A New Acquaintance of Oligodendrocyte Precursor Cells in the Central Nervous System.

Oligodendrocyte precursor cells (OPCs) are a heterogeneous multipotent population in the central nervous system (CNS) that appear during embryogenesis and persist as resident cells in the adult brain parenchyma. OPCs could generate oligodendrocytes to participate in myelination. Recent advances have renewed our knowledge of OPC biology by discovering novel markers of oligodendroglial cells, the myelin-independent roles of OPCs, and the regulatory mechanism of OPC development. In this review, we will explore the updated knowledge on OPC identity, their multifaceted roles in the CNS in health and diseases, as well as the regulatory mechanisms that are involved in their developmental stages, which hopefully would contribute to a further understanding of OPCs and attract attention in the field of OPC biology.

An easy-to-perform method for microvessel isolation and primary brain endothelial cell culture to study Alzheimer's disease.

Dysfunction of the blood-brain barrier (BBB) has been increasingly recognised as a critical early event in Alzheimer's disease (AD) pathophysiology. Central to this mechanism is the impaired function of brain endothelial cells (BECs), the primary structural constituents of the BBB, the study of which is imperative for understanding AD pathophysiology. However, the published methods to isolate BECs are time-consuming and have a low success rate. Here, we developed a rapid and streamlined protocol for BEC isolation without using transgenic reporters, flow cytometry, and magnetic beads, which are essential for existing methods. Using this novel protocol, we isolated high-purity BECs from cell clusters of cortical microvessels from wild-type and APPswe/PS1dE9 (APP/PS1, a classical AD model) mice at 2, 4 and 9 months of age. Reduced levels of tight junction proteins Claudin-5 and Zonula Occludens-1, as well as glucose transporter 1, were observed in the isolated cortical microvessels from APP/PS1 mice and amyloid-ß (Aß) oligomer-treated BECs from wild-type mice. Trans-well permeability assay showed increased FITC-dextran leakage in BECs treated with Aß, suggesting impaired BBB permeability. BECs obtained using our novel protocol can undergo various experimental analyses, including immunofluorescence staining, western blotting, real-time PCR, and trans-well permeability assay. In conclusion, our novel protocol represents a reliable and valuable tool for in vitro modelling BBB to study AD-related mechanisms and develop targeted therapeutic strategies.

BOK-engaged mitophagy alleviates neuropathology in Alzheimer's disease.

Mitochondrial malfunction associated with impaired mitochondrial quality control and self-renewal machinery, known as mitophagy, is an under-appreciated mechanism precipitating synaptic loss and cognitive impairments in Alzheimer's disease (AD). Promoting mitophagy has been shown to improve cognitive function in AD animals. However, the regulatory mechanism was unclear, which formed the aim of this study. Here, we found that a neuron-specific loss of Bcl-2 family member BOK in AD patients and APPswe/PS1dE9 (APP/PS1) mice is closely associated with mitochondrial damage and mitophagy defects. We further revealed that BOK is the key to the Parkin-mediated mitophagy through competitive binding to the MCL1/Parkin complex, resulting in Parkin release and translocation to damaged mitochondria to initiate mitophagy. Furthermore, overexpressing bok in hippocampal neurons of APP/PS1 mice alleviated mitophagy and mitochondrial malfunction, resulting in improved cognitive function. Conversely, the knockdown of bok worsened the aforementioned AD-related changes. Our findings uncover a novel mechanism of BOK signaling through regulating Parkin-mediated mitophagy to mitigate amyloid pathology, mitochondrial and synaptic malfunctions, and cognitive decline in AD, thus representing a promising therapeutic target.

Remyelination-oriented clemastine treatment attenuates neuropathies of optic nerve and retina in glaucoma.

As one of the top causes of blindness worldwide, glaucoma leads to diverse optic neuropathies such as degeneration of retinal ganglion cells (RGCs). It is widely accepted that the level of intraocular pressure (IOP) is a major risk factor in human glaucoma, and reduction of IOP level is the principally most well-known method to prevent cell death of RGCs. However, clinical studies show that lowering IOP fails to prevent RGC degeneration in the progression of glaucoma. Thus, a comprehensive understanding of glaucoma pathological process is required for developing new therapeutic strategies. In this study, we provide functional and histological evidence showing that optic nerve defects occurred before retina damage in an ocular hypertension glaucoma mouse model, in which oligodendroglial lineage cells were responsible for the subsequent neuropathology. By treatment with clemastine, an Food and Drug Administration (FDA)-approved first-generation antihistamine medicine, we demonstrate that the optic nerve and retina damages were attenuated via promoting oligodendrocyte precursor cell (OPC) differentiation and enhancing remyelination. Taken together, our results reveal the timeline of the optic neuropathies in glaucoma and highlight the potential role of oligodendroglial lineage cells playing in its treatment. Clemastine may be used in future clinical applications for demyelination-associated glaucoma.

