nanometer scale high surface area volume ratios, comes contact synapses, blood vessels, other cells. Recent progress is challenging conventional view morphologically homogeneous throughout brain; instead, they display circuit‐ region‐specific morphological diversity may contribute heterogeneous astrocyte‐neuron spatiotemporal interplay different brain areas. Further, structure found be plastic activity‐dependent. We beginning understand how astrocyte structural plasticity contributes change/loss traditionally known a hallmark for reactive astrogliosis, common pathological feature many neurological disorders. However, recent data suggest deficits preceding astrogliosis drive disease progression. review summarizes advances diversity, plasticity, disease‐related deficits.

Язык: Английский

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Astrocytic and microglial cells as the modulators of neuroinflammation in Alzheimer’s disease

Journal of Neuroinflammation, Год журнала: 2022, Номер 19(1)

Опубликована: Авг. 17, 2022

Abstract Neuroinflammation is instigated by the misfiring of immune cells in central nervous system (CNS) involving microglia and astrocytes as key cell-types. a consequence CNS injury, infection, toxicity, or autoimmunity. It favorable well detrimental process for neurodevelopment associated processes. Transient activation inflammatory response release cytokines growth factors positively affects development post-injury tissue. However, chronic uncontrolled responses may lead to various neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's (PD), amyotrophic lateral sclerosis, multiple sclerosis. These diseases have variable clinical pathological features, but are underlaid aggregation misfolded proteins with cytotoxic effect. Notably, abnormal glial could mediate neuroinflammation, leading condition. Microglia, type cell, resident form forefront defense system. Dysfunctional astrocyte, different kind cell homeostatic function, impairs protein aggregate (amyloid-beta plaque) clearance AD. Studies shown that undergo alterations their genetic profile, cellular molecular responses, thus promote dysfunctional cross-talk Hence, targeting astrocytes-driven pathways resolve particular layers neuroinflammation set reliable therapeutic intervention AD progression.

Язык: Английский

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Role of astroglial toll-like receptors (TLRs) in central nervous system infections, injury and neurodegenerative diseases

Brain Behavior and Immunity, Год журнала: 2020, Номер 91, С. 740 - 755

Опубликована: Окт. 8, 2020

Central nervous system (CNS) innate immunity plays essential roles in infections, neurodegenerative diseases, and brain or spinal cord injuries. Astrocytes microglia are the principal cells that mediate CNS. Pattern recognition receptors (PRRs), expressed by astrocytes microglia, sense pathogen-derived endogenous ligands released damaged initiate immune response. Toll-like (TLRs) a well-characterized family of PRRs. The contribution microglial TLR signaling to CNS pathology has been extensively investigated. Even though assume wide variety key functions, information about role astroglial TLRs disease injuries is limited. Because display heterogeneity exhibit phenotypic plasticity depending on effectors present local milieu, they can exert both detrimental beneficial effects. modulators these paradoxical properties. goal current review highlight played diseases. We discuss host defense as well dissemination viral bacterial infections examine link between pathogenesis diseases evidence showing pivotal influence sterile inflammation injury. Finally, we define research questions areas warrant further investigations context astrocytes, TLRs, dysfunction.

Язык: Английский

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Where Is Dopamine and how do Immune Cells See it?: Dopamine-Mediated Immune Cell Function in Health and Disease

Journal of Neuroimmune Pharmacology, Год журнала: 2019, Номер 15(1), С. 114 - 164

Опубликована: Май 11, 2019

Язык: Английский

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Astrocytes: a double-edged sword in neurodegenerative diseases

Neural Regeneration Research, Год журнала: 2021, Номер 16(9), С. 1702 - 1702

Опубликована: Янв. 1, 2021

Astrocytes play multifaceted and vital roles in maintaining neurophysiological function of the central nervous system by regulating homeostasis, increasing synaptic plasticity, sustaining neuroprotective effects. become activated as a result inflammatory responses during progression pathological changes associated with neurodegenerative disorders. Reactive astrocytes (neurotoxic A1 A2) are triggered disease pathogenesis due to neuroinflammation ischemia. However, only limited body literature describes morphological functional diseases. The present review investigated detrimental beneficial diseases reported recent studies, these cells have promising therapeutic potential offer new approaches for treatment

Язык: Английский

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Engineered virus-like particles for transient delivery of prime editor ribonucleoprotein complexes in vivo

Nature Biotechnology, Год журнала: 2024, Номер 42(10), С. 1526 - 1537

Опубликована: Янв. 8, 2024

Prime editing enables precise installation of genomic substitutions, insertions and deletions in living systems. Efficient vitro vivo delivery prime components, however, remains a challenge. Here we report editor engineered virus-like particles (PE-eVLPs) that deliver proteins, guide RNAs nicking single as transient ribonucleoprotein complexes. We systematically v3 v3b PE-eVLPs with 65- to 170-fold higher efficiency human cells compared PE-eVLP construct based on our previously reported base eVLP architecture. In two mouse models genetic blindness, injections resulted therapeutically relevant levels the retina, protein expression restoration partial visual function rescue. Optimized support ribonucleoproteins, enhancing potential safety by reducing off-target obviating possibility oncogenic transgene integration.

Язык: Английский

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From Synapses to Circuits, Astrocytes Regulate Behavior

Frontiers in Neural Circuits, Год журнала: 2022, Номер 15

Опубликована: Янв. 4, 2022

Astrocytes are non-neuronal cells that regulate synapses, neuronal circuits, and behavior. ensheath synapses to form the tripartite synapse where astrocytes influence formation, function, plasticity. Beyond synapse, recent research has revealed astrocyte influences on nervous system extend modulation of circuitry Here we review findings active role in behavioral with a focus vivo studies, primarily mice. Using tools acutely manipulate astrocytes, such as optogenetics or chemogenetics, studies reviewed here have demonstrated causal for sleep, memory, sensorimotor behaviors, feeding, fear, anxiety, cognitive processes like attention flexibility. Current future directions astrocyte-specific manipulation, including methods probing heterogeneity, discussed. Understanding contribution circuit activity organismal behavior will be critical toward understanding how function gives rise

Язык: Английский

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Role of pyroptosis in the pathogenesis of various neurological diseases

Brain Behavior and Immunity, Год журнала: 2024, Номер 117, С. 428 - 446

Опубликована: Фев. 7, 2024

Язык: Английский

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