Enhanced autophagic clearance of amyloid-βvia histone deacetylase 6-mediated V-ATPase assembly and lysosomal acidification protects against Alzheimer's disease in vitro and in vivo

Recent studies have suggested that abnormal acidification of lysosomes induces autophagic accumulation of amyloid-βin neurons,which is a key step in senile plaque formation.Therefore,resto ring normal lysosomal function and rebalancing lysosomal acidification in neurons in the brain may be a new treatment strategy for Alzheimer's disease.Microtubule acetylation/deacetylation plays a central role in lysosomal acidification.Here,we show that inhibiting the classic microtubule deacetylase histone deacetylase 6 with an histone deacetylase 6 shRNA or thehistone deacetylase 6 inhibitor valproic acid promoted lysosomal reacidification by modulating V-ATPase assembly in Alzheimer's disease.Fu rthermore,we found that treatment with valproic acid markedly enhanced autophagy.promoted clearance of amyloid-βaggregates,and ameliorated cognitive deficits in a mouse model of Alzheimer's disease.Our findings demonstrate a previously unknown neuroprotective mechanism in Alzheimer's disease,in which histone deacetylase 6 inhibition by valproic acid increases V-ATPase assembly and lysosomal acidification.

Nanomaterials-mediated lysosomal regulation:a robust protein-clearance approach for the treatment of Alzheimer’s disease

Alzheimer’s disease is a debilitating,progressive neurodegenerative disorder characterized by the progressive accumulation of abnormal proteins,including amyloid plaques and intracellular tau tangles,primarily within the brain.Lysosomes,crucial intracellular organelles responsible for protein degradation,play a key role in maintaining cellular homeostasis.Some studies have suggested a link between the dysregulation of the lysosomal system and pathogenesis of neurodegenerative diseases,including Alzheimer’s disease.Restoring the normal physiological function of lysosomes hold the potential to reduce the pathological burden and improve the symptoms of Alzheimer’s disease.Currently,the efficacy of drugs in treating Alzheimer’s disease is limited,with major challenges in drug delivery efficiency and targeting.Recently,nanomaterials have gained widespread use in Alzheimer’s disease drug research owing to their favorable physical and chemical properties.This review aims to provide a comprehensive overview of recent advances in using nanomaterials(polymeric nanomaterials,nanoemulsions,and carbon-based nanomaterials)to enhance lysosomal function in treating Alzheimer’s disease.This review also explores new concepts and potential therapeutic strategies for Alzheimer’s disease through the integration of nanomaterials and modulation of lysosomal function.In conclusion,this review emphasizes the potential of nanomaterials in modulating lysosomal function to improve the pathological features of Alzheimer’s disease.The application of nanotechnology to the development of Alzheimer’s disease drugs brings new ideas and approaches for future treatment of this disease.

The emerging roles of vacuolar-type ATPase-dependent Lysosomal acidification in neurodegenerative diseases

Background Lysosomes digest extracellular material from the endocytic pathway and intracellular material from the autophagic pathway.This process is performed by the resident hydrolytic enzymes activated by the highly acidic pH within the lysosomal lumen.Lysosome pH gradients are mainly maintained by the vacuolar(H+)ATPase(or V-ATPase),which pumps protons into lysosomal lumen by consuming ATP.Dysfunction of V-ATPase affects lysosomal acidification,which disrupts the clearance of substrates and leads to many disorders,including neurodegenerative diseases.Main body As a large multi-subunit complex,the V-ATPase is composed of an integral membrane V0 domain involved in proton translocation and a peripheral V1 domain catalyzing ATP hydrolysis.The canonical functions of V-ATPase rely on its H+-pumping ability in multiple vesicle organelles to regulate endocytic traffic,protein processing and degradation,synaptic vesicle loading,and coupled transport.The other non-canonical effects of the V-ATPase that are not readily attributable to its proton-pumping activity include membrane fusion,pH sensing,amino-acid-induced activation of mTORC1,and scaffolding for protein-protein interaction.In response to various stimuli,V-ATPase complex can reversibly dissociate into V1 and V0 domains and thus close ATP-dependent proton transport.Dysregulation of pH and lysosomal dysfunction have been linked to many human diseases,including neurodegenerative disorders such as Alzheimer disease,Parkinson’s disease,amyotrophic lateral sclerosis as well as neurodegenerative lysosomal storage disorders.Conclusion V-ATPase complex is a universal proton pump and plays an important role in lysosome acidification in all types of cells.Since V-ATPase dysfunction contributes to the pathogenesis of multiple neurodegenerative diseases,further understanding the mechanisms that regulate the canonical and non-canonical functions of V-ATPase will reveal molecular details of disease process and help assess V-ATPase or molecules related to its regulation as therapeutic targets.

Regulation of lysosomal ion homeostasis by channels and transporters

Lysosomes are the major organelles that carry out degradation functions. They integrate and digest materials compartmental- ized by endocytosis, phagocytosis or autophagy. In addition to more than 60 hydrolases residing in the lysosomes, there are also ion channels and transporters that mediate the flux or transport of H＋, Ca2＋, Na＋, K＋, and C1- across the lysosomal mem- branes. Defects in ionic exchange can lead to abnormal lysosome morphology, defective vesicle trafficking, impaired autoph- agy, and diseases such as neurodegeneration and lysosomal storage disorders. The latter are characterized by incomplete lyso- somal digestion and accumulation of toxic materials inside enlarged intracellular vacuoles. In addition to degradation, recent studies have revealed the roles of lysosomes in metabolic pathways through kinases such as mechanistic target of rapamycin （mTOR） and transcriptional regulation through calcium signaling molecules such as transcription factor EB （TFEB） and cal- cineurin. Owing to the development of new approaches including genetically encoded fluorescence probes and whole endoly- sosomal patch clamp recording techniques, studies on lysosomal ion channels have made remarkable progress in recent years. In this review, we will focus on the current knowledge of lysosome-resident ion channels and transporters, discuss their roles in maintaining lysosomal function, and evaluate how their dysfunction can result in disease.

Schisandrol A protects AGEs-induced neuronal cells death by allosterically targeting ATP6V0d1 subunit of V-ATPase

Diabetes have been shown to cause progressive neuronal injury with pain and numbness via advanced glycation end-products(AGEs)-induced neuronal cell apoptosis;however, the valuable drug targets for diabetic neuropathy have been poorly reported so far. In this study, we discovered a natural small-molecule schisandrol A(SolA) with significant protective effect against AGEs-induced neuronal cell apoptosis. ATP6V0D1, a major subunit of vacuolar-type ATPase(V-ATPase) in lysosome was identified as a crucial cellular target of SolA. Moreover, SolA allosterically mediated ATP6V0D1 conformation via targeting a unique cysteine 335 residue to activate V-ATPase-dependent lysosomal acidification.Interestingly, SolA-induced lysosome pH downregulation resulted in a mitochondrial-lysosomal crosstalk by selectively promoting mitochondrial BH3-only protein BIM degradation, thereby preserving mitochondrial homeostasis and neuronal cells survival. Collectively, our findings reveal ATP6V0D1 is a valuable pharmacological target for diabetes-associated neuronal injury via controlling lysosomal acidification, and also provide the first small-molecule template allosterically activating V-ATPase for preventing diabetic neuropathy.