alpha-synuclein and Cerebrovascular-Disorders

α-Synuclein (α-Syn) is a small, soluble, disordered protein that is widely expressed in the nervous system. Although its physiological functions are not yet fully understood, it is mainly involved in synaptic vesicle transport, neurotransmitter synthesis and release, cell membrane homeostasis, lipid synthesis, mitochondrial and lysosomal activities, and heavy metal removal. The complex and inconsistent pathological manifestations of α-Syn are attributed to its structural instability, mutational complexity, misfolding, and diverse posttranslational modifications. These effects trigger mitochondrial dysfunction, oxidative stress, and neuroinflammatory responses, resulting in neuronal death and neurodegeneration. Several recent studies have discovered the pathogenic roles of α-Syn in traumatic and vascular central nervous system diseases, such as traumatic spinal cord injury, brain injury, and stroke, and in aggravating the processes of neurodegeneration. This review aims to highlight the structural and pathophysiological changes in α-Syn and its mechanism of action in traumatic and vascular diseases of the central nervous system.

Topics: alpha-Synuclein; Animals; Central Nervous System Diseases; Cerebrovascular Disorders; Humans; Trauma, Nervous System

Chronic cerebral hypoperfusion (CCH) is an important pathophysiological basis for AD and vascular cognitive impairment (VCI), but the underlying mechanisms are not completely clear. Age-related mitochondrial aging-like changes were closely associated with nervous system diseases and ischemia. This study aimed to observe the changes of cognitive function and hippocampal mitochondrial aging in rats with CCH.. Healthy male SD rats were randomly divided into CCH group and sham group, and then were randomly divided into four subgroups [1-, 4-, 12- and 24-week (W) groups]. The cognitive function of rats was detected by the Open field, Object recognition and Morris water maze tests. The mitochondrial structure was observed under electron microscope. The mitochondrial alpha-synuclein was detected by western blotting and immunofluorescence, and the MtDNA4834bp deletion and the PGC-1alpha levels were detected by PCR in the hippocampus of rats.. The lasting spatial learning and memory deficits were more obvious in CCH group. The mitochondrial shape, cristae and vacuolation showed more obvious damage in CCH group. Mitochondrial DNA4834bp deletion rate in CCH group was significantly increased at 4W and 12W with decreased abnormality, and PGC-1α was increased at each time points, wherein the 12W group showed significant increase. The mitochondrial alpha-synuclein in CCH group was increased more obviously. The increase of alpha-synuclein in the hippocampal DG in CCH group was more obvious.. CCH induced long-term spatial learning and memory deficits. The related alterations of mitochondrial aging and alpha-synuclein in the hippocampus are crucial for VCI pathogenesis.

Topics: Aging; alpha-Synuclein; Animals; Cerebrovascular Disorders; Cognitive Dysfunction; Hippocampus; Male; Maze Learning; Memory Disorders; Mitochondria; Models, Animal; Rats; Rats, Sprague-Dawley; Spatial Learning

The pathological impact of chronic cerebral hypoperfusion (CCH) on Alzheimer's disease (AD) is still poorly understood. In the present study, we investigated the role of CCH on an AD mouse model in phosphorylated tau and α-synuclein pathology, neurovascular unit, cerebrovascular remodeling, and neurovascular trophic coupling. Moreover, examined protective effect of a new antioxidant Twendee X (TwX).. APP23 mice were implanted to bilateral common carotid arteries stenosis with ameroid constrictors to gradually decrease the cerebral blood flow. The effects of the administration of TwX were evaluated by immunohistochemical analysis and Immunofluorescent histochemistry.. Our findings indicate that administration of a new antioxidative mixture TwX substantially reduced the above neuropathologic abnormalities, suggesting a potential therapeutic benefit of TwX for AD with CCH.

Topics: alpha-Synuclein; Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Antioxidants; Ascorbic Acid; Brain; Cerebrovascular Disorders; Cystine; Dietary Supplements; Disease Models, Animal; Female; Genetic Predisposition to Disease; Glutamine; Male; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Neurovascular Coupling; Phenotype; Phosphorylation; tau Proteins

Elevated plasma total homocysteine is associated with increased risk of dementia/Alzheimer's disease, but underlying pathophysiological mechanisms are not fully understood. This study investigated possible links between baseline homocysteine, and post-mortem neuropathological and magnetic resonance imaging findings up to 10 years later in the Vantaa 85+ population including people aged ≥85 years. Two hundred and sixty-five individuals had homocysteine and autopsy data, of which 103 had post-mortem brain magnetic resonance imaging scans. Methenamine silver staining was used for amyloid-β and modified Bielschowsky method for neurofibrillary tangles and neuritic plaques. Macroscopic infarcts were identified from cerebral hemispheres, brainstem and cerebellum slices. Standardized methods were used to determine microscopic infarcts, cerebral amyoloid angiopathy, and α-synuclein pathology. Magnetic resonance imaging was used for visual ratings of the degree of medial temporal lobe atrophy, and periventricular and deep white matter hyperintensities. Elevated baseline homocysteine was associated with increased neurofibrillary tangles count at the time of death: for the highest homocysteine quartile, odds ratio (95% confidence interval) was 2.60 (1.28-5.28). The association was observed particularly in people with dementia, in the presence of cerebral infarcts, and with longer time between the baseline homocysteine assessment and death. Also, elevated homocysteine tended to relate to amyloid-β accumulation, but this was seen only with longer baseline-death interval: odds ratio (95% confidence interval) was 2.52 (0.88-7.19) for the highest homocysteine quartile. On post-mortem magnetic resonance imaging, for the highest homocysteine quartile odds ratio (95% confidence interval) was 3.78 (1.12-12.79) for more severe medial temporal atrophy and 4.69 (1.14-19.33) for more severe periventricular white matter hyperintensities. All associations were independent of several potential confounders, including common vascular risk factors. No relationships between homocysteine and cerebral macro- or microinfarcts, cerebral amyoloid angiopathy or α-synuclein pathology were detected. These results suggest that elevated homocysteine in adults aged ≥85 years may contribute to increased Alzheimer-type pathology, particularly neurofibrillary tangles burden. This effect seems to be more pronounced in the presence of cerebrovascular pathology. Randomized controlled trials are needed t

Topics: Aged, 80 and over; alpha-Synuclein; Alzheimer Disease; Apolipoproteins E; Cerebral Amyloid Angiopathy; Cerebrovascular Disorders; Community Health Planning; Diagnosis; Female; Homocysteine; Humans; Magnetic Resonance Imaging; Male; Neurofibrillary Tangles; Plaque, Amyloid

Recent studies have shown an association between rapid eye movement sleep behavior disorder (RBD) and neurodegenerative disorders, especially alpha-synucleinopathies.. We investigated regional cerebral blood flow (rCBF) changes using single photon emission computed tomography (SPECT) in patients with idiopathic RBD (iRBD), to determine functional brain alterations associated with the disorder.. The SPECT data of 24 patients with iRBD were compared with those of 18 age-matched normal controls using statistical parametric mapping 2.. We found decreased rCBF in the parietooccipital lobe (precuneus), limbic lobe, and cerebellar hemispheres in patients with iRBD, which is commonly seen in patients with Lewy body disease (Parkinson's disease and dementia with Lewy bodies) or multiple system atrophy.. Our SPECT study suggests that iRBD can be a presymptomatic stage of alpha-synucleinopathies.

Topics: Aged; alpha-Synuclein; Cerebral Arteries; Cerebrovascular Circulation; Cerebrovascular Disorders; Comorbidity; Female; Humans; Male; Middle Aged; Radionuclide Imaging; REM Sleep Behavior Disorder