Tau truncation in the pathogenesis of Alzheimer's disease:a narrative review

Alzheimer's disease is characterized by two major neuropathological hallmarks—the extracellularβ-amyloid plaques and intracellular neurofibrillary tangles consisting of aggregated and hyperphosphorylated Tau protein.Recent studies suggest that dysregulation of the microtubuleassociated protein Tau,especially specific proteolysis,could be a driving force for Alzheimer's disease neurodegeneration.Tau physiologically promotes the assembly and stabilization of microtubules,whereas specific truncated fragments are sufficient to induce abnormal hyperphosphorylation and aggregate into toxic oligomers,resulting in them gaining prion-like characteristics.In addition,Tau truncations cause extensive impairments to neural and glial cell functions and animal cognition and behavior in a fragment-dependent manner.This review summarizes over 60 proteolytic cleavage sites and their corresponding truncated fragments,investigates the role of specific truncations in physiological and pathological states of Alzheimer's disease,and summarizes the latest applications of strategies targeting Tau fragments in the diagnosis and treatment of Alzheimer's disease.

miRNA-21-5p is an important contributor to the promotion of injured peripheral nerve regeneration using hypoxia-pretreated bone marrow-derived neural crest cells

Our previous study found that rat bone marrow–derived neural crest cells(acting as Schwann cell progenitors)have the potential to promote long-distance nerve repair.Cell-based therapy can enhance peripheral nerve repair and regeneration through paracrine bioactive factors and intercellular communication.Nevertheless,the complex contributions of various types of soluble cytokines and extracellular vesicle cargos to the secretome remain unclear.To investigate the role of the secretome and extracellular vesicles in repairing damaged peripheral nerves,we collected conditioned culture medium from hypoxia-pretreated neural crest cells,and found that it significantly promoted the repair of sensory neurons damaged by oxygen-glucose deprivation.The mRNA expression of trophic factors was highly expressed in hypoxia-pretreated neural crest cells.We performed RNA sequencing and bioinformatics analysis and found that miR-21-5p was enriched in hypoxia-pretreated extracellular vesicles of neural crest cells.Subsequently,to further clarify the role of hypoxia-pretreated neural crest cell extracellular vesicles rich in miR-21-5p in axonal growth and regeneration of sensory neurons,we used a microfluidic axonal dissociation model of sensory neurons in vitro,and found that hypoxia-pretreated neural crest cell extracellular vesicles promoted axonal growth and regeneration of sensory neurons,which was greatly dependent on loaded miR-21-5p.Finally,we constructed a miR-21-5p-loaded neural conduit to repair the sciatic nerve defect in rats and found that the motor and sensory functions of injured rat hind limb,as well as muscle tissue morphology of the hind limbs,were obviously restored.These findings suggest that hypoxia-pretreated neural crest extracellular vesicles are natural nanoparticles rich in miRNA-21-5p.miRNA-21-5p is one of the main contributors to promoting nerve regeneration by the neural crest cell secretome.This helps to explain the mechanism of action of the secretome and extracellular vesicles of neural crest cells in repairing damaged peripheral nerves,and also promotes the application of miR-21-5p in tissue engineering regeneration medicine.

Long noncoding RNA H19 regulates degeneration and regeneration of injured peripheral nerves

Our previous studies have shown that long noncoding RNA(lncRNA)H19 is upregulated in injured rat sciatic nerve during the process of Wallerian degeneration,and that it promotes the migration of Schwann cells and slows down the growth of dorsal root ganglion axons.However,the mechanism by which lncRNA H19 regulates neural repair and regeneration after peripheral nerve injury remains unclear.In this study,we established a Sprague-Dawley rat model of sciatic nerve transection injury.We performed in situ hybridization and found that at 4–7 days after sciatic nerve injury,lncRNA H19 was highly expressed.At 14 days before injury,adeno-associated virus was intrathecally injected into the L4–L5 foramina to disrupt or overexpress lncRNA H19.After overexpression of lncRNA H19,the growth of newly formed axons from the sciatic nerve was inhibited,whereas myelination was enhanced.Then,we performed gait analysis and thermal pain analysis to evaluate rat behavior.We found that lncRNA H19 overexpression delayed the recovery of rat behavior function,whereas interfering with lncRNA H19 expression improved functional recovery.Finally,we examined the expression of lncRNA H19 downstream target SEMA6D,and found that after lncRNA H19 overexpression,the SEMA6D protein level was increased.These findings suggest that lncRNA H19 regulates peripheral nerve degeneration and regeneration through activating SEMA6D in injured nerves.This provides a new clue to understand the role of lncRNA H19 in peripheral nerve degeneration and regeneration.

