Endothelial LRP1-ICD Accelerates Cognition-Associated Alpha-Synuclein Pathology and Neurodegeneration through PARP1 Activation in a Mouse Model of Parkinson's Disease.

Parkinson's disease (PD) is characterized by progressive loss of dopaminergic neurons and accumulation of misfolded alpha-synuclein (αSyn) into Lewy bodies. In addition to motor impairment, PD commonly presents with cognitive impairment, a non-motor symptom with poor outcome. Cortical αSyn pathology correlates closely with vascular risk factors and vascular degeneration in cognitive impairment. However, how the brain microvasculature regulates αSyn pathology and neurodegeneration remains unclear. Here, we constructed a rapidly progressive PD model by injecting alpha-synuclein preformed fibrils (αSyn PFFs) into the cerebral cortex and striatum. Brain capillaries in mice with cognitive impairment showed a reduction in diameter and length after 6 months, along with string vessel formation. The intracellular domain of low-density lipoprotein receptor-related protein-1 (LRP1-ICD) was upregulated in brain microvascular endothelium. LRP1-ICD promoted αSyn PFF uptake and exacerbated endothelial damage and neuronal apoptosis. Then, we overexpressed LRP1-ICD in brain capillaries using an adeno-associated virus carrying an endothelial-specific promoter. Endothelial LRP1-ICD worsened αSyn PFF-induced vascular damage, αSyn pathology, or neuron death in the cortex and hippocampus, resulting in severe motor and cognitive impairment. LRP1-ICD increased the synthesis of poly(adenosine 5'-diphosphate-ribose) (PAR) in the presence of αSyn PFFs. Inhibition of PAR polymerase 1 (PARP1) prevented vascular-derived injury, as did loss of PARP1 in the endothelium, which was further implicated in endothelial cell proliferation and inflammation. Together, we demonstrate a novel vascular mechanism of cognitive impairment in PD. These findings support a role for endothelial LRP1-ICD/PARP1 in αSyn pathology and neurodegeneration, and provide evidence for vascular protection strategies in PD therapy.

TGR5 Agonist INT-777 Alleviates Inflammatory Neurodegeneration in Parkinson's Disease Mouse Model by Modulating Mitochondrial Dynamics in Microglia.

Parkinson's disease (PD) is one of the most common chronic progressive neurodegenerative diseases that affects both motor and non-motor functions. Bile acids modulate the immune system by targeting brain receptors. INT-777, a 6α-ethyl-23(S)-methyl derivative of cholic acid (S-EMCA), acts as an agonist for Takeda G protein-coupled receptor-5 (TGR5) and has neuroprotective properties. However, the effects of INT-777 on PD have not yet been investigated. In a subchronic PD model, mice treated with 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) developed motor deficits and cognitive impairment that were ameliorated after intranasal administration of INT-777. INT-777 prevented MPTP-induced neurodegeneration and microglia activation in the substantia nigra pars compacta, hippocampus, and cortical layer V. Based on bioinformatics and wet lab data, INT-777 inhibited microglia activation by suppressing the release of tumor necrosis factor alpha (TNF-α) in the hippocampus, along with secondary chemokines (C-C motif ligand 3 (CCL3) and CCL6) in these three brain regions. INT-777 inhibited TNF-α production by repairing mitochondrial damage, which was associated with nuclear factor-erythroid 2-related factor-2 (NRF2) activation and p62/LC3B-mediated autophagy. INT-777 reversed the downregulation of heme oxygenase-1 (HO1), NAD(P)H quinone oxidoreductase-1 (NQO1) and accumulation of p62 in microglia treated with 1-methyl-4-phenylpyridinium (MPP+). However, TGR5 knockdown in microglia abolished INT-777's inhibition of TNF-α release, resulting in neuronal death. Therefore, PD cognitive impairment is associated with hippocampal TNF-α elevation as a result of mitochondrial damage in microglia. Our data reveal the potential role of TGR5 in modulating inflammation-mediated neurodegeneration in PD, and provides new insights for bile acid metabolites as promising disease-modifying drugs for PD.

Reduced Retinal Microvascular Perfusion in Patients With Stroke Detected by Optical Coherence Tomography Angiography.

Currently there is a shortage of biomarkers for stroke, one of the leading causes of death and disability in aging populations. Retinal vessels offer a unique and accessible "window" to study the microvasculature in vivo. However, the relationship between the retinal microvasculature and stroke is not entirely clear. To investigate the retinal microvascular characteristics in stroke, we recruited patients with stroke and age-matched control subjects from a tertiary hospital in China. The macular vessel density (VD) in the superficial capillary plexus (SCP) and deep capillary plexus (DCP), foveal avascular zone (FAZ) metrics, and optical coherence tomography angiography (OCTA) measured optic disc VD were recorded for analysis. A total of 189 patients with stroke and 195 control subjects were included. After adjusting for sex, visual acuity, systolic and diastolic blood pressure, a history of smoking, levels of hemoglobulin (HbA1c), cholesterol, and high-density lipoprotein (HDL), the macular VD of SCP and DCP in all sectors was decreased in patients with stroke. In the stroke group, the VD around the FAZ and the VD of the optic disk were lower. Logistic regression found the parafovea-superior-hemi VD of DCP > 54.53% [odds ratio (OR): 0.169] as a protective factor of stroke. Using the integration of all OCTA parameters and traditional risk factors, the area under the receiver operating characteristic (AUC) curve of distinguishing patients with stroke was 0.962, with a sensitivity of 0.944 and a specificity of 0.871. Our study demonstrates that the retinal VD is decreased in patients with stroke independently of the traditional risk factors of stroke, which may shed light on the monitoring of stroke using the retinal microvascular parameters.

