Mechanosensitive Piezo1 channel regulation of microglial cell function and implications to neurodegenerative diseases and neuroinflammation

Microglial cells are the key immunocompetent cells in the central nervous system (CNS) and play a crucial role in CNS health and disease (Paolicelli et al.,2022).Under the homeostatic conditions,microglial cells assume diverse and dynamic states,depending upon interactions with neighboring cells and structures in local contextual settings,continuously patrol brain parenchyma utilizing their highly mobile fine processes,phagocytize protein aggregates,unwanted synapses and cells to maintain CNS health,and secrete neurotrophic factors to support neuronal function (Colonna and Butovsky,2017;Paolicelli et al.,2022).

Melastatin-related transient receptor potential 2 channel in Aβ_(42)-induced neuroinflammation: implications to Alzheimer's disease mechanism and development of therapeutics

Alzheimer’s disease （AD） is an age-related eurodegenerative disease that represents the most common cause of dementia among the elderly people. With the increasingly aging population, AD has presented an overwhelming healthcare challenge to modern society; the World Alzheimer Report 2015 has estimated that 46.8 million people worldwide lived with dementia in 2015 and this number will rise to 74.7 million in 2030 and that the total cost of dementia was 818 billion in US$ in 2015 and will reach two trillion in 2030. Post-mortem studies have identified two histopathological hallmarks in the brains of AD patients; extracellular senile plaque with elevated deposition of amyloid β （Aβ） peptides, and intracellular neurofibrillary tangle composed of hyper-phosphorylated microtubule-associated protein tau.Etiologically, progressive neuronal loss within the cerebral cortex and hippocampus regions of the brain leads to irreversible decline in, and eventually complete loss of, memory and other cognitive functions that afflict AD patients. The widely-accepted amyloid cascade hypothesis for AD pathogenesis holds that accumulation and aggregation of neurotoxic Aβ peptides, due to imbalance of their generation and clearance as a result of changes in genetic makeup, aging and/or exposure to environmental risk factors, is a major and early trigger of AD. This hypothesis has continuously gained support by preclinical and clinical studies （Selkoe and Hardy, 2016）. However, the intensive and costly drug discovery efforts over the past decades based on such a hypothesis have proved extremely frustrating in developing effective therapeutics to treat or slow down the progress of AD, highlighting the need for more research to improve our understanding towards the cellular and molecular mechanisms by which Aβ peptides bring about neurotoxicity and cognitive dysfunction.

Basal Forebrain Cholinergic Innervation Induces Depression-Like Behaviors Through Ventral Subiculum Hyperactivation

Malfunction of the ventral subiculum(vSub),the main subregion controlling the output connections from the hippocampus,is associated with major depressive disorder(MDD).Although the vSub receives cholinergic innervation from the medial septum and diagonal band of Broca(MSDB),whether and how the MSDB-to-vSub cholinergic circuit is involved in MDD is elusive.Here,we found that chronic unpredictable mild stress(CUMS)induced depression-like behaviors with hyperactivation of vSub neurons,measured by c-fos staining and whole-cell patch-clamp recording.By retrograde and anterograde tracing,we confirmed the dense MSDB cholinergic innervation of the vSub.In addition,transient restraint stress in CUMS increased the level of ACh in the vSub.Furthermore,chemogenetic stimulation of this MSDB-vSub innervation in ChAT-Cre mice induced hyperactivation of vSub pyramidal neurons along with depression-like behaviors;and local infusion of atropine,a muscarinic receptor antagonist,into the vSub attenuated the depression-like behaviors induced by chemogenetic stimulation of this pathway and CUMS.Together,these findings suggest that activating the MSDB-vSub cholinergic pathway induces hyperactivation of vSub pyramidal neurons and depression-like behaviors,revealing a novel circuit underlying vSub pyramidal neuronal hyperactivation and its associated depression.

