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    • Tau was recently shown to participate in stress

    2018-10-25

    Tau was recently shown to participate in stress granule biology, and persistence of stress granules stimulates tau aggregation (). RNA binding proteins are present in neurofibrillary pathology in mouse models of tauopathy and in human cases of tauopathy, including Alzheimer\'s disease (). Persistent stress granules directly stimulate tau aggregation and tau stimulates stress granules, indicating that the biology is bi-directional. Indeed, stimulation of stress granule formation appears to be an important biological function of tau. These accumulating data combined with the recent work by Kobayashi et al., the “mislocalization” of tau to the somatodendritic arbor appears to occur by biological design rather than as a pathological mistake. The cumulative impact of all of these studies broadens our perception of the roles of tau in biology and disease. It is now apparent that tau exists in many different domains within the neuron, and the function of tau varies depending on the neuronal domain being considered. The expanding biology of tau is apparent in recent studies demonstrating that tau knockout impairs synaptic plasticity and interferes with neuronal and behavioral response to stress (). A reduced stress response dampens the toxicity of Aβ but might also leave the neuron less able to cope with other types of stress (). Managing the excessive tau-directed stress response in AD and other tauopathies might end up being analogous to treatment of hypertension where the therapeutic goal is to reduce persistently high blood pressure, but not eliminate blood pressure. In the same way, the goal for treating neurodegenerative disease might be to reduce a persistently hyperactive translational stress response without eliminating the stress response. Conflicts of Interest Statement
    Circadian (i.e. 24-hour) rhythms regulate much of our physiology, a regulation that is supported by rhythmicity in individual atm kinase inhibitor of the body. Maintenance of cellular rhythms as well as proper coordination of circadian clocks across different tissues is increasingly recognized to be important for metabolic health and in disease prevention (). Long term follow up of rotating night shift workers strongly supports a link between circadian rhythm disturbance and coronary disease (). With a growing interest in what “zietgebers”—or time-givers—influence our internal 24-h clock, the study by Akashi et al. in this issue of starts to address the question as to what extent the link between metabolism and circadian rhythmicity is bidirectional in the context of cardiovascular disease (). Using a mouse model of human familial hypercholesterolemia, the authors reveal that ablation of the low density lipoprotein receptor (LDLR) itself induces circadian abnormalities that may further exacerbate the phenotype expected from loss of LDLR alone. First addressed for its potential role in familial hypersholesterolemia almost 30years ago (), the LDLR is a cell surface-associated protein that binds to and uptakes a variety of cholesterol-containing molecules. Specifically, its interactions include those with apolipoprotein B100 and apolipoprotein E, both of which contribute to the phospholipid component of low density lipoprotein (LDL) or very low density lipoprotein (VLDL) cholesterol transport particles, respectively. Thus, the LDLR serves as a primary mechanism of cholesterol transport in vivo. Using an knockout model () which has an elevated serum cholesterol (200–400mg/dL under normal diet and >2000mg/dL under high fat diet [HFD] feeding conditions), Akashi et al. reveal that severe hypercholesterolemia in −/− mice, induces a significant increase in period length under “free-running” (24-h constant dark/DD) conditions compared to WT controls on HFD. Furthermore, −/− mice fed a HFD show a bimodal activity pattern of activity in free running conditions. To determine whether circadian disruption itself exacerbates the effects of the loss of LDLR at the level of hypercholesterolemia-induced arteriosclerosis, Akashi et al. crossed mice mutant for the circadian gene (mPer2) () with −/− mice ( −/− m/m). Using the double −/− m/m mice, the authors reveal that HFD produces an accelerated arteriosclerosis phenotype, with double knockout mice having larger aortic lesions slightly earlier under HFD compared to −/− single mutants under entrained (LD) lighting conditions. Perhaps surprisingly, under free-running conditions elevation in plaque size compared to single −/− knockout mice occurred somewhat later after the introduction to HFD in −/− m/m mice.