Numerous investigations support decreased glutamatergic signaling as a pathogenic mechanism of schizophrenia: yet molecular underpinnings for such dysregulation are largely unknown. In the postmortem dorsolateral prefrontal cortex, we found striking decreases in tyrosine phosphorylation of N-methyl-D aspartate (NMDA) receptor subunit 2 (GluN2), which is critical for neuroplasticity. The decreased GluN2 activity in schizophrenia may not be due to downregulation of NMDA receptors since MK-801 binding and NMDA receptor complexes in the PSD were in fact increased in schizophrenia cases. At the post-receptor level, however, we found striking reductions in the protein kinase C, Pyk 2 and Src kinase activity, which in tandem can decrease GluN2 activation. Given that Src serves as a hub of various signaling mechanisms impacting GluN2 phosphorylation, we postulated that Src hypoactivity may result from convergent alterations of various schizophrenia susceptibility pathways and thus mediate their impacts on NMDA receptor signaling. Indeed, the DLPFC of schizophrenia cases exhibit increased PSD-95 and erbB4 and decreased RPTPa and dysbindin-1, each of which reduces Src activity via protein interaction with Src. To test genomic underpinnings for Src hypoactivity, we examined genome wide association study results, incorporating 13,394 cases and 34,676 controls, which yielded no significant association of individual variants of Src and its direct regulators with schizophrenia. However, a wider protein-protein interaction based network centered on Src, showed significant enrichment of gene-level associations with schizophrenia compared to other psychiatric illnesses. Our results together demonstrate striking decreases in NMDA receptor signaling at the post-receptor level and propose Src as a nodal point of convergent dysregulations impacting NMDA receptor pathway via protein-protein associations.
Background The real‐world impact of remote pulmonary artery pressure (PAP) monitoring on New York Heart Association (NYHA) class improvement and heart failure (HF) hospitalization rate is presented here from a single center. Hypothesis Methods Seventy‐seven previously hospitalized outpatients with NYHA class III HF were offered PAP monitoring via device implantation in a multidisciplinary HF‐management program. Prospective effectiveness analyses compared outcomes in 34 hemodynamically monitored patients to a group of similar patients (n = 32) who did not undergo device implantation but received usual care. NYHA class and 6‐minute walk testing were assessed at baseline and 90 days. All hospitalizations were collected after 6 months of the implantation date (average follow‐up, 15 months) and compared with the number of hospitalizations experienced prior to hemodynamic monitoring. Results Patients in both groups had similar distributions of age, sex, and ejection fraction. After 90 days, 61.8% of the monitored patients had NYHA class improvement of ≥1, compared with 12.5% in the controls (P < 0.001). Distance walked in 6 minutes increased by 54.5 meters in the monitored group (253.0 ± 25.6 meters to 307.4 ± 26.3 meters; P < 0.005), whereas no change was seen in the usual‐care group. After implantation, 19.4% of the monitored group had ≥1 HF hospitalization, compared with 100% who had been hospitalized in the year prior to implantation. The monitored group had a significantly lower HF hospitalization rate (0.16; 95% confidence interval: 0.06‐0.35 hospitalizations/patient‐year) compared with the year prior (1.0 hospitalizations/patient‐year; P < 0.001). Conclusions Hemodynamic‐guided HF management leads to significant improvements in NYHA class and HF hospitalization rate in a real‐world setting compared with usual care delivered in a comprehensive disease‐management program.
BackgroundThe apolipoprotein E ε4 (APOE4) genotype is a prominent late-onset Alzheimer’s disease (AD) risk factor. ApoE4 disrupts memory function in rodents and may contribute to both plaque and tangle formation.MethodsCoimmunoprecipitation and Western blot detection were used to determine: 1) the effects of select fragments from the apoE low-density lipoprotein (LDL) binding domain and recombinant apoE subtypes on amyloid beta (Aβ)42-α7 nicotinic acetylcholine receptor (α7nAChR) interaction and tau phosphorylation in rodent brain synaptosomes; and 2) the level of Aβ42-α7nAChR complexes in matched controls and patients with mild cognitive impairment (MCI) and dementia due to AD with known APOE genotypes.ResultsIn an ex vivo study using rodent synaptosomes, apoE141–148 of the apoE promotes Aβ42-α7nAChR association and Aβ42-induced α7nAChR-dependent tau phosphorylation. In a single-blind study, we examined lymphocytes isolated from control subjects, patients with MCI and dementia due to AD with known APOE genotypes, sampled at two time points (1 year apart). APOE ε4 genotype was closely correlated with heightened Aβ42-α7nAChR complex levels and with blunted exogenous Aβ42 effects in lymphocytes derived from AD and MCI due to AD cases. Similarly, plasma from APOE ε4 carriers enhanced the Aβ42-induced Aβ42-α7nAChR association in rat cortical synaptosomes. The progression of cognitive decline in APOE ε4 carriers correlated with higher levels of Aβ42-α7nAChR complexes in lymphocytes and greater enhancement by their plasma of Aβ42-induced Aβ42-α7nAChR association in rat cortical synaptosomes.ConclusionsOur data suggest that increased lymphocyte Aβ42-α7nAChR-like complexes may indicate the presence of AD pathology especially in APOE ε4 carriers. We show that apoE, especially apoE4, promotes Aβ42-α7nAChR interaction and Aβ42-induced α7nAChR-dependent tau phosphorylation via its apoE141–148 domain. These apoE-mediated effects may contribute to the APOE ε4-driven neurodysfunction and AD pathologies.
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