多肽靶向嵌合体通过促进tau蛋白特异性去磷酸化治疗阿尔茨海默病和其他tau蛋白病

Abnormal hyperphosphorylation and accumulation of tau protein play a pivotal role in neurodegeneration in Alzheimer’s disease(AD)and many other tauopathies.Selective elimination of hyperphosphorylated tau is promising for the therapy of these diseases.We have conceptualized a strategy,named dephosphorylation-targeting chimeras(DEPTACs),for specifically hijacking phosphatases to tau to debilitate its hyperphosphorylation.Here,we conducted the step-by-step optimization of each constituent motif to generate DEPTACs with reasonable effectiveness in facilitating the dephosphorylation and subsequent clearance of pathological tau.Specifically,for one of the selected chimeras,D16,we demonstrated its significant efficiency in rescuing the neurodegeneration caused by neurotoxic K18-tau seeds in vitro.Moreover,intravenous administration of D16 also alleviated tau pathologies in the brain and improved memory deficits in AD mice.These results suggested DEPTACs as targeted modulators of tau phosphorylation,which hold therapeutic potential for AD and other tauopathies.

TRPM2 Mediates Hepatic Ischemia–Reperfusion Injury via Ca^(2+) -Induced Mitochondrial Lipid Peroxidation through Increasing ALOX12 Expression

Hepatic ischemia–reperfusion(IR)injury is a serious clinical problem that complicates liver resection and transplantation.Despite recent advances in understanding of the pathophysiology of hepatic IR injury,effective interventions and therapeutics are still lacking.Here,we examined the role of transient receptor potential melastatin 2(TRPM2),a Ca^(2+)-permeable,non-selective cation channel,in mediating hepatic IR injury.Our data showed that TRPM2 deficiency attenuated IR-induced liver dysfunction,inflammation,and cell death in mice.Moreover,RNA sequencing analysis indicated that TRPM2-induced IR injury occurs via ferroptosis-related pathways.Consistently,as a ferroptosis inducer,(1S,3R)-RSL3 treatment induced mitochondrial dysfunction in hepatocytes and a TRPM2 inhibitor suppressed this.Interestingly,TRPM2-mediated calcium influx caused mitochondrial calcium accumulation via the mitochondrial Ca^(2+)-selective uniporter and increased the expression level of arachidonate 12-lipoxygenase(ALOX12),which results in mitochondrial lipid peroxidation during hepatic IR injury.Furthermore,hepatic IR injury-induced ferroptosis was obviously relieved by a TRPM2 inhibitor or calcium depletion,both in vitro and in vivo.Collectively,these findings demonstrate a crucial role for TRPM2-mediated ferroptosis in hepatic IR injury via increased Ca^(2+)-induced ALOX12 expression,indicating that pharmacological inhibition of TRPM2 may provide an effective therapeutic strategy for hepatic IR injury-related diseases,such as during liver resection and transplantation.

Current understanding of metal ions in the pathogenesis of Alzheimer’s disease

Background The homeostasis of metal ions,such as iron,copper,zinc and calcium,in the brain is crucial for maintaining normal physiological functions.Studies have shown that imbalance of these metal ions in the brain is closely related to the onset and progression of Alzheimer’s disease(AD),the most common neurodegenerative disorder in the elderly.Main body Erroneous deposition/distribution of the metal ions in different brain regions induces oxidative stress.The metal ions imbalance and oxidative stress together or independently promote amyloid-β(Aβ)overproduction by activatingβ-orγ-secretases and inhibitingα-secretase,it also causes tau hyperphosphorylation by activating protein kinases,such as glycogen synthase kinase-3β(GSK-3β),cyclin-dependent protein kinase-5(CDK5),mitogen-activated protein kinases(MAPKs),etc.,and inhibiting protein phosphatase 2A(PP2A).The metal ions imbalances can also directly or indirectly disrupt organelles,causing endoplasmic reticulum(ER)stress;mitochondrial and autophagic dysfunctions,which can cause or aggravate Aβand tau aggregation/accumulation,and impair synaptic functions.Even worse,the metal ions imbalance-induced alterations can reversely exacerbate metal ions misdistribution and deposition.The vicious cycles between metal ions imbalances and Aβ/tau abnormalities will eventually lead to a chronic neurodegeneration and cognitive deficits,such as seen in AD patients.Conclusion The metal ions imbalance induces Aβand tau pathologies by directly or indirectly affecting multiple cellular/subcellular pathways,and the disrupted homeostasis can reversely aggravate the abnormalities of metal ions transportation/deposition.Therefore,adjusting metal balance by supplementing or chelating the metal ions may be potential in ameliorating AD pathologies,which provides new research directions for AD treatment.