Amelioration of cognitive deficits in plaque‐bearing Alzheimer's disease model mice through selective reduction of nascent soluble A42 without affecting other A pools

Given that amyloid‐β 42 (Aβ42) is believed to be a culprit in Alzheimer's disease (AD), reducing Aβ42 production should be a potential therapeutic approach. γ‐Secretase modulators (GSMs) cause selective reduction of Aβ42 or both reduction of Aβ42 and Aβ40 without affecting total Aβ through shifting the γ‐cleavage position in amyloid precursor protein. We recently reported on GSM‐2, one of the second‐generation GSMs, that selectively reduced brain Aβ42 level and significantly ameliorated cognitive deficits in plaque‐free 5.5‐month‐old Tg2576 AD model mice. Here, we investigated the effects of GSM‐2 on 10‐, 14‐, and 18‐month‐old mice which had age‐dependent increase in amyloid plaques. Eight‐day treatment with GSM‐2 significantly ameliorated cognitive deficits measured by Y‐maze task in the mice of any age. However, GSM‐2 reduced brain soluble Aβ42 only in 10‐month‐old mice. In contrast, GSM‐2 markedly reduced newly synthesized soluble Aβ42 in both 10‐ and 18‐month‐old mice with similar efficacy when measured using the stable isotope‐labeling technique, suggesting that nascent Aβ42 plays a more significant role than plaque‐associated soluble Aβ42 in the cognitive deterioration of Tg2576 mice. These findings further indicate the potential utility of approach to reducing Aβ42 synthesis in AD therapeutic regimens.     

Discovery of novel scaffolds for γ-secretase modulators without an arylimidazole moiety

Gamma-secretase modulators (GSMs) selectively inhibit the production of amyloid-β 42 (Aβ42) and may therefore be useful in the management of Alzheimer’s disease. Most heterocyclic GSMs that are not derived from nonsteroidal anti-inflammatory drugs contain an arylimidazole moiety that potentially inhibits cytochrome P450 (CYP) activity. Here, we discovered imidazopyridine derivatives that represent a new class of scaffold for GSMs, which do not have a strongly basic end group such as arylimidazole. High-throughput screening identified 2-methyl-8-[(2-methylbenzyl)oxy]-3-(pyridin-4-yl)imidazo[1,2-a]pyridine (3a), which inhibited the cellular production of Aβ42 (IC₅₀?=?7.1?µM) without changing total production of Aβ. Structural optimization of this series of compounds identified 5-[8-(benzyloxy)-2-methylimidazo[1,2-a]pyridin-3-yl]-2-ethylisoindolin-1-one (3m) as a potent inhibitor of Aβ42 (IC₅₀?=?0.39?µM) but not CYP3A4. Further, 3m demonstrated a sustained pharmacokinetic profile in mice and sufficiently penetrated the brain.     

Sleep Apnea Syndrome (SAS) Clinical Practice Guidelines 2020

Sleep and Biological Rhythms - The prevalence of sleep-disordered breathing (SDB) is reportedly very high. Among SDBs, the incidence of obstructive sleep apnea (OSA) is higher than previously...     

Calpain activation is required for glutamate-induced p27 down-regulation in cultured cortical neurons

Recent evidence suggests that cell cycle-related molecules play pivotal roles in multiple forms of cell death in post-mitotic neurons. Nevertheless, it remains unclear what molecular mechanisms are involved in the regulation of expression levels and activities of these molecules. We showed previously that treatment with extracellular glutamate decreases cyclin-dependent kinase inhibitor p27 before neuronal cell death. In this study, we demonstrate that reductions of both p27 and neuronal viability were dependent on activity of calpain, a Ca(2+)-dependent protease, but not on activity of caspase 3. Interestingly, the glutamate-induced reduction of p27 was not dependent on the ubiquitin-proteasome system. In fact, p27 was present only in the neuronal nucleus, whereas calpain 1, a ubiquitous calpain, was observed both in the neuronal nucleus and cytoplasm in control cultures. Glutamate treatment did not change the localization patterns of p27 and calpain 1. It reduced p27 expression level in the nucleus in a calpain-dependent manner. In vitro experiments using neuronal cell lysate and p27 recombinant protein revealed that p27 was degraded as a substrate of activated calpain 1. These results suggest that calpain(s), activated by glutamate treatment, degrade(s) p27 in the nucleus of neurons, which might promote aberrant cell cycle progression.     

Epidemiological study of the associations between sleep complaints and metabolic syndrome in Japan

Sleep and Biological Rhythms - The purpose of this study was to examine the associations of sleep complaints, such as insomnia and snoring, with metabolic syndrome. Data from a national study...     

