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Parkinson's disease (PD) is a neurodegenerative disorder characterized by both motor symptoms and non-motor features. A hallmark of PD is the misfolding and accumulation of alpha-synuclein (α-syn), which triggers neuroinflammation and drives neurodegeneration. Microglia, brain cells that play a central role in neuroinflammatory responses and help clear various unnecessary molecules within the brain, thus maintaining the brain's internal environment, respond to α-syn through mechanisms involving inflammation, propagation, and clearance. This review delves into the complex interplay between α-syn and microglia, elucidating how these interactions drive PD pathogenesis. Furthermore, we discuss emerging therapeutic strategies targeting the α-syn–microglia axis, with a focus on modulating microglial functions to mitigate neuroinflammation, enhance clearance, and prevent α-syn propagation, emphasizing their potential to slow PD progression. [ABSTRACT FROM AUTHOR]

Upregulation of reactive oxygen species (ROS) levels is a principal feature observed in the brains of neurodegenerative diseases such as Parkinson's disease (PD) and Alzheimer's disease (AD). In these diseases, oxidative stress can disrupt the blood–brain barrier (BBB). This disruption allows neurotoxic plasma components, blood cells, and pathogens to enter the brain, leading to increased ROS production, mitochondrial dysfunction, and inflammation. Collectively, these factors result in protein modification, lipid peroxidation, DNA damage, and, ultimately, neural cell damage. In this review article, we present the mechanisms by which oxidative damage leads to BBB breakdown in brain diseases. Additionally, we summarize potential therapeutic approaches aimed at reducing oxidative damage that contributes to BBB disruption in neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Spinocerebellar ataxia (SCA) is a heterogeneous disorder characterized by impaired balance and coordination caused by cerebellar dysfunction. The absence of treatments approved by the U.S. Food and Drug Administration for SCA has driven the investigation of alternative therapeutic strategies, including stem cell therapy. Mesenchymal stem cells (MSCs), known for their multipotent capabilities, have demonstrated significant potential in treating SCA. This review examines how MSCs may promote neuronal growth, enhance synaptic connectivity, and modulate brain inflammation. Recent findings from preclinical and clinical studies are also reviewed, emphasizing the promise of MSC therapy in addressing the unmet needs of SCA patients. Furthermore, ongoing clinical trials and future directions are proposed to address the limitations of the current approaches. [ABSTRACT FROM AUTHOR]

Background and Purpose: There is a scarcity of information regarding the role of prothrombin kringle‐2 (pKr‐2), which can be generated by active thrombin, in hippocampal neurodegeneration and Alzheimer's disease (AD). Experimental Approach To assess the role of pKr‐2 in association with the neurotoxic symptoms of AD, we determined pKr‐2 protein levels in post‐mortem hippocampal tissues of patients with AD and the hippocampi of five familial AD (5XFAD) mice compared with those of age‐matched controls and wild‐type (WT) mice, respectively. In addition, we investigated whether the hippocampal neurodegeneration and object memory impairments shown in 5XFAD mice were mediated by changes to pKr‐2 up‐regulation. Key Results: Our results demonstrated that pKr‐2 was up‐regulated in the hippocampi of patients with AD and 5XFAD mice, but was not associated with amyloid‐β aggregation in 5XFAD mice. The up‐regulation of pKr‐2 expression was inhibited by preservation of the blood–brain barrier (BBB) via addition of caffeine to their water supply or by treatment with rivaroxaban, an inhibitor of factor Xa that is associated with thrombin production. Moreover, the prevention of up‐regulation of pKr‐2 expression reduced neurotoxic symptoms, such as hippocampal neurodegeneration and object recognition decline due to neurotoxic inflammatory responses in 5XFAD mice. Conclusion and Implications: We identified a novel pathological mechanism of AD mediated by abnormal accumulation of pKr‐2, which functions as an important pathogenic factor in the adult brain via blood brain barrier (BBB) breakdown. Thus, pKr‐2 represents a novel target for AD therapeutic strategies and those for related conditions. [ABSTRACT FROM AUTHOR]