Endothelial DR6 in blood-brain barrier malfunction in Alzheimer's disease.

The impairment of the blood-brain barrier (BBB) has been increasingly recognised as a critical element in the early pathogenesis of Alzheimer's disease (AD), prompting a focus on brain endothelial cells (BECs), which serve as the primary constituents of the BBB. Death receptor 6 (DR6) is highly expressed in brain vasculature and acts downstream of the Wnt/ß-catenin pathway to promote BBB formation during development. Here, we found that brain endothelial DR6 levels were significantly reduced in a murine model of AD (APPswe/PS1dE9 mice) at the onset of amyloid-ß (Aß) accumulation. Toxic Aß25-35 oligomer treatment recapitulated the reduced DR6 in cultured BECs. We further showed that suppressing DR6 resulted in BBB malfunction in the presence of Aß25-35 oligomers. In contrast, overexpressing DR6 increased the level of BBB functional proteins through the activation of the Wnt/ß-catenin and JNK pathways. More importantly, DR6 overexpression in BECs was sufficient to rescue BBB dysfunction in vitro. In conclusion, our findings provide new insight into the role of endothelial DR6 in AD pathogenesis, highlighting its potential as a therapeutic target to tackle BBB dysfunction in early-stage AD progression.

Input-output specific orchestration of aversive valence in lateral habenula during stress dynamics. / åŽ‹åŠ›åŠ¨æ€è¿‡ç¨‹ä¸­è´Ÿæ€§æƒ ç»ªåœ¨å¤–ä¾§ç¼°æ ¸çš„"è¾“å ¥-输出"特异性整合.

Stress has been considered as a major risk factor for depressive disorders, triggering depression onset via inducing persistent dysfunctions in specialized brain regions and neural circuits. Among various regions across the brain, the lateral habenula (LHb) serves as a critical hub for processing aversive information during the dynamic process of stress accumulation, thus having been implicated in the pathogenesis of depression. LHb neurons integrate aversive valence conveyed by distinct upstream inputs, many of which selectively innervate the medial part (LHbM) or lateral part (LHbL) of LHb. LHb subregions also separately assign aversive valence via dissociable projections to the downstream targets in the midbrain which provides feedback loops. Despite these strides, the spatiotemporal dynamics of LHb-centric neural circuits remain elusive during the progression of depression-like state under stress. In this review, we attempt to describe a framework in which LHb orchestrates aversive valence via the input-output specific neuronal architecture. Notably, a physiological form of Hebbian plasticity in LHb under multiple stressors has been unveiled to incubate neuronal hyperactivity in an input-specific manner, which causally encodes chronic stress experience and drives depression onset. Collectively, the recent progress and future efforts in elucidating LHb circuits shed light on early interventions and circuit-specific antidepressant therapies.

Targeting connexins: possible game changer in managing neuropathic pain?

Neuropathic pain is a chronic debilitating condition caused by nerve injury or a variety of diseases. At the core of neuropathic pain lies the aberrant neuronal excitability in the peripheral and/or central nervous system (PNS and CNS). Enhanced connexin expression and abnormal activation of connexin-assembled gap junctional channels are prominent in neuropathic pain along with reactive gliosis, contributing to neuronal hypersensitivity and hyperexcitability. In this review, we delve into the current understanding of how connexin expression and function contribute to the pathogenesis and pathophysiology of neuropathic pain and argue for connexins as potential therapeutic targets for neuropathic pain management.

Efficacy of exercise rehabilitation for managing patients with Alzheimer's disease.

Alzheimer's disease (AD) is a progressive and degenerative neurological disease characterized by the deterioration of cognitive functions. While a definitive cure and optimal medication to impede disease progression are currently unavailable, a plethora of studies have highlighted the potential advantages of exercise rehabilitation for managing this condition. Those studies show that exercise rehabilitation can enhance cognitive function and improve the quality of life for individuals affected by AD. Therefore, exercise rehabilitation has been regarded as one of the most important strategies for managing patients with AD. Herein, we provide a comprehensive analysis of the currently available findings on exercise rehabilitation in patients with AD, with a focus on the exercise types which have shown efficacy when implemented alone or combined with other treatment methods, as well as the potential mechanisms underlying these positive effects. Specifically, we explain how exercise may improve the brain microenvironment and neuronal plasticity. In conclusion, exercise is a cost-effective intervention to enhance cognitive performance and improve quality of life in patients with mild to moderate cognitive dysfunction. Therefore, it can potentially become both a physical activity and a tailored intervention. This review may aid the development of more effective and individualized treatment strategies to address the challenges imposed by this debilitating disease, especially in low- and middle-income countries.