27-Hydroxycholesterol Drives the Spread of α-Synuclein Pathology in Parkinson's Disease.

BACKGROUND: The accumulation and aggregation of α-synuclein (α-Syn) are characteristic of Parkinson's disease (PD). Epidemiological evidence indicates that hyperlipidemia is associated with an increased risk of PD. The levels of 27-hydroxycholesterol (27-OHC), a cholesterol oxidation derivative, are increased in the brain and cerebrospinal fluid of patients with PD. However, whether 27-OHC plays a role in α-Syn aggregation and propagation remains elusive. OBJECTIVE: The aim of this study was to determine whether 27-OHC regulates α-Syn aggregation and propagation. METHODS: Purified recombinant α-Syn, neuronal cultures, and α-Syn fibril-injected mouse model of PD were treated with 27-OHC. In addition, CYP27A1 knockout mice were used to investigate the effect of lowering 27-OHC on α-Syn pathology in vivo. RESULTS: 27-OHC accelerates the aggregation of α-Syn and enhances the seeding activity of α-Syn fibrils. Furthermore, the 27-OHC-modified α-Syn fibrils localize to the mitochondria and induce mitochondrial dysfunction and neurotoxicity. Injection of 27-OHC-modified α-Syn fibrils induces enhanced spread of α-Syn pathology and dopaminergic neurodegeneration compared with pure α-Syn fibrils. Similarly, subcutaneous administration of 27-OHC facilitates the seeding of α-Syn pathology. Genetic deletion of cytochrome P450 27A1 (CYP27A1), the enzyme that converts cholesterol to 27-OHC, ameliorates the spread of pathologic α-Syn, degeneration of the nigrostriatal dopaminergic pathway, and motor impairments. These results indicate that the cholesterol metabolite 27-OHC plays an important role in the pathogenesis of PD. CONCLUSIONS: 27-OHC promotes the aggregation and spread of α-Syn. Strategies aimed at inhibiting the CYP27A1-27-OHC axis may hold promise as a disease-modifying therapy to halt the progression of α-Syn pathology in PD. © 2023 International Parkinson and Movement Disorder Society.

Leukoaraiosis severity is related to increased risk of early neurological deterioration in acute ischemic stroke: a retrospective observational study.

OBJECTIVES: The relationship between leukoaraiosis and early neurological deterioration in acute cerebral infarction patients remains controversial. We tried to determine whether an association existed between leukoaraiosis and early neurological deterioration in patients with acute ischemic stroke. MATERIALS AND METHODS: We retrospectively enrolled acute cerebral infarction patients admitted to our our department within 4.5-72.0 h of symptom onset between January 2016 and March 2022. On the basis of the van Swieten scale, leukoaraiosis was evaluated as supratentorial white matter hypoattenuation on admission head CT and graded as 0 (absent), 1 (mild), 2 (moderate) and 3-4 (severe). Early neurological deterioration was defined as an increase in the National Institute of Health Stroke Scale score by > = 2 points in the total score, or > = 1 point in motor power within the first seven days after admission. RESULTS: Among 736 patients, 522 (70.9%) patients had leukoaraiosis, and of these, 332 (63.6%) had mild leukoaraiosis, 41 (7.9%) had moderate leukoaraiosis, and 149 (28.5%) had severe leukoaraiosis. 118 (16.0%) patients experienced early neurological deterioration: 20 of the 214 (9.5%) patients without leukoaraiosis and 98 of the 522 (18.8%) patients with leukoaraiosis. In multiple regression analysis, we found van Swieten scale predicted early neurological deterioration independently (OR = 1.570; 95% CI: 1.226-2.012). CONCLUSIONS: Leukoaraiosis is common in acute cerebral infarction patients and leukoaraiosis severity is related to increased risk of early neurological deterioration in the patients.

Cofilin promotes tau pathology in Alzheimer's disease.

