Apolipoprotein E lipoprotein particles inhibit amyloid-β uptake through cell surface heparan sulphate proteoglycan

Binding affinity of heparin-apoE3 interaction. (A) Representative dot blot of heparin and apoE3 particles. Heparin was spotted onto nitrocellulose membrane along with mouse monoclonal anti-apoE antibody, WUE4, as a positive control and normal mouse IgG as a background. Membrane strips were incubated with increasing concentrations of apoE3 particles from immortalized astrocytes. Membrane-bound apoE was then visualized by biotin-conjugate anti-apoE antibody and infrared streptavidin secondary antibody. (B) Integrated infrared signal intensities from each dot were obtained and the average intensities from three independent experiments were plotted to acquire binding affinity curve and the dissociation constant (Kd). (TIF 2432 kb

Impairment of Fast Axonal Transport in Alzheimer's Disease

Alzheimer’s Disease (AD) manifests as memory deficit in early stages, and progresses into a more severe stage where patients may lose the ability to communicate and control bodily functions. Despite extensive studies, the cause of AD remains unclear except for a small number of cases in which genetic mutations in Presenilin 1 (PS1), Presenilin 2 (PS2) and Amyloid Precursor Protein (APP) have been identified. The mechanism through which these mutations cause pathogenesis is yet to be elucidated, and there is currently no cure. Accumulations of filamentous tau and Aβ plaques represent pathological hallmarks of AD. Previous work from our laboratory and others identified fast axonal transport (FAT) as a critical neuronal process that is regulated by phosphorylation of the microtubule-based motor proteins kinesin and dynein. Impairment of FAT can result in dying back neuropathy of affected neurons in which synaptic dysfunction initially occurs followed by axonal retraction, with cell death as a final stage. The phenotype of dying back neuropathy is characteristic of many neurodegenerative diseases including AD. Dysregulation of phosphotransferases that are involved in FAT have been reported in both human patients and animal models of AD. In this study, we have demonstrated that soluble oligomeric form of Aβ42 impairs both directions of FAT in squid axoplasm through a mechanism involving abnormal phosphorylation of kinesin by endogenous serine/threonine kinase CK2. We have further investigated effects of kinase activation on the binding of motor proteins to microtubules and to cargo vesicles. Studies using mouse primary cortical neurons revealed that binding of both kinesin and dynein to microtubules are negatively affected by activation of CK2 while association of motor proteins and vesicles were not affected. Also, studies with animal models of AD confirmed and extended our observations of impaired FAT caused by kinase dysregulation. Put together, these data demonstrate that dysregulation of kinases plays a critical role in pathogenesis of AD by impairing both anterograde and retrograde FAT

Total apolipoprotein E levels and specific isoform composition in cerebrospinal fluid and plasma from Alzheimer's disease patients and controls

The apolipoprotein E (ApoE) epsilon 4 allele is the strongest risk factor of sporadic Alzheimer's disease (AD), however, the fluid concentrations of ApoE and its different isoforms (ApoE2, ApoE3 and ApoE4) in AD patients and among APOE genotypes (APOE epsilon 2, epsilon 3, epsilon 4) remain controversial. Using a novel mass spectrometry-based method, we quantified total ApoE and specific ApoE isoform concentrations and potential associations with age, cognitive status, cholesterol levels and established AD biomarkers in cerebrospinal fluid (CSF) from AD patients versus non-AD individuals with different APOE genotypes. We also investigated plasma total ApoE and ApoE isoform composition in a subset of these individuals. In total n = 43 AD and n = 43 non-AD subjects were included. We found that CSF and plasma total ApoE levels did not correlate with age or cognitive status and did not differ between AD and non-AD subjects deeming ApoE as an unfit diagnostic marker for AD. Also, whereas CSF ApoE levels did not vary between APOE genotypes APOE epsilon 4 carriers exhibited significantly decreased plasma ApoE levels attributed to a specific decrease in the ApoE4 isoform concentrations. CSF total ApoE concentrations were positively associated with CSF, total tau, tau phosphorylated at Thr181 and A beta 1-42 of which the latter association was weaker and only present in APOE epsilon 4 carriers indicating a differential involvement of ApoE in tau versus A beta-linked neuropathological processes. Future studies need to elucidate whether the observed plasma ApoE4 deficiency is a life-long condition in APOE E > 4 carriers and whether this decrease in plasma ApoE predisposes APOE E > 4 carriers to AD

