Genetic Screening of Patients with Sporadic Alzheimer's Disease and Frontotemporal Lobar Degeneration in the Chinese Population.

Background: Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) account for the vast majority of neurodegenerative dementias. AD and FTLD have different clinical phenotypes with a genetic overlap between them and other dementias. Objective: This study aimed to identify the genetic spectrum of sporadic AD and FTLD in the Chinese population. Methods: A total of 74 sporadic AD and 29 sporadic FTLD participants were recruited. All participants underwent whole-exome sequencing (WES) and testing for a hexanucleotide expansion in C9orf72 was additionally performed for participants with negative WES results. Results: Four known pathogenic or likely pathogenic variants, including PSEN1 (p.G206D), MAPT (p.R5H), LRRK2 (p.W1434*), and CFAP43 (p.C934*), were identified in AD participants, and 1 novel pathogenic variant of ANXA11 (p.D40G) and two known likely pathogenic variants of MAPT (p.D177V) and TARDBP (p.I383V) were identified in FTLD participants. Twenty-four variants of uncertain significance as well as rare variants in risk genes for dementia, such as ABCA7, SORL1, TRPM7, NOS3, MPO, and DCTN1, were also found. Interestingly, several variants in participants with semantic variant primary progressive aphasia were detected. However, no participants with C9orf72 gene variants were found in the FTLD cohort. Conclusions: There was a high frequency of genetic variants in Chinese participants with sporadic AD and FTLD and a complex genetic overlap between these two types of dementia and other neurodegenerative diseases.

Efficacy of interventional closure therapy on cryptogenic stroke with coexisting patent foramen ovale in young patients and its impact on serum fibrinogen and D-dimer levels.

OBJECTIVE: To explore the efficacy of interventional closure therapy in young patients with cryptogenic stroke and coexisting patent foramen ovale and analyze its impact on serum fibrinogen and D-dimer levels. METHODS: All subjects in this study were young stroke patients with PFO. After excluding patients who did not meet the inclusion criteria, they were registered and divided into two groups based on the treatment method: the closure group and the medical group. RESULTS: There were no significant differences in basic clinical data between the two groups, indicating comparability (p > 0.05). The closure group showed better heart function after treatment compared to the medical group, with significant differences (p < 0.05). Headache symptoms in the closure group were less severe than those in the medical group after treatment, with significant differences (p < 0.05). Laboratory indicators in the closure group were better than those in the medical group after treatment, with significant differences (p < 0.05). Serum fibrinogen and D-dimer levels in the closure group were lower than those in the medical group after treatment, with significant differences (p < 0.05). CONCLUSION: Interventional closure therapy demonstrated positive effects on young patients with cryptogenic stroke and coexisting PFO, showing improvements in heart function, headache symptoms, and blood coagulation parameters. While the study suggests potential benefits, cautious interpretation is warranted, given the observational study design. Further research with a larger sample size and long-term follow-up is needed to validate these findings.

Ulinastatin protects brain against cerebral ischemia/reperfusion injury through inhibiting MMP-9 and alleviating loss of ZO-1 and occludin proteins in mice.

BACKGROUND: The effects of Ulinastatin (UTI) on the blood-brain barrier (BBB) in the acute phase of cerebral ischemia/reperfusion (I/R) are not clear. This study was to investigate the potential protective effects of UTI on the BBB and the underlying mechanisms. METHODS: Male CD-1 mice were subjected to transient middle cerebral artery occlusion (tMCAO) and randomly assigned to four groups: Sham (sham-operated), tMCAO (tMCAO+0.9% saline), UTI-L (tMCAO+UTI 1500U/100g) and UTI-H (tMCAO+UTI 3000U/100g) group. UTI was administered immediately after reperfusion in the UTI-L and UTI-H groups. At 24h after reperfusion, the neurological deficit, brain water content, and infarct volume were determined. Western blot and quantitative reverse transcription polymerase chain reaction (qRT-PCR) were used to examine the expression of matrix metalloproteinase (MMP)-9, Zonula occludens-1 (ZO-1) and occludin in ischemic cerebral cortex. The integrity of the BBB was assessed by the leakage of Evans blue. RESULTS: Compared with tMCAO group, both UTI-L and UTI-H groups showed significantly (P<0.001) ameliorated the neurological deficit (2.00±0.71 and 1.60±0.55 vs. 4.60±0.55), lessened brain water content (82.99%±0.21% and 82.05%±0.59% vs. 84.28%±0.0.57%) and decreased the infarct volume (38.52%±1.72% and 24.78%±1.20% vs. 49.48%±1.93%). In addition, significantly (P<0.001) decreased expression of MMP-9 (0.48±0.06 and 0.37±0.05 vs.0.76±0.10 for protein and 2.88±0.23 and 2.17±0.16 vs. 3.90±0.24 for mRNA) and alleviated loss of ZO-1 (0.19±0.04 and 0.24±0.05 vs. 0.25±0.03) and occludin (0.74±0.08 and 0.87±0.07 vs. 0.94±0.06) proteins were observed in both UTI-L and UTI-H groups. CONCLUSION: UTI protects the brain against ischemic injury potentially via down-regulating the expression of MMP-9 and alleviating loss of ZO-1 and occludin proteins to restore the BBB permeability.