Lutein delays photoreceptor degeneration in a mouse model of retinitis pigmentosa

Retinitis pigmentosa is a retinal disease characterized by photoreceptor degeneration.There is currently no effective treatment for retinitis pigmentosa.Although a mixture of lutein and other antioxidant agents has shown promising effects in protecting the retina from degeneration,the role of lutein alone remains unclear.In this study,we administered intragastric lutein to Pde6brd10 model mice,which display degeneration of retinal photoreceptors,on postnatal days 17(P17)to P25,when rod apoptosis reaches peak.Lutein at the optimal protective dose of 200 mg/kg promoted the survival of photoreceptors compared with vehicle control.Lutein increased rhodopsin expression in rod cells and opsin expression in cone cells,in line with an increased survival rate of photoreceptors.Functionally,lutein improved visual behavior,visual acuity,and retinal electroretinogram responses in Pde6brd10 mice.Mechanistically,lutein reduced the expression of glial fibrillary acidic protein in Müller glial cells.The results of this study confirm the ability of lutein to postpone photoreceptor degeneration by reducing reactive gliosis of Müller cells in the retina and exerting anti-inflammatory effects.This study was approved by the Laboratory Animal Ethics Committee of Jinan University(approval No.LACUC-20181217-02)on December 17,2018.

Transferrin receptor 1 plays an important role in muscle development and denervation-induced muscular atrophy

Previous studies demonstrate an accumulation of transferrin and transferrin receptor 1(TfR1) in regenerating peripheral nerves.However, the expression and function of transferrin and TfR1 in the denervated skeletal muscle remain poorly understood.In this study, a mouse model of denervation was produced by complete tear of the left brachial plexus nerve.RNA-sequencing revealed that transferrin expression in the denervated skeletal muscle was upregulated, while TfR1 expression was downregulated.We also investigated the function of TfR1 during development and in adult skeletal muscles in mice with inducible deletion or loss of TfR1.The ablation of TfR1 in skeletal muscle in early development caused severe muscular atrophy and early death.In comparison, deletion of TfR1 in adult skeletal muscles did not affect survival or glucose metabolism, but caused skeletal muscle atrophy and motor functional impairment, similar to the muscular atrophy phenotype observed after denervation.These findings suggest that TfR1 plays an important role in muscle development and denervation-induced muscular atrophy.This study was approved by the Institutional Animal Care and Use Committee of Beijing Institute of Basic Medical Sciences, China(approval No.SYXK 2017-C023) on June 1, 2018.

Metabolomics analysis of poly(L-lactic acid)nanofibers’performance on PC12 cell differentiation

The aim of this article is to reveal the influence of aligned/random poly(L-lactic acid)(PLLA)nanofibers on PC12 cell differentiation from the perspective of metabolic level.First,three materials-PLLA aligned nanofibers(PLLA AF),PLLA random nanofibers(PLLA RF)and PLLA films(control)-were prepared by electrospinning and spin coating.Their surface morphologies were characterized.Subsequently,the cell viability,cell morphology and neurite length of PC12 cells on the surface of the three materials were evaluated,indicating more neurites in the PLLA RF groups but the longer average neurite length in the PLLA AF groups.Next,the metabolite profiles of PC12 cells cultured on the surface of the three nanofibers after 12 h,24 h and 36 h showed that,compared with the control,51,48 and 31 types of differential metabolites were detected at the three time points among the AF groups,respectively;and 56,45 and 41 types among the RF groups,respectively.Furthermore,the bioinformatics analysis of differential metabolites identified two pathways and three metabolites critical to PC12 cell differentiation influenced by the nanofibers.In addition,the verification experiment on critical metabolites and metabolic pathways were performed.The integrative analysis combining cytology,metabolomics and bioinformatics approaches revealed that though both PLLA AF and RF were capable of stimulating the synthesis of neurotransmitters,the PLLA AF were more beneficial for PC12 cell differentiation,whereas the PLLA RF were less effective.