Clinical benefit of platinum doublet combination therapy in older adults with advanced non‐small cell lung cancer: A prospective multicenter study by the National Hospital Organization in Japan

Abstract Background Previous trials suggest that older adults with non‐small cell lung cancer (NSCLC) derive benefit from platinum doublet combination therapy, but its superiority is controversial. Although geriatric assessment variables are used to assess the individual risk of severe toxicity and clinical outcomes in older patients, the standard first‐line treatment is still debated. Therefore, we aimed to identify the risk factors for clinical outcomes in older patients with NSCLC. Methods Patients aged ≥75 years with advanced NSCLC treated at any of 24 National Hospital Organization institutions completed a pre‐first‐line chemotherapy assessment, including patient characteristics, treatment variables, laboratory test values, and geriatric assessment variables. We evaluated whether these variables were the risk factors for progression‐free survival (PFS) and overall survival (OS). Results A total of 148 patients with advanced NSCLC were treated with combination therapy (n = 90) or monotherapy (n = 58). Median PFS was 5.3 months and OS was 13.6 months. We identified that hypoalbuminemia (hazard ratio [HR] 2.570, 95% confidence interval [CI]: 1.117–5.913, p = 0.0264) was a risk factor for PFS and monotherapy (HR 1.590, 95% CI: 1.070–2.361, p = 0.0217), lactate dehydrogenase (HR 3.682, 95% CI: 1.013–13.39, p = 0.0478), and high C‐reactive protein (HR 2.038, 95% CI: 1.141–3.642, p = 0.0161) were risk factors for OS. The median OS was significantly longer in patients treated with combination therapy than in those who received monotherapy (16.5 months vs. 10.3 months; HR 0.684, 95% CI: 0.470–0.995, p = 0.0453). Discussion Platinum doublet combination therapy may be beneficial in older patients with NSCLC. Identification of risk factors will assist in the development of a personalized treatment strategy

Impact of sex and APOE4 on cerebral amyloid angiopathy in Alzheimer’s disease

Photograph used for a story in the Oklahoma City Times newspaper. Caption: "Elk City's Robert Pitts break tape first in heat of 220 in Cowboy Relays at Stillwater. Jarrett Phillips of Vinita finishes second, just ahead of Jimmy Green of Purcell. Pitts was second to Terry Sparks of Hominy in the finals.

Survival Impact of Second-Line Immune Checkpoint Inhibitors in Older Patients With Advanced Squamous-Cell NSCLC: Post Hoc Analysis of the CAPITAL Study

Introduction: In the CAPITAL study, a randomized phase 3 study, wherein carboplatin plus nab-paclitaxel treatment was compared with docetaxel treatment for older patients with squamous-cell lung cancer, the former became the new standard of care for such patients. Our study aimed to evaluate whether the efficacy of second-line immune checkpoint inhibitors (ICIs) affected the primary analysis of overall survival (OS). Methods: Herein, we performed a post hoc analysis of the impact of second-line ICIs on OS, safety in each group of participants aged more than 75 years, and intracycle nab-paclitaxel skip status. Results: Patients were randomly allocated to the carboplatin plus nab-paclitaxel (nab-PC) arm (n = 95) or the docetaxel (D) arm (n = 95). Of these patients, 74 of 190 (38.9%) were transferred to ICIs for second-line treatment (nab-PC arm: 36, D arm: 38). A survival benefit was numerically observed only for patients for whom first-line therapy was terminated owing to disease progression (median OS [nab-PC arm]: with and without ICIs, 321 and 142 d, respectively; median OS [D arm]: with and without ICIs, 311 and 256 d, respectively). The OS among patients who received ICI after adverse events was similar in the two arms. In the D arm, a significantly higher frequency of grade greater than or equal to 3 adverse events was observed among patients aged more than or equal to 75 years (86.2%) than among those aged less than 75 years (65.6%, p = 0.041), including a significantly higher frequency of neutropenia (84.6% versus 62.5%, p = 0.032); no such differences were observed in the nab-PC arm. Conclusions: We found that second-line ICI treatment seemed to have a little impact on OS