Salvianolic Acids for Injection (SAFI) promotes functional recovery and neurogenesis via sonic hedgehog pathway after stroke in mice.

There is a pressing need of developing approaches for delayed post-stroke therapy for patients who fail to receive thrombolysis within the narrow time window. Neuroprotection of Salvianolic Acids for Injection (SAFI) for cerebral ischemia-reperfusion injury in acute phase has been well documented. The current study was to determine the influence of SAFI at the subacute phase after stroke in mice, and to elucidate the underlying mechanisms. Adult male C57BL/6 mice were subjected to permanent occlusion of the distal middle cerebral artery (dMCAO), followed by daily intraperitoneal injection of SAFI 24 h after stroke for 14 days. Motor behavior was measured by neurological function evaluations weekly, and proliferation, migration, survival and differentiation of neural progenitor cells (NPCs) were examined with immunohistochemistry. Sonic hedgehog (Shh) inhibitor cyclopamine (CYC) was injected to determine the involvement of Shh pathway in the therapeutic effects of SAFI. The results showed that SAFI led to dramatic brain functional improvement, elevated NPCs proliferation, and prompted long-term survival of newborn neurons in the subventricular zone (SVZ). Up-regulation of Shh, Ptch and nuclear translocation of Gli1 were observed in the peri-infarct region, accompanied with robust production of Brain derived neurotrophic factor (BDNF) and Nerve growth factor (NGF). Simultaneous administration with CYC strikingly attenuated the beneficial outcomes of SAFI as well as abolished SAFI induced BDNF and NGF production. Collectively, our study demonstrated SAFI significantly promoted long-term functional recovery and neurogenesis, which might be dependent on Shh signaling mediated BDNF and NGF production. Therefore, SAFI might serve as a potential clinically translatable therapy during recovery stage after stroke.

Salvianolic acids enhance cerebral angiogenesis and neurological recovery by activating JAK2/STAT3 signaling pathway after ischemic stroke in mice.

Post-stroke angiogenesis facilitates neurovascular remodeling process and promotes neurological recovery. Proangiogenic effects of Salvianolic acids (Sals) have been reported in various ischemic disorders. However, the underlying mechanisms are still poorly understood. Previous studies of our laboratory have demonstrated that activating Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling pathway is involved in the protection against cerebral ischemia/reperfusion injury. In this study, we investigated the impacts of Sals on angiogenesis and long-term neurological recovery after ischemic stroke as well as the potential mechanisms. Male mice subjected to permanent distal middle cerebral artery occlusion were administrated with Sals, 5-bromo-2'-deoxyuridine, and JAK2 inhibitor AG490 once daily from day 1 to day 14 after distal middle cerebral artery occlusion. Compared with the control group, Sals treatment significantly improved neurological recovery at day 14 and 28 after ischemic stroke. Sals enhanced post-stroke angiogenesis, pericytes and astrocytic endfeet covered ratio in the peri-infarct area. The JAK2/STAT3 signaling pathway was activated by Sals in the angiogenesis process, and inhibition of JAK2/STAT3 signaling blocked the effects of Sals on post-stroke angiogenesis and neurological recovery as well as abolished the mediation of proangiogenic factors. In summary, these data suggest that Sals administration enhances cerebral angiogenesis and promotes neurological recovery after ischemic stroke, mediated by the activation of JAK2/STAT3 signaling pathway.

Ulinastatin downregulates TLR4 and NF-kB expression and protects mouse brains against ischemia/reperfusion injury.

