Rush University Medical Center

About: Rush University Medical Center is a healthcare organization based out in Chicago, Illinois, United States. It is known for research contribution in the topics: Population & Medicine. The organization has 13915 authors who have published 29027 publications receiving 1379216 citations. The organization is also known as: Rush Presbyterian St. Luke's Medical Center.

The Complex PrPc-Fyn Couples Human Oligomeric Aβ with Pathological Tau Changes in Alzheimer's Disease

Abstract: Amid controversy, the cellular form of the prion protein PrP(c) has been proposed to mediate oligomeric amyloid-β (Aβ)-induced deficits. In contrast, there is consistent evidence that the Src kinase Fyn is activated by Aβ oligomers and leads to synaptic and cognitive impairment in transgenic animals. However, the molecular mechanism by which soluble Aβ activates Fyn remains unknown. Combining the use of human and transgenic mouse brain tissue as well as primary cortical neurons, we demonstrate that soluble Aβ binds to PrP(c) at neuronal dendritic spines in vivo and in vitro where it forms a complex with Fyn, resulting in the activation of the kinase. Using the antibody 6D11 to prevent oligomeric Aβ from binding to PrP(c), we abolished Fyn activation and Fyn-dependent tau hyperphosphorylation induced by endogenous oligomeric Aβ in vitro. Finally, we showed that gene dosage of Prnp regulates Aβ-induced Fyn/tau alterations. Together, our findings identify a complete signaling cascade linking one specific endogenous Aβ oligomer, Fyn alteration, and tau hyperphosphorylation in cellular and animal models modeling aspects of the molecular pathogenesis of Alzheimer's disease.

Chronic distress and incidence of mild cognitive impairment

Abstract: Objective: Mild cognitive impairment (MCI) is associated with increased morbidity and mortality but its development is not well understood. Here we test the hypothesis that chronic psychological distress is associated with increased incidence of MCI in old age. Methods: Participants are older persons from two cohort studies with uniform annual clinical evaluations which included detailed cognitive testing and clinical classification of MCI. We excluded persons with dementia or MCI at baseline; follow-up data were available on 1,256 persons without cognitive impairment (95% of those eligible). At baseline, they completed a six-item measure of neuroticism (mean = 15.6, SD = 6.6), an indicator of the tendency to experience psychological distress. Results: During up to 12 years of follow-up, 482 persons (38%) developed MCI. Risk of MCI increased by about 2% for each one unit increase on the distress scale (relative risk [RR] = 1.02; 95% CI: 1.01, 1.04), with the association slightly stronger in men than women. Overall, a distress-prone person (score = 24, 90th percentile) was about 40% more likely to develop MCI than someone not prone to distress (score = 8, 10th percentile). Adjustment for depressive symptomatology at baseline did not substantially change results (RR = 1.02; 95% CI: 1.00, 1.03). Depressive symptoms were also related to risk of MCI but not after controlling for distress score. In mixed-effects models, higher distress score was associated with lower level of function in multiple cognitive domains at baseline and more rapid cognitive decline, especially in episodic memory. Conclusion: Among older persons without manifest cognitive impairment, higher level of chronic psychological distress is associated with increased incidence of mild cognitive impairment.

Transcranial magnetic stimulation (tms) for major depression: a multisite, naturalistic, observational study of acute treatment outcomes in clinical practice

Abstract: Background Few studies have examined the effectiveness of transcranial magnetic stimulation (TMS) in real-world clinical practice settings Methods Forty-two US-based clinical TMS practice sites treated 307 outpatients with Major Depressive Disorder (MDD), and persistent symptoms despite antidepressant pharmacotherapy Treatment was based on the labeled procedures of the approved TMS device Assessments were performed at baseline, week 2, at the point of maximal acute benefit, and at week 6 when the acute course extended beyond 6 weeks The primary outcome was change in the Clinician Global Impressions-Severity of Illness from baseline to end of acute phase Secondary outcomes were change in continuous and categorical outcomes on self-report depression scales (9-Item Patient Health Questionnaire [PHQ-9], and Inventory of Depressive Symptoms-Self Report [IDS-SR]) Results Patients had a mean ± SD age of 486 ± 142 years and 668% were female Patients received an average of 25 (± 24) antidepressant treatments of adequate dose and duration without satisfactory improvement in this episode There was a significant change in CGI-S from baseline to end of treatment (−19 ± 14, P < 0001) Clinician-assessed response rate (CGI-S) was 580% and remission rate was 371% Patient-reported response rate ranged from 564 to 415% and remission rate ranged from 287 to 265%, (PHQ-9 and IDS-SR, respectively) Conclusion Outcomes demonstrated response and adherence rates similar to research populations These data indicate that TMS is an effective treatment for those unable to benefit from initial antidepressant medication

Regulation and termination of NADPH oxidase activity.

Abstract: NADPH oxidase of phagocytes plays a crucial role in host defense by producing reactive oxygen species (ROS) that are intended to kill invading microbes. Many other cells produce ROS for signaling purposes. The respiratory burst oxidase in human neutrophils is the main but not exclusive subject of this review, because it is archetypical and has been studied most extensively. The activity of this enzyme must be controlled in phagocytes to prevent collateral damage, and in non-phagocytic cells to perform its signaling role. With many stimuli, NADPH oxidase activity is transient. Various forms of evidence indicate that sustained NADPH oxidase activity requires continuous renewal of the enzyme complex, without which rapid deactivation occurs. This review considers mechanisms that have been proposed to terminate the phagocyte respiratory burst. Changes in the phosphorylation state of p47phox and in the species of nucleotide bound to Rac seem to be the dominant factors in deactivation.

U1 small nuclear ribonucleoprotein complex and RNA splicing alterations in Alzheimer's disease.

Abstract: Deposition of insoluble protein aggregates is a hallmark of neurodegenerative diseases. The universal presence of β-amyloid and tau in Alzheimer’s disease (AD) has facilitated advancement of the amyloid cascade and tau hypotheses that have dominated AD pathogenesis research and therapeutic development. However, the underlying etiology of the disease remains to be fully elucidated. Here we report a comprehensive study of the human brain-insoluble proteome in AD by mass spectrometry. We identify 4,216 proteins, among which 36 proteins accumulate in the disease, including U1-70K and other U1 small nuclear ribonucleoprotein (U1 snRNP) spliceosome components. Similar accumulations in mild cognitive impairment cases indicate that spliceosome changes occur in early stages of AD. Multiple U1 snRNP subunits form cytoplasmic tangle-like structures in AD but not in other examined neurodegenerative disorders, including Parkinson disease and frontotemporal lobar degeneration. Comparison of RNA from AD and control brains reveals dysregulated RNA processing with accumulation of unspliced RNA species in AD, including myc box-dependent-interacting protein 1, clusterin, and presenilin-1. U1-70K knockdown or antisense oligonucleotide inhibition of U1 snRNP increases the protein level of amyloid precursor protein. Thus, our results demonstrate unique U1 snRNP pathology and implicate abnormal RNA splicing in AD pathogenesis.