Cortical Proteins Associated With Cognitive Resilience in Community-Dwelling Older Persons.

Importance: Identifying genes and proteins for cognitive resilience (ie, targets that may be associated with slowing or preventing cognitive decline regardless of the presence, number, or combination of common neuropathologic conditions) provides a complementary approach to developing novel therapeutics for the treatment and prevention of Alzheimer disease and related dementias. Objective: To identify proteins associated with cognitive resilience via a proteome-wide association study of the human dorsolateral prefrontal cortex. Design, Setting, and Participants: This study used data from 391 community-dwelling older persons who participated in the Religious Orders Study and the Rush Memory and Aging Project. The Religious Orders Study began enrollment January 1, 1994, and the Rush Memory and Aging Project began enrollment September 1, 1997, and data were collected and analyzed through October 23, 2019. Exposures: Participants had undergone annual detailed clinical examinations, postmortem evaluations, and tandem mass tag proteomics analyses. Main Outcomes and Measures: The outcome of cognitive resilience was defined as a longitudinal change in cognition over time after controlling for common age-related neuropathologic indices, including Alzheimer disease, Lewy bodies, transactive response DNA-binding protein 43, hippocampal sclerosis, infarcts, and vessel diseases. More than 8000 high abundance proteins were quantified from frozen dorsolateral prefrontal cortex tissue using tandem mass tag and liquid chromatography-mass spectrometry. Results: There were 391 participants (273 women); their mean (SD) age was 79.7 (6.7) years at baseline and 89.2 (6.5) years at death. Eight cortical proteins were identified in association with cognitive resilience: a higher level of NRN1 (estimate, 0.140; SE, 0.024; P = 7.35 × 10-9), ACTN4 (estimate, 0.321; SE, 0.065; P = 9.94 × 10-7), EPHX4 (estimate, 0.198; SE, 0.042; P = 2.13 × 10-6), RPH3A (estimate, 0.148; SE, 0.031; P = 2.58 × 10-6), SGTB (estimate, 0.211; SE, 0.045; P = 3.28 × 10-6), CPLX1 (estimate, 0.136; SE, 0.029; P = 4.06 × 10-6), and SH3GL1 (estimate, 0.179; SE, 0.039; P = 4.21 × 10-6) and a lower level of UBA1 (estimate, -0.366; SE, 0.076; P = 1.43 × 10-6) were associated with greater resilience. Conclusions and Relevance: These protein signals may represent novel targets for the maintenance of cognition in old age.

Down-regulation of UBA6 exacerbates brain injury by inhibiting the activation of Notch signaling pathway to promote cerebral cell apoptosis in rat acute cerebral infarction model.

This study aimed to examine the UBA6 role in brain injury mediated by acute cerebral infarction (ACI). In order to screen potential therapeutic targets for ACI, two expression profiles, including GSE97537 and GSE97533 datasets, were downloaded from the GEO database. The Venn method to identify the common DEGs. 68 up-regulated overlapping DEGs and 51 down-regulated overlapping DEGs were used to construct the PPI network by STRING online database. UBA6 was identified as a hub gene by the CytoHubba plugin from Cytoscape. GO and KEGG pathway enrichment analyses were conducted using DAVID online website. UBA6 knockout exacerbated MCAO-mediated brain injury and cell apoptosis in rat brain tissues by H&E and TTC staining and TUNEL assay. The results of flow cytometry and western blot assays further demonstrated that UBA6 inhibition induced the apoptosis of hippocampal neurons and increased cleaved-caspase-3/9 protein levels. Notch1, NICD and Hes1 protein levels were suppressed by down-regulated UBA6. UBA6 was lowly expression in poor prognosis group of 100 patients with ACI. Logistic regression analysis indicated that hypertension, blood glucose, urokinase dose, UBA6 expression and AF were the main risk factors of poor prognosis after thrombolytic therapy for patients with ACI. The ROC curve analysis showed that the sensitivity and specificity of UBA6 was good (sensitivity 100%, specificity 89%, and AUC = 0.772) to be used to evaluate the poor prognosis of ACI. In conclusion, down-regulated UBA6 intensified MCAO-induced brain injury by inhibiting the activation of Notch signaling pathway to promote the apoptosis of hippocampal neurons and was used to predict the poor prognosis of ACI.

Lower AMP-activated protein kinase level is associated with the vulnerability of coronary atherosclerotic plaques by attenuating the expression of monocyte autophagy.

BACKGROUND: Coronary atherosclerotic plaque formation is driven by macrophage infiltration. Monocytes and macrophages contribute to the progression of atherosclerosis. However, research on the relationship between AMP-activated protein kinase (AMPK) and vulnerable atherosclerotic plaques is still insufficient. In the present study, we aimed to elucidate the adaptive mechanism between autophagy of peripheral blood monocytes (PBMs) and the rupture of atherosclerotic plaques. We investigated whether AMPK and autophagy of monocytes can enhance the stability of coronary atherosclerotic plaques in the human body. PATIENTS AND METHODS: Samples of PBMs were collected and isolated from all patients with stable angina pectoris (SAP), non-ST-segment elevation acute coronary syndrome, ST-segment elevation acute myocardial infarction, and without coronary artery disease (control). Then, western blot was used to detect the expression levels of AMPK and autophagy-related protein. RESULTS: The expression levels of beclin-1 and ATG7 were all significantly lower in the acute coronary syndrome groups than those in the SAP and control groups (all P<0.01). The level of phosphorylated AMPK was significantly decreased in patients with acute coronary syndrome compared with those in the SAP and control groups (P<0.01). However, there was no statistical difference between the SAP group and the control group. The activation of mTOR was distinctly increased in the STEMI group (P<0.05). CONCLUSION: Therefore, our work is novel in showing that AMPK of PBMs may decrease plaque vulnerability and subsequent plaque rupture through activation of autophagy.