The molecular mechanisms mediating the aggregation and transmission of tau in AD remain unclear. Here, we show that the actin-binding protein cofilin is cleaved by a cysteine protease asparagine endopeptidase (AEP) at N138 in the brains of patients with AD. The AEP-generated cofilin 1-138 fragment interacts with tau and promotes its aggregation. The mixed fibrils consisting of cofilin 1-138 and tau are more pathogenic to cells than pure tau fibrils. Furthermore, overexpression of cofilin 1-138 in the brain facilitates the propagation of pathological tau aggregates and promotes AD-like cognitive impairments in tau P301S mice. However, mice infected with adeno-associated viruses (AAVs) encoding an AEP-uncleavable cofilin mutant show attenuated tau pathology and cognitive impairments compared with mice injected with AAVs encoding wild-type cofilin. Together, these observations support the role of the cofilin 1-138 fragment in the aggregation and transmission of tau pathology during the onset and progression of AD.

Cofilin 1 promotes the pathogenicity and transmission of pathological α-synuclein in mouse models of Parkinson's disease.

The pathological hallmark of Parkinson's disease (PD) is the presence of Lewy bodies (LBs) with aggregated α-synuclein being the major component. The abnormal α-synuclein aggregates transfer between cells, recruit endogenous α-synuclein into toxic LBs, and finally trigger neuronal injury. However, the molecular mechanisms mediating the aggregation and transmission of pathological α-synuclein remain unknown. Previously we found that cofilin 1, a member of the actin-binding protein, promotes the aggregation and pathogenicity of α-synuclein in vitro. Here we further investigated the effect of cofilin 1 in mouse models of PD. We found that the mixed fibrils composed of cofilin 1 and α-synuclein are more pathogenic to mice and more prone to propagation than pure α-synuclein fibrils. Overexpression of cofilin 1 enhances the seeding and spreading of α-synuclein aggregates, and induces PD-like behavioral impairments in mice. Together, these results illustrate the important role of cofilin 1 in the pathogenicity and transmission of α-synuclein during the onset and progression of PD.

Cholesterol Metabolism in Neurodegenerative Diseases: Molecular Mechanisms and Therapeutic Targets.

Cholesterol is an indispensable component of the cell membrane and plays vital roles in critical physiological processes. Brain cholesterol accounts for a large portion of total cholesterol in the human body, and its content must be tightly regulated to ensure normal brain function. Disorders of cholesterol metabolism in the brain are linked to neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and other atypical cognitive deficits that arise at old age. However, the specific role of cholesterol metabolism disorder in the pathogenesis of neurodegenerative diseases has not been fully elucidated. Statins that are a class of lipid-lowering drugs have been reported to have a positive effect on neurodegenerative diseases. Herein, we reviewed the physiological and pathological conditions of cholesterol metabolism and discussed the possible mechanisms of cholesterol metabolism and statin therapy in neurodegenerative diseases.

Cofilin 1 promotes the aggregation and cell-to-cell transmission of α-synuclein in Parkinson's disease.

The histopathological hallmark of Parkinson's disease (PD) is the presence of fibrillar aggregates referred to as Lewy bodies (LBs), in which α-synuclein is the major component. Converging evidence supports the prion-like transmission of α-synuclein aggregates in the onset and progression of PD. Intracellular α-synuclein aggregates into pathological fibrils, which can be transferred from aggregate-producing cells to aggregate-free cells, triggering neuronal injury and the progression of pathology. However, the specific mechanisms mediating the aggregation and transmission of pathological α-synuclein remain unknown. Here we show that cofilin 1 binds to α-synuclein and promotes its aggregation. The mixed fibrils consist of cofilin 1 and α-synuclein are more compact and more potent than pure α-synuclein fibrils in seeding α-synuclein aggregation. Cofilin 1 also facilitates the uptake of α-synuclein fibrils and finally induces neuronal dysfunction. Together, these observations indicate that cofilin 1 acts as a crucial mediator in the aggregation and propagation of pathological α-synuclein, contributing to the pathogenesis of PD.

