Leveraging the glymphatic and meningeal lymphatic systems as therapeutic strategies in Alzheimer's disease: an updated overview of nonpharmacological therapies.

Understanding and treating Alzheimer's disease (AD) has been a remarkable challenge for both scientists and physicians. Although the amyloid-beta and tau protein hypothesis have largely explained the key pathological features of the disease, the mechanisms by which such proteins accumulate and lead to disease progression are still unknown. Such lack of understanding disrupts the development of disease-modifying interventions, leaving a therapeutic gap that remains unsolved. Nonetheless, the recent discoveries of the glymphatic pathway and the meningeal lymphatic system as key components driving central solute clearance revealed another mechanism underlying AD pathogenesis. In this regard, this narrative review integrates the glymphatic and meningeal lymphatic systems as essential components involved in AD pathogenesis. Moreover, it discusses the emerging evidence suggesting that nutritional supplementation, non-invasive brain stimulation, and traditional Chinese medicine can improve the pathophysiology of the disease by increasing glymphatic and/or meningeal lymphatic function. Given that physical exercise is a well-regarded preventive and pro-cognitive intervention for dementia, we summarize the evidence suggesting the glymphatic system as a mediating mechanism of the physical exercise therapeutic effects in AD. Targeting these central solute clearance systems holds the promise of more effective treatment strategies.

Increasing Adiponectin Signaling by Sub-Chronic AdipoRon Treatment Elicits Antidepressant- and Anxiolytic-Like Effects Independent of Changes in Hippocampal Plasticity.

(1) Background: Adiponectin is an adipocyte-secreted hormone that has antidepressant- and anxiolytic-like effects in preclinical studies. Here, we investigated the antidepressant- and anxiolytic-like effects of sub-chronic treatment with AdipoRon, an adiponectin receptor agonist, and its potential linkage to changes in hippocampal adult neurogenesis and synaptic plasticity. (2) Methods: Different cohorts of wild-type C57BL/6J and CamKIIα-Cre male mice were treated with sub-chronic (7 days) AdipoRon, followed by behavioral, molecular, and electrophysiological experiments. (3) Results: 7-day AdipoRon treatment elicited antidepressant- and anxiolytic-like effects but did not affect hippocampal neurogenesis. AdipoRon treatment reduced hippocampal brain-derived neurotrophic factor (BDNF) levels, neuronal activation in the ventral dentate gyrus, and long-term potentiation of the perforant path. The knockdown of N-methyl-D-aspartate (NMDA) receptor subunits GluN2A and GluN2B in the ventral hippocampus did not affect the antidepressant- and anxiolytic-like effects of AdipoRon. (4) Conclusions: Increasing adiponectin signaling through sub-chronic AdipoRon treatment results in antidepressant- and anxiolytic-like effects independent of changes in hippocampal structural and synaptic function.

Central Adiponectin Signaling - A Metabolic Regulator in Support of Brain Plasticity.

Brain plasticity and metabolism are tightly connected by a constant influx of peripheral glucose to the central nervous system in order to meet the high metabolic demands imposed by neuronal activity. Metabolic disturbances highly affect neuronal plasticity, which underlies the prevalent comorbidity between metabolic disorders, cognitive impairment, and mood dysfunction. Effective pro-cognitive and neuropsychiatric interventions, therefore, should consider the metabolic aspect of brain plasticity to achieve high effectiveness. The adipocyte-secreted hormone, adiponectin, is a metabolic regulator that crosses the blood-brain barrier and modulates neuronal activity in several brain regions, where it exerts neurotrophic and neuroprotective properties. Moreover, adiponectin has been shown to improve neuronal metabolism in different animal models, including obesity, diabetes, and Alzheimer's disease. Here, we aim at linking the adiponectin's neurotrophic and neuroprotective properties with its main role as a metabolic regulator and to summarize the possible mechanisms of action on improving brain plasticity via its role in regulating the intracellular energetic activity. Such properties suggest adiponectin signaling as a potential target to counteract the central metabolic disturbances and impaired neuronal plasticity underlying many neuropsychiatric disorders.

ß-Klotho promotes glycolysis and glucose-stimulated insulin secretion via GP130.

Impaired glucose-stimulated insulin secretion (GSIS) is a hallmark of type-2 diabetes. However, cellular signaling machineries that control GSIS remain incompletely understood. Here, we report that ß-klotho (KLB), a single-pass transmembrane protein known as a co-receptor for fibroblast growth factor 21 (FGF21), fine tunes GSIS via modulation of glycolysis in pancreatic ß-cells independent of the actions of FGF21. ß-cell-specific deletion of Klb but not Fgf21 deletion causes defective GSIS and glucose intolerance in mice and defective GSIS in islets of type-2 diabetic mice is mitigated by adenovirus-mediated restoration of KLB. Mechanistically, KLB interacts with and stabilizes the cytokine receptor subunit GP130 by blockage of ubiquitin-dependent lysosomal degradation, thereby facilitating interleukin-6-evoked STAT3-HIF1α signaling, which in turn transactivates a cluster of glycolytic genes for adenosine triphosphate production and GSIS. The defective glycolysis and GSIS in Klb-deficient islets are rescued by adenovirus-mediated replenishment of STAT3 or HIF1α. Thus, KLB functions as a key cell-surface regulator of GSIS by coupling the GP130 receptor signaling to glucose catabolism in ß-cells and represents a promising therapeutic target for diabetes.

The Role of MicroRNA and Microbiota in Depression and Anxiety.

Depression and anxiety are devastating disorders. Understanding the mechanisms that underlie the development of depression and anxiety can provide new hints on novel treatments and preventive strategies. Here, we summarize the latest findings reporting the novel roles of gut microbiota and microRNAs (miRNAs) in the pathophysiology of depression and anxiety. The crosstalk between gut microbiota and the brain has been reported to contribute to these pathologies. It is currently known that some miRNAs can regulate bacterial growth and gene transcription while also modulate the gut microbiota composition, suggesting the importance of miRNAs in gut and brain health. Treatment and prevention strategies for neuropsychiatric diseases, such as physical exercise, diet, and probiotics, can modulate the gut microbiota composition and miRNAs expressions. Nonetheless, there are critical questions to be addressed to understand further the mechanisms involved in the interaction between the gut microbiota and miRNAs in the brain. This review summarizes the recent findings of the potential roles of microbiota and miRNA on the neuropathology of depression and anxiety, and its potential as treatment strategies.