L-Asparaginase Exerts Neuroprotective Effects in an SH-SY5Y-A53T Model of Parkinson's Disease by Regulating Glutamine Metabolism.

Background: Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide and involves deficiencies in alpha-synuclein (α-Syn) degradation. Effective therapeutic strategies for PD are urgently needed. L-asparaginase (L-ASNase) has been developed for therapeutic applications in many fields because it catalyzes the hydrolysis of asparagine and glutamine in cancer cells, which may also activate autophagy and induce the degradation of accumulated α-Syn. However, the efficacy and related mechanism of L-ASNase in PD remain poorly understood. Methods: We determined the correlation between L-ASNase and autophagic degradation of α-Syn in a cell model of PD. Mitochondrial function and apoptosis were examined in the presence or absence of L-ASNase. Then, we applied GC-MS/MS targeted amino acid metabolomics analysis to validate the amino acid regulation induced by L-ASNase treatment. Glutamine was added to verify whether the neuroprotective effect was induced by deprivation of glutamine. α-Syn-related autophagy and mitochondrial fusion/fission dynamics were detected to explore the mechanism of L-ASNase-based therapy in PD. Results: L-ASNase activated the autophagic degradation of α-Syn in a cell model of PD without cytotoxicity at specific concentrations/times. Under these conditions, L-ASNase showed substantial neuroprotective effects, including improvements in mitochondrial function and decreased apoptosis. Through GC-MS/MS targeted analysis, glutamine metabolism was identified as the target of L-ASNase in PD treatment, and the neuroprotective effect of L-ASNase was reduced after glutamine supplementation. Conclusions: Our study demonstrated for the first time that L-ASNase had a neuroprotective effect on a cell model of PD through a moderate deprivation of glutamine, which induced autophagic activation and mitochondrial fusion. Therefore, we demonstrated that L-ASNase could be a promising and effective drug for PD treatment.

A Follow-up Study of Cerebral Microbleeds in Patients Who Received Stents for Symptomatic Cerebral Artery Stenosis.

BACKGROUND: The aims of this study were to explore (i) the dynamic changes in cerebral microbleeds (CMBs) in patients with symptomatic cerebral artery stenosis who received endovascular stent-assisted angioplasty and (ii) the risk factors associated with the new incidence of CMBs as well as whether CMBs increased the risk of vascular events in these patients. METHODS: Clinical information and magnetic resonance images were collected on admission and 3 months after endovascular stent-assisted angioplasty. Based on susceptibility-weighted imaging, the patients were divided into groups with or without newly developed CMBs, and between-group differences in risk factors were compared. We also compared whether CMBs increased the risk of vascular events among those patients. RESULTS: Seventy-three patients completed the relevant follow-up examinations. After an average follow-up period of 109 days, 7 (9.6%) patients showed new CMBs. A univariate analysis showed that the number of lacunar infarcts and the increase in systolic blood pressure were higher in patients with new CMBs than in those without new CMBs, and these differences were significant (P = 0.034, P = 0.001). Increased systolic blood pressure was an independent risk factor for developing new CMBs (P = 0.017). CONCLUSIONS: CMBs may be a continuously progressing cerebral small-vessel disease. The newly developed CMBs in patients with intracranial and/or extracranial stents were associated with increased systolic blood pressure but not with the number of baseline CMBs.

Neuroprotection by platelet-activating factor acetylhydrolase in a mouse model of transient cerebral ischemia.

Neuronal damage after transient cerebral ischemia is exacerbated by signaling pathways involving activated platelet-activating factor (PAF) and ameliorated by PAF-acetylhydrolase (PAF-AH); but whether cerebral neurons can be rescued by human recombinant PAF-AH (rPAF-AH) remains unknown. Adult male mice underwent a 60 min middle cerebral artery occlusion (MCAO) and reperfusion for 24h. Then, the mice received intravenous tail injections with different drugs. Neurological behavioral function was evaluated by Bederson's test, and cerebral infarction volume was assessed with tetrazolium chloride (TTC) staining. mRNA and protein expression levels of matrix metalloproteinase-2 (MMP-2, collagenase-1), MMP-9 (gelatinase-B), and vascular endothelial growth factor (VEGF) were determined by quantitative real-time PCR (RT-PCR) and western blot analysis, respectively. Compared with the vehicle group, rPAF-AH significantly improved sensorimotor function (42%, P=0.0001). The volume of non-infarcted brain tissue was increased by the rPAF-AH treatment (16.3±4.6% vs. 46.0±10.3%, respectively). rPAF-AH significantly reduced mRNA and protein levels of MMP-2 and MMP-9, but increased the mRNA (P<0.001) and protein levels (P<0.01) of VEGF. These results demonstrate that rPAF-AH provides neuroprotection against ischemic injury. Neuroprotection might be induced not only by decrease in MMP-2 and MMP-9 expression, but also by increased VEGF expression.