Recent evidence reveals that aberrant brain insulin signaling plays an important role in the pathology of Alzheimer’s disease (AD). Intranasal insulin administration has been reported to improve memory and attention in healthy participants and in AD patients. However, the underlying molecular mechanisms are poorly understood. Here, we treated intracerebroventricular streptozotocin-injected (ICV-STZ) rats, a commonly used animal model of sporadic AD, with daily intranasal delivery of insulin (2 U/day) for 6 consecutive weeks and then studied their cognitive function with the Morris water maze test and biochemical changes via Western blotting. We observed cognitive deficits, tau hyperphosphorylation, and neuroinflammation in the brains of ICV-STZ rats. Intranasal insulin treatment for 6 weeks significantly improved cognitive function, attenuated the level of tau hyperphosphorylation, ameliorated microglial activation, and enhanced neurogenesis in ICV-STZ rats. Additionally, our results indicate that intranasal delivery of insulin probably attenuates tau hyperphosphorylation through the down-regulation of ERK1/2 and CaMKII in the brains of ICV-STZ rats. Our findings demonstrate a beneficial effect of intranasal insulin and provide the mechanistic basis for treating AD patients with intranasal insulin.
These findings broaden the mutational and clinical spectrum of CADASIL and provide additional evidences for the existence of founder effect in CADASIL patients.
SummaryBrain insulin signaling deficits contribute to multiple pathological features of Alzheimer's disease (AD). Although intranasal insulin has shown efficacy in patients with AD, the underlying mechanisms remain largely unillustrated. Here, we demonstrate that intranasal insulin improves cognitive deficits, ameliorates defective brain insulin signaling, and strongly reduces β‐amyloid (Aβ) production and plaque formation after 6 weeks of treatment in 4.5‐month‐old APPswe/PS1dE9 (APP/PS1) mice. Furthermore, c‐Jun N‐terminal kinase activation, which plays a pivotal role in insulin resistance and AD pathologies, is significantly inhibited. The alleviation of amyloid pathology by intranasal insulin results mainly from enhanced nonamyloidogenic processing and compromised amyloidogenic processing of amyloid precursor protein (APP), and from a reduction in apolipoprotein E protein which is involved in Aβ metabolism. In addition, intranasal insulin effectively promotes hippocampal neurogenesis in APP/PS1 mice. This study, exploring the mechanisms underlying the beneficial effects of intranasal insulin on Aβ pathologies in vivo for the first time, highlights important preclinical evidence that intranasal insulin is potentially an effective therapeutic method for the prevention and treatment of AD.
BackgroundAdenomyosis is a benign disease with elevated CA125 level.Case presentationWe report 3 cases with adenomyosis who developed ischemic stroke during menstruation. The levels of CA125, CA19–9, and D-dimer were elevated, which dropped markedly after the menstrual phase. The development of nonbacterial thrombotic endocarditis (NBTE) and stenosis of the cerebral arteries associated with hypercoagulable state and the hyperviscosity nature of the mucinous protein may be the underlying mechanisms.ConclusionOur report suggests that adenomyosis might be a risk factor for ischemic stroke in middle-aged patients.
Pulmonary alveolar microlithiasis (PAM) is a rare autosomal recessive disorder characterized by the deposition of calcium phosphate microliths throughout the lungs. Currently the mutation of SLC34A2 gene was considered responsible for PAM. Here we reported the studies on mutation analysis of the SLC34A2 gene in three familial members and one unrelated subject of PAM by DNA direct sequencing. Meanwhile, we also reviewed and analyzed the published studies of the SLC34A2 gene mutation in PAM patients. The three familial patients were siblings of an inbred family whose parents were cousins. All four patients presented recurrent cough and exertional dyspnea. Diagnosis of PAM was made according to the typical manifestation of radiology. One homozygous mutation of the SLC34A2 gene, c.910A > T (p.K304X) was identified. The review of the SLC34A2 gene mutation showed multiple mutation symbols in PAM patients from China, Turkey, and Japan respectively. The present study supports that the clinical features, pathological and radiological characteristics of Chinese PAM patients are similar to those reported in other countries. Our investigation revealed that the c.910A > T mutation in the SCL34A2 gene was responsible for PAM patients in China. The review of literatures suggests that exon7 and exon8 seemed liable to be affected typical Mongoloid of PAM, and exon8 might be the screen target for Chinese patients.
We performed direct DNA sequencing of the RAB7L1 and SLC41A1 genes within the PARK16 locus in 205 Chinese Parkinson's disease (PD) patients. Three novel heterozygous variants were identified in SLC41A1: c.436A > G (causing p.Lys146Glu), c.1440A > G (causing p.Pro480Pro), and c.552 + 50G > A. These three variants were not present in any of the 210 genetically unrelated healthy controls of the same ethnic origin. No changes were identified in the RAB7L1 gene. Additionally, for the eight core PARK16 SNPs, no significant difference in allele or genotype frequencies was observed between PD patients and controls. Further analysis is required to determine the role of genes within the PARK16 locus in development of PD.
Alpha-synucleinopathy is postulated to be central to both idiopathic rapid eye movement sleep behaviour disorder (iRBD) and Parkinson’s disease (PD). Growing evidence suggests an association between the diminished clearance of α-synuclein and glymphatic system dysfunction. However, evidence accumulating primarily based on clinical data to support glymphatic system dysfunction in patients with iRBD and PD is currently insufficient. This study aimed to use diffusion tensor image analysis along the perivascular space (DTI-ALPS) to evaluate glymphatic system activity and its relationship to clinical scores of disease severity in patients with possible iRBD (piRBDs) and those with PD. Further, we validated the correlation between the ALPS index and the prognosis of PD longitudinally. Overall, 168 patients with PD, 119 piRBDs, and 129 healthy controls were enroled. Among them, 50 patients with PD had been longitudinally reexamined. Patients with PD exhibited a lower ALPS index than those with piRBDs (P = 0.036), and both patient groups showed a lower ALPS index than healthy controls (P < 0.001 and P = 0.001). The ALPS index and elevated disease severity were negatively correlated in the piRBD and PD subgroups. Moreover, the ALPS index was correlated with cognitive decline in patients with PD in the longitudinal analyses. In conclusion, DTI-ALPS provided neuroimaging evidence of glymphatic system dysfunction in piRBDs and patients with PD; however, the potential of assessing the pathological progress of α-synucleinopathies as an indicator is worth verifying. Further development of imaging methods for glymphatic system function is also warranted.
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