Dataset Information

Decreased neuronal synaptosome associated protein 29 contributes to poststroke cognitive impairment by disrupting presynaptic maintenance.

ABSTRACT: Background: Poststroke cognitive impairments are common in stroke survivors, and pose a high risk of incident dementia. However, the cause of these cognitive impairments is obscure and required an investigation. Methods: Oxygen-glucose deprivation (OGD) model and middle cerebral artery occlusion (MCAO) model were used to imitate in vitro or in vivo acute cerebral ischemia, respectively. The differentially expressed synaptosome associated protein 29 (SNAP29)-interacting proteins upon ischemia and reperfusion were analyzed with bioinformatics analysis and the results indicated that the changes of SNAP29 after acute ischemia were mainly involved in the synaptic functions. The outcomes of SNAP29 reduction were assessed with SNAP29 knockdown, which mimicked the distribution of SNAP29 along neuronal processes after acute ischemia. Using the whole-cell patch clamp recording method and transmission electron microscope, the pre-synaptic function and readily releasable pool (RRP) were observed after SNAP29 knock down. Using photogenetic manipulations and behavioral tests, the neuronal projection and cognitive functions of mice with SNAP29 knock down in hippocampus CA1 region were evaluated. Results: It was found that SNAP29 protein levels decreased in both in vitro and in vivo ischemic models. Further, the SNAP29 reduction wasn't associated with impaired autophagy flux and neuronal survival. When SNAP29 was knocked down in primary cortical neurons, the frequency of AMPARs-mediated mEPSCs, but not the amplitude, significantly decreased. Meanwhile, the mice with SNAP29 knockdown at CA1 region of hippocampus developed an impairment in hippocampus-mPFC (middle prefrontal cortex) circuit and behavioral dysfunctions. Moreover, the size of RRP at presynaptic sites was diminished. Conclusion: Since SNAP29 protein levels didn't significantly influence the neuronal survival and its decrease was sufficient to disturb the neural circuit via a presynaptic manner, the SNAP29-associated strategies may be an efficient target against poststroke synaptic dysfunction and cognitive deficits.

SUBMITTER: Yan W

PROVIDER: S-EPMC7978312 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BackgroundInfection and inflammation are dementia risk factors in population-based cohorts; however, studies in stroke are scarce. We determined the prevalence of infection after stroke and routinely measured inflammatory biomarkers during hospitalization and their associations with acute and 6-month cognitive impairment.Methods and resultsA prospective stroke cohort completed the Oxford Cognitive Screen at ≤2 weeks and 6 months after stroke. Infection, inflammatory markers (C-reactive protein, white cell count, and neutrophil/lymphocyte ratio), and systemic inflammatory response syndrome were ascertained throughout admission with electronic patient records supplemented by hand searches. Associations with acute and 6-month global and domain-specific cognitive impairment were analyzed using multivariable regression, adjusting for demographic/vascular factors and stroke severity. Among 255 patients (mean age, 73.9 [SD, 12.6] years; 46.3% women; mean education, 12.6 [SD, 3.7] years; median National Institutes of Health Stroke Scale score 5 [range, minimum-maximum, 0-30]), infection was present in 90 patients (35.3%) at mean 4.4 (SD, 6.9) days after stroke, consisting predominantly of pneumonia (47/90; 52%) and urinary tract infection (39/90; 43%). Admission white cell count was elevated in 25.1% (n=64; mean, 9.5×109/L [SD, 3.2×109/L]), C-reactive protein in 41.2% (n=105; mean, 27.5 [SD, 50.9 mg/L]), neutrophil/lymphocyte ratio in 55.7% (n=97; mean, 5.5 [SD, 4.5]), and systemic inflammatory response syndrome in 26.6% (n=53 [45.2%] positive during hospitalization). Infection was associated with acute and 6-month poststroke cognitive impairment (P<0.05adj) with stronger associations acutely for severe infection (infection+systemic inflammatory response syndrome; P=0.03adj). Acute language, executive function and attention domain impairments, and 6-month number processing impairment were associated with infection (P<0.05adj). No significant relationships were found for any biomarker and cognitive impairment.ConclusionsInfection and elevations in routinely measured inflammatory biomarkers are common following stroke; however, only infection is associated with poststroke cognitive impairment, suggesting that increases in these biomarkers may be nonspecific. Infection may present a tractable target for reducing poststroke cognitive impairment.

Project description:BackgroundPTEN, a syndromic autism spectrum disorder (ASD) risk gene, is mutated in approximately 10% of macrocephalic ASD cases. Despite the described genetic association between PTEN and ASD and ensuing studies, we continue to have a limited understanding of how PTEN disruption drives ASD pathogenesis and maintenance.MethodsWe derived neural stem cells (NSCs) from the dentate gyrus (DG) of Ptenm3m4 mice, a model that recapitulates PTEN-ASD phenotypes. We subsequently characterized the expression of stemness factors, proliferation, and differentiation of neurons and glia in Ptenm3m4 NSCs using immunofluorescent and immunoblotting approaches. We also measured Creb phosphorylation by Western blot analysis and expression of Creb-regulated genes with qRT-PCR.ResultsThe m3m4 mutation decreases Pten localization to the nucleus and its global expression over time. Ptenm3m4 NSCs exhibit persistent stemness characteristics associated with increased proliferation and a resistance to neuronal maturation during differentiation. Given the increased proliferation of Ptenm3m4 NSCs, a significant increase in the population of immature neurons relative to mature neurons occurs, an approximately tenfold decrease in the ratio between the homozygous mutant and wildtype. There is an opposite pattern of differentiation in some Ptenm3m4 glia, specifically an increase in astrocytes. These aberrant differentiation patterns associate with changes in Creb activation in Ptenm3m4/m3m4 NSCs. We specifically observed loss of Creb phosphorylation at S133 in Ptenm3m4/m3m4 NSCs and a subsequent decrease in expression of Creb-regulated genes important to neuronal function (i.e., Bdnf). Interestingly, Bdnf treatment is able to partially rescue the stunted neuronal maturation phenotype in Ptenm3m4/m3m4 NSCs.ConclusionsConstitutional disruption of Pten nuclear localization with subsequent global decrease in Pten expression generates abnormal patterns of differentiation, a stunting of neuronal maturation. The propensity of Pten disruption to restrain neurons to a more progenitor-like state may be an important feature contributing to PTEN-ASD pathogenesis.

Dataset Information

Decreased neuronal synaptosome associated protein 29 contributes to poststroke cognitive impairment by disrupting presynaptic maintenance.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets