NLRP3-mediated autophagy dysfunction links gut microbiota dysbiosis to tau pathology in chronic sleep deprivation

Emerging evidence indicates that sleep deprivation(SD)can lead to Alzheimer’s disease(AD)-related pathological changes and cognitive decline.However,the underlying mechanisms remain obscure.In the present study,we identified the existence of a microbiota-gut-brain axis in cognitive deficits resulting from chronic SD and revealed a potential pathway by which gut microbiota affects cognitive functioning in chronic SD.Our findings demonstrated that chronic SD in mice not only led to cognitive decline but also induced gut microbiota dysbiosis,elevated NLRP3 inflammasome expression,GSK-3βactivation,autophagy dysfunction,and tau hyperphosphorylation in the hippocampus.Colonization with the“SD microbiota”replicated the pathological and behavioral abnormalities observed in chronic sleep-deprived mice.Remarkably,both the deletion of NLRP3 in NLRP3-/-mice and specific knockdown of NLRP3 in the hippocampus restored autophagic flux,suppressed tau hyperphosphorylation,and ameliorated cognitive deficits induced by chronic SD,while GSK-3βactivity was not regulated by the NLRP3 inflammasome in chronic SD.Notably,deletion of NLRP3 reversed NLRP3 inflammasome activation,autophagy deficits,and tau hyperphosphorylation induced by GSK-3βactivation in primary hippocampal neurons,suggesting that GSK-3β,as a regulator of NLRP3-mediated autophagy dysfunction,plays a significant role in promoting tau hyperphosphorylation.Thus,gut microbiota dysbiosis was identified as a contributor to chronic SD-induced tau pathology via NLRP3-mediated autophagy dysfunction,ultimately leading to cognitive deficits.Overall,these findings highlight GSK-3βas a regulator of NLRP3-mediated autophagy dysfunction,playing a critical role in promoting tau hyperphosphorylation.

Senktide blocks aberrant RTN3 interactome to retard memory decline and tau pathology in social isolated Alzheimer’s disease mice

Sporadic or late-onset Alzheimer’s disease(LOAD)accounts for more than 95%of Alzheimer’s disease(AD)cases without any family history.Although genome-wide association studies have identified associated risk genes and loci for LOAD,numerous studies suggest that many adverse environmental factors,such as social isolation,are associated with an increased risk of dementia.However,the underlying mechanisms of social isolation in AD progression remain elusive.In the current study,we found that 7 days of social isolation could trigger pattern separation impairments and presynaptic abnormalities of the mossy fibre-CA3 circuit in AD mice.We also revealed that social isolation disrupted histone acetylation and resulted in the downregulation of 2 dentate gyrus(DG)-enriched miRNAs,which simultaneously target reticulon 3(RTN3),an endoplasmic reticulum protein that aggregates in presynaptic regions to disturb the formation of functional mossy fibre boutons(MFBs)by recruiting multiple mitochondrial and vesicle-related proteins.Interestingly,the aggregation of RTN3 also recruits the PP2A B subunits to suppress PP2A activity and induce tau hyperphosphorylation,which,in turn,further elevates RTN3 and forms a vicious cycle.Finally,using an artificial intelligence-assisted molecular docking approach,we determined that senktide,a selective agonist of neurokinin3 receptors(NK3R),could reduce the binding of RTN3 with its partners.Moreover,application of senktide in vivo effectively restored DG circuit disorders in socially isolated AD mice.Taken together,our findings not only demonstrate the epigenetic regulatory mechanism underlying mossy fibre synaptic disorders orchestrated by social isolation and tau pathology but also reveal a novel potential therapeutic strategy for AD.

Tau in Alzheimer’s Disease:Pathological Alterations and an Attractive Therapeutic Target

Alzheimer’s disease(AD)is an age-related neurodegenerative disease with two major hallmarks:extracellular amyloid plaques made of amyloid-β(Aβ)and intracellular neurofibrillary tangles(NFTs)of abnormally hyperphosphorylated tau.The number of NFTs correlates positively with the severity of dementia in AD patients.However,there is still no efficient therapy available for AD treatment and prevention so far.A deeper understanding of AD pathogenesis has identified novel strategies for the generation of specific therapies over the past few decades.Several studies have suggested that the prion-like seeding and spreading of tau pathology in the brain may be a key driver of AD.Tau protein is considered as a promising candidate target for the development of therapeutic interventions due to its considerable pathological role in a variety of neurodegenerative disorders.Abnormal tau hyperphosphorylation plays a detrimental pathological role,eventually leading to neurodegeneration.In the present review,we describe the recent research progresses in the pathological mechanisms of tau protein in AD and briefly discuss tau-based therapeutic strategies.