BACKGROUND: Inflammatory damage plays an important role in ischemic stroke and provides potential targets for therapy. Ulinastatin (UTI), a drug used to treat shock and acute pancreatitis in clinic, has attracted attention for its protective effects through immunomodulatory and anti-inflammatory properties. However, the effect of UTI in the acute phase of cerebral ischemia/reperfusion (I/R) is not clear. This study is to investigate the potential neuroprotective effect of UTI and explore its underlying mechanisms. METHODS: Male CD-1 mice were subjected to transient middle cerebral artery occlusion (tMCAO) and randomly assigned into four groups: Sham (sham-operated) group, tMCAO (tMCAO + 0.9% saline) group, UTI-L (tMCAO + UTI 1500 U/100 g), and UTI-H (tMCAO + UTI 3000 U/100 g) group. UTI was administered immediately after reperfusion in the UTI-L and UTI-H groups. About 24 h after the reperfusion, the neurological deficit, brain water content, and infarct volume were detected. Immunohistochemistry, western blot and quantitative reverse transcription polymerase chain reaction (qRT-PCR) were used to detect the expression of TLR4 and NF-κB in the ischemic cerebral cortex. RESULTS: Compared with tMCAO group, both UTI-L and UTI-H groups dramatically ameliorated neurological deficit (p < 0.05), lessened the brain water content (p < 0.05) and infarct volume (p < 0.05), and decreased the expression of TLR4 and NF-κB. CONCLUSION: These results showed that UTI protected the brain against ischemic injury which may be due to the alleviation of inflammation reaction in early stage through downregulating TLR4 and NF-κB expression.

Remote limb ischemic postconditioning protects mouse brain against cerebral ischemia/reperfusion injury via upregulating expression of Nrf2, HO-1 and NQO-1 in mice.

Remote ischemic postconditioning (RIPostC) is a promising therapeutic intervention, which has been discovered to reduce ischemia/reperfusion (I/R) injury in heart, kidney, brain and skeletal muscle experimentally. However, its potential protective mechanisms have not been well elucidated. The aim of this study was to investigate the protective effect of RIPostC in cerebral I/R injury and explore the new putative mechanisms of neuroprotection elicited by it. Focal cerebral ischemia was induced by transient middle cerebral artery occlusion (tMCAO) in male CD1 mice. RIPostC was generated by three cycles of 5-min reperfusion/5-min occlusion of the bilateral femoral artery on the bilateral limbs at the onset of middle cerebral artery reperfusion. RIPostC significantly improved neurological outcome, lessened infarct volume and brain edema, upregulated the expression of Nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) and quinone oxidoreductase-1 (NQO-1) and activity of superoxide dismutase (SOD), and downregulaed the formation of malondialdehyde (MDA) (p < 0.05). Taken together, these findings demonstrated that RIPostC protected the brain from I/R injury after focal cerebral ischemia by reducing oxidative stress and activating the Nrf2-ARE (antioxidant response element) pathway.

Cinnamaldehyde inhibits inflammation and brain damage in a mouse model of permanent cerebral ischaemia.

BACKGROUND AND PURPOSE: Recent findings suggest the importance of inflammation in the pathogenesis of cerebral ischaemia and its potential as a therapeutic target. Cinnamaldehyde is a diterpene with a wide range of anti-inflammatory effects thus may be advantageous in the treatment of cerebral ischaemia. The present study examined the potential therapeutic effects of cinnamaldehyde on cerebral ischaemia using a mouse model with permanent middle cerebral artery occlusion. EXPERIMENTAL APPROACH: Male CD-1 mice, which had the middle cerebral artery occluded, were treated (i.p.) with cinnamaldehyde. Neuroprotection by cinnamaldehyde was analysed by evaluating neurological deficit scores, brain oedema and infarct volume. Expressions of signal transduction molecules and inflammatory mediators were measured by Western blotting, qRT-PCR and immunohistochemical staining. Activation of NF-κB was assessed by Western blotting, immunohistochemistry and immunofluorescence. KEY RESULTS: Cinnamaldehyde reduced the neurological deficit scores, brain oedema and infarct volume. Cinnamaldehyde suppressed the activation of signal transduction molecules including toll-like receptor 4, tumour necrosis receptor-associated factor 6 and NF-κB, attenuated the increased levels of TNF-α, IL-1ß, CCL2 and endothelial-leukocyte adhesion molecule-1 and ultimately reduced leukocyte infiltration into the ischaemic brain areas after cerebral ischaemia. CONCLUSIONS AND IMPLICATIONS: Cinnamaldehyde protects against cerebral ischaemia injury by inhibiting inflammation, partly mediated by reducing the expression of toll-like receptor 4, tumour necrosis receptor-associated factor 6 and the nuclear translocation of NF-κB. Our findings suggest that cinnamaldehyde may serve as a new candidate for further development as a treatment for stroke.