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Background and Purpose: Amyloid‐β (Aβ) peptide is one of the more important pathological markers in Alzheimer's disease (AD). The development of AD impairs autophagy, which results in an imbalanced clearance of Aβ. Our previous research demonstrated that AdipoRon, an agonist of adiponectin receptors, decreased the deposition of Aβ and enhanced cognitive function in AD. However, the exact mechanisms by which AdipoRon affects Aβ clearance remain unclear. Experimental Approach: We studied how AdipoRon affects autophagy in HT22 cells and APP/PS1 transgenic mice. We also investigated the signalling pathway involved and used pharmacological inhibitors to examine the role of autophagy in this process. Key Results: AdipoRon promotes Aβ clearance by activating neuronal autophagy in the APP/PS1 transgenic mice. Interestingly, we found that AdipoRon induces the nuclear translocation of GAPDH, where it interacts with the SIRT1/DBC1 complex. This interaction then leads to the release of DBC1 and the activation of SIRT1, which in turn activates autophagy. Importantly, we found that inhibiting either GAPDH or SIRT1 to suppress the activity of SIRT1 counteracts the elevated autophagy and decreased Aβ deposition caused by AdipoRon. This suggests that SIRT1 plays a critical role in the effect of AdipoRon on autophagic induction in AD. Conclusion and Implications: AdipoRon promotes the clearance of Aβ by enhancing autophagy through the AdipoR1/AMPK‐dependent nuclear translocation of GAPDH and subsequent activation of SIRT1. This novel molecular pathway sheds light on the modulation of autophagy in AD and may lead to the development of new therapeutic strategies targeting this pathway. [ABSTRACT FROM AUTHOR]

Chronic stress induces depression and insulin resistance, between which there is a bidirectional relationship. However, the mechanisms underlying this comorbidity remain unclear. White adipose tissue (WAT), innervated by sympathetic nerves, serves as a central node in the interorgan crosstalk through adipokines. Abnormal secretion of adipokines is involved in mood disorders and metabolic morbidities. We describe here a brain–sympathetic nerve–adipose circuit originating in the hypothalamic paraventricular nucleus (PVN) with a role in depression and insulin resistance induced by chronic stress. PVN neurons are labelled after inoculation of pseudorabies virus (PRV) into WAT and are activated under restraint stress. Chemogenetic manipulations suggest a role for the PVN in depression and insulin resistance. Chronic stress increases the sympathetic innervation of WAT and downregulates several antidepressant and insulin‐sensitizing adipokines, including leptin, adiponectin, Angptl4 and Sfrp5. Chronic activation of the PVN has similar effects. β‐adrenergic receptors translate sympathetic tone into an adipose response, inducing downregulation of those adipokines and depressive‐like behaviours and insulin resistance. We finally show that AP‐1 has a role in the regulation of adipokine expression under chronic stress. Synopsis: Under chronic stress, the PVN increases sympathetic innervation of adipose tissues and represses adipokine expression through AP‐1, which contributes to the development of depression and insulin resistance.Chronic activation of PVN neurons responding to restraint stress contributes to the development of depression and insulin resistance.Chronic activation of PVN neurons responding to restraint stress increases sympathetic innervation of adipose tissues.The β‐adrenergic receptors translate sympathetic tone into the expression regulation of some adipokines, including leptin, adiponectin, Angptl4, Sfrp5 and Fbn1.AP‐1 proteins have a role in the regulation of adipokine expression by the PVN–sympathetic nerve pathway. [ABSTRACT FROM AUTHOR]

A substantial percentage of late‐life depression patients also have an cognitive impairment, which severely affects the life quality, while the co‐occurring mechanisms are still unclear. Physical exercise can ameliorate both depressive behaviors and cognitive dysfunction, but the molecular mechanisms underlying its beneficial effects remain elusive. In this study, we uncover a novel adipose tissue to hippocampus crosstalk mediated by Adiponectin‐Notch pathway, with an impact on hippocampal neurogenesis and cognitive function. Adiponectin, an adipocyte‐derived hormone, could activate Notch signaling in the hippocampus through upregulating ADAM10 and Notch1, two key molecules in the Notch signaling. Chronic stress inhibits the Adiponectin‐Notch pathway and induces impaired hippocampal neurogenesis and cognitive dysfunction, which can be rescued by AdipoRon and running. Inhibition Notch signaling by DAPT mimics the adverse effects of chronic stress on hippocampal neurogenesis and cognitive function. Adiponectin knockout mice display depressive‐like behaviors, associated with inhibited Notch signaling, impaired hippocampal neurogenesis and cognitive dysfunction. Physical exercise could activate Adiponectin‐Notch pathway, and improve hippocampal neurogenesis and cognitive function, while deleting adiponectin gene or inhibiting Notch signaling blocks its beneficial effects. Together, our data not only suggest that Adiponectin‐Notch pathway is involved in the pathogenesis of cognitive dysfunction associated with depression, but also contributes to the therapeutic effect of physical exercise. This work helps to decipher the etiology of cognitive impairment associated with depression and hence will provide a potential innovative therapeutic target for these patients. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is an age‐related neurodegenerative disease, and the imbalance between production and clearance of β‐amyloid (Aβ) is involved in its pathogenesis. Autophagy is an intracellular degradation pathway whereby leads to removal of aggregated proteins, up‐regulation of which may be a plausible therapeutic strategy for the treatment of AD. Histamine H3 receptor (H3R) is a presynaptic autoreceptor regulating histamine release via negative feedback way. Our previous study showed that thioperamide, as an antagonist of H3R, enhances autophagy and protects against ischemic injury. However, the effect of thioperamide on autophagic function and Aβ pathology in AD remains unknown. In this study, we found that thioperamide promoted cognitive function, ameliorated neuronal loss, and Aβ pathology in APP/PS1 transgenic (Tg) mice. Interestingly, thioperamide up‐regulated autophagic level and lysosomal function both in APP/PS1 Tg mice and in primary neurons under Aβ‐induced injury. The neuroprotection by thioperamide against AD was reversed by 3‐MA, inhibitor of autophagy, and siRNA of Atg7, key autophagic‐related gene. Furthermore, inhibition of activity of CREB, H3R downstream signaling, by H89 reversed the effect of thioperamide on promoted cell viability, activated autophagic flux, and increased autophagic‐lysosomal proteins expression, including Atg7, TFEB, and LAMP1, suggesting a CREB‐dependent autophagic activation by thioperamide in AD. Taken together, these results suggested that H3R antagonist thioperamide improved cognitive impairment in APP/PS1 Tg mice via modulation of the CREB‐mediated autophagy and lysosomal pathway, which contributed to Aβ clearance. This study uncovered a novel mechanism involving autophagic regulating behind the therapeutic effect of thioperamide in AD. [ABSTRACT FROM AUTHOR]