Temperature affects lung fluid and recoil during high tidal ventilation at low resting volume

Effects of tidal volume (VT), end-expiratory pressure (EEP), and environmental temperature (Tenv) on elastic recoil force (Pel) and edema formation were examined in open-chest anesthetized rabbits. Sixty-two rabbits in four groups were ventilated for 3 h with VT of either 10 or 25 ml/kg body wt, EEP of 0 or 2 cmH2O, and Tenv of 18 or 35 degrees C. After ventilation, Pel at 80% of total lung capacity (P80) was significantly increased when ventilation was performed with the combination of large VT, 0 EEP, and low Tenv. This change was prevented by altering any one of the three conditions, e.g., small VT, positive EEP, or high Tenv. Similarly, elevation of minimum surface tension and reduction of surface activity index of lavages from excised lungs after ventilation were observed only when increased P80 was noted. Additionally, the increase of P80 was well correlated with increment of wet weight-to-dry weight ratio and degree of perivascular cuffing and alveolar edema formation of excised lungs. These results indicate that elevation of Pel after high tidal ventilation in open-chest animals in vivo was influenced by level of EEP and Tenv and that the degree of edema formation was closely related to the increase of Pel. The increased Pel is presumably primary and causes fluid accumulation.     

Factors influencing adherence to nasal continuous positive airway pressure in obstructive sleep apnea patients in Japan

Adherence to nasal continuous positive airway pressure (n-CPAP) therapy is a clinically important requirement for obstructive sleep apnea (OSA); however, some patients often find difficulty even in continuing with treatment. We suggest that rather than the objective results such as the severity of OSA, adherence to n-CPAP therapy is more greatly influenced by the subjective factors of each patient, such as awareness of OSA, and adverse effects of treatment. We surveyed patients with OSA who initiated n-CPAP at our sleep center, with at least 12 months of follow-up data. In total, 937 patients, including those who had already discontinued therapy, were surveyed via questionnaires, 732 completed questionnaires. According to self-reported adherence data, patients were split into three groups (no-adherence, good adherence, and poor adherence). Furthermore, various issues with treatment were extracted using questionnaires and tabulated to retrospectively examine factors influencing adherence. The adherence rate was 78.1 % among 732 patients who initiated n-CPAP ≥1 year previously. Commonly reported issues in the non-adherence group were respiratory difficulty, insomnia/lack of sleep, and no effect of treatment felt/no improvement in symptoms. Similarly, air pressure discomfort and mask falling were significantly associated with poor adherence. Compared with objective data obtained using polysomnography, adherence may be more significantly influenced by subjective predictors, including clinical symptoms and intuitive complaints accompanying treatment. Our results suggested that the identification of patients with these predictors during the early phase after treatment initiation and continuous intervention for them may be the first step towards developing better adherence.

     

Differential involvement of cell cycle reactivation between striatal and cortical neurons in cell death induced by 3-nitropropionic acid

Recent evidence suggests that unscheduled cell cycle activity leads to neuronal cell death. 3-Nitropropionic acid (3-NP) is an irreversible inhibitor of succinate dehydrogenase and induces cell death in both striatum and cerebral cortex. Here we analyzed the involvement of aberrant cell cycle progression in 3-NP-induced cell death in these brain regions. 3-NP reduced the level of cyclin-dependent kinase inhibitor p27 in striatum but not in cerebral cortex. 3-NP also induced phosphorylation of retinoblastoma protein, a marker of cell cycle progression at late G(1) phase, only in striatum. Pharmacological experiments revealed that cyclin-dependent kinase activity and N-methyl-d-aspartate (NMDA) receptor were cooperatively involved in cell death by 3-NP in striatal neurons, whereas only NMDA receptor was involved in 3-NP-induced neurotoxicity in cortical neurons. Death of striatal neurons was preceded by elevation of somatic Ca(2+) and activation of calpain, a Ca(2+)-dependent protease. Both striatal p27 down-regulation and cell death provoked by 3-NP were dependent on calpain activity. Moreover, transfection of p27 small interfering RNA reduced striatal cell viability. In cortical neurons, however, there was no change in somatic Ca(2+) and calpain activity by 3-NP, and calpain inhibitors were not protective. These results suggest that 3-NP induces aberrant cell cycle progression and neuronal cell death via p27 down-regulation by calpain in striatum but not in the cerebral cortex. This is the first report for differential involvement of cell cycle reactivation in different brain regions and lightens the mechanism for region-selective vulnerability in human disease, including Huntington disease.