Gaze Estimation Method Using Analysis of Electrooculogram Signals and Kinect Sensor.

A gaze estimation system is one of the communication methods for severely disabled people who cannot perform gestures and speech. We previously developed an eye tracking method using a compact and light electrooculogram (EOG) signal, but its accuracy is not very high. In the present study, we conducted experiments to investigate the EOG component strongly correlated with the change of eye movements. The experiments in this study are of two types: experiments to see objects only by eye movements and experiments to see objects by face and eye movements. The experimental results show the possibility of an eye tracking method using EOG signals and a Kinect sensor.

EOG-sEMG Human Interface for Communication.

The aim of this study is to present electrooculogram (EOG) and surface electromyogram (sEMG) signals that can be used as a human-computer interface. Establishing an efficient alternative channel for communication without overt speech and hand movements is important for increasing the quality of life for patients suffering from amyotrophic lateral sclerosis, muscular dystrophy, or other illnesses. In this paper, we propose an EOG-sEMG human-computer interface system for communication using both cross-channels and parallel lines channels on the face with the same electrodes. This system could record EOG and sEMG signals as "dual-modality" for pattern recognition simultaneously. Although as much as 4 patterns could be recognized, dealing with the state of the patients, we only choose two classes (left and right motion) of EOG and two classes (left blink and right blink) of sEMG which are easily to be realized for simulation and monitoring task. From the simulation results, our system achieved four-pattern classification with an accuracy of 95.1%.

Tanshinone IIA protects PC12 cells from ß-amyloid(25-35)-induced apoptosis via PI3K/Akt signaling pathway.

For the aging populations of any nation, Dementia is becoming a primary problem and Alzheimer's dementia (AD) is the most common type. However, until now, there is no effective treatment for AD. Tanshinone IIA (Tan IIA) has been reported for neuroprotective potential to against amyloid ß peptides (Aß)-induced cytotoxicity in the rat pheochromocytoma cell line PC-12, which is widely used as AD research model, but the mechanism still remains unclear. To investigate the effect of Tan IIA and the possible molecular mechanism in the apoptosis of PC12 cells, we induced apoptosis in PC12 cells with ß-amyloid(25-35), and treated cells with Tan IIA. After 24 h treatment, we found that Tan IIA increased the cell viability and reduced the number of apoptotic cells induced by Aß(25-35). However, neuroprotection of Tan IIA was abolished by PI3K inhibitor LY294002. Meanwhile, Treatment with lithium chloride, a phosphorylation inhibitor of GSK3ß, which is a downstream target of PI3K/Akt, can block Aß(25-35)-induced cell apoptosis in a Tan IIA-like manner. Our findings suggest that Tan IIA is an effective neuroprotective agent and a viable candidate in AD therapy and PI3K/Akt activation and GSK3ß phosphorylation are involved in the neuroprotection of Tan IIA.

Schisandrin B protects PC12 cells by decreasing the expression of amyloid precursor protein and vacuolar protein sorting 35.

PC12 cell injury was induced using 20 µM amyloid ß-protein 25-35 to establish a model of Alzheimer's disease. The cells were then treated with 5, 10, and 25 µM Schisandrin B. Methylthiazolyldiphenyl-tetrazolium bromide assays and Hoechst 33342 staining results showed that with increasing Schisandrin B concentration, the survival rate of PC12 cells injured by amyloid ß-protein 25-35 gradually increased and the rate of apoptosis gradually decreased. Reverse transcription-PCR, immunocytochemical staining and western blot results showed that with increasing Schisandrin B concentration, the mRNA and protein expression of vacuolar protein sorting 35 and amyloid precursor protein were gradually decreased. Vacuolar protein sorting 35 and amyloid precursor protein showed a consistent trend for change. These findings suggest that 5, 10, and 25 µM Schisandrin B antagonizes the cellular injury induced by amyloid ß-protein 25-35 in a dose-dependent manner. This may be caused by decreasing the expression of vacuolar protein sorting 35 and amyloid precursor protein.