Targeting autophagy in Alzheimer's disease:Animal models and mechanisms

Alzheimer's disease(AD)is an age-related progressive neurodegenerative disorder that leads to cognitive impairment and memory loss.Emerging evidence suggests that autophagy plays an important role in the pathogenesis of AD through the regulation of amyloid-beta(Aβ)and tau metabolism,and that autophagy dysfunction exacerbates amyloidosis and tau pathology.Therefore,targeting autophagy may be an effective approach for the treatment of AD.Animal models are considered useful tools for investigating the pathogenic mechanisms and therapeutic strategies of diseases.This review aims to summarize the pathological alterations in autophagy in representative AD animal models and to present recent studies on newly discovered autophagy-stimulating interventions in animal AD models.Finally,the opportunities,difficulties,and future directions of autophagy targeting in AD therapy are discussed.

Profiling neuroprotective potential of trehalose in animal models of neurodegenerative diseases:a systematic review

Trehalose,a unique nonreducing crystalline disaccharide,is a potential disease-modifying treatment for neurodegenerative diseases associated with protein misfolding and aggregation due to aging,intrinsic mutations,or autophagy dysregulation.This systematic review summarizes the effects of trehalose on its underlying mechanisms in animal models of selected neurodegenerative disorders(tau pathology,synucleinopathy,polyglutamine tract,and motor neuron diseases).All animal studies on neurodegenerative diseases treated with trehalose published in Medline(accessed via EBSCOhost)and Scopus were considered.Of the 2259 studies screened,29 met the eligibility criteria.According to the SYstematic Review Center for Laboratory Animal Experiment(SYRCLE)risk of bias tool,we reported 22 out of 29 studies with a high risk of bias.The present findings support the purported role of trehalose in autophagic flux and protein refolding.This review identified several other lesser-known pathways,including modifying amyloid precursor protein processing,inhibition of reactive gliosis,the integrity of the blood-brain barrier,activation of growth factors,upregulation of the downstream antioxidant signaling pathway,and protection against mitochondrial defects.The absence of adverse events and improvements in the outcome parameters were observed in some studies,which supports the transition to human clinical trials.It is possible to conclude that trehalose exerts its neuroprotective effects through both direct and indirect pathways.However,heterogeneous methodologies and outcome measures across the studies rendered it impossible to derive a definitive conclusion.Translational studies on trehalose would need to clarify three important questions:1)bioavailability with oral administration,2)optimal time window to confer neuroprotective benefits,and 3)optimal dosage to confer neuroprotection.

The role of pathological tau in synaptic dysfunction in Alzheimer’s diseases

Alzheimer's disease(AD)is a neurodegenerative disease characterized by progressive cognitive decline,accompanied by amyloid-β(Aβ)overload and hyperphosphorylated tau accumulation in the brain.Synaptic dysfunction,an important pathological hallmark in AD;is recognized as the main cause of the cognitive impairments.Accumulating evidence suggests that synaptic dysfunction could be an early pathological event in AD.Pathological tau,which is detached from axonal microtubules and mislocalized into pre-and postsynaptic neuronal compartments,is suggested to induce synaptic dysfunction in several ways,including reducing mobility and release of presynaptic vesicles,decreasing glutamatergic receptors,impairing the maturation of dendritic spines at postsynaptic terminals,disrupting mitochondrial transport and function in synapses,and promoting the phagocytosis of synapses by microglia.Here,we review the current understanding of how pathological tau mediates synaptic dysfunction and contributes to cognitive decline in AD.We propose that elucidating the mechanism by which pathological tau impairs synaptic function is essential for exploring novel therapeutic strategies for AD.

Brain metabolism in Alzheimer’s disease:biological mechanisms of exercise

Alzheimer’s disease(AD)is a major subtype of neurodegenerative dementia caused by long-term interactions and accumulation of multiple adverse factors,accompanied by dysregulation of numerous intracellular signaling and molecular pathways in the brain.At the cellular and molecular levels,the neuronal cellular milieu of the AD brain exhibits metabolic abnormalities,compromised bioenergetics,impaired lipid metabolism,and reduced overall metabolic capacity,which lead to abnormal neural network activity and impaired neuroplasticity,thus accelerating the formation of extracellular senile plaques and intracellular neurofibrillary tangles.The current absence of effective pharmacological therapies for AD points to the urgent need to investigate the benefits of non-pharmacological approaches such as physical exercise.Despite the evidence that regular physical activity can improve metabolic dysfunction in the AD state,inhibit different pathophysiological molecular pathways associated with AD,influence the pathological process of AD,and exert a protective effect,there is no clear consensus on the specific biological and molecular mechanisms underlying the advantages of physical exercise.Here,we review how physical exercise improves crucial molecular pathways and biological processes associated with metabolic disorders in AD,including glucose metabolism,lipid metabolism,Aβmetabolism and transport,iron metabolism and tau pathology.How metabolic states influence brain health is also presented.A better knowledge on the neurophysiological mechanisms by which exercise improves AD metabolism can contribute to the development of novel drugs and improvement of non-pharmacological interventions.

Cognitive Impairment in Idiopathic Normal Pressure Hydrocephalus

Idiopathic normal pressure hydrocephalus(iNPH)is a significant cause of the severe cognitive decline in the elderly population.There is no cure for iNPH,but cognitive symptoms can be partially alleviated through cerebrospinal fluid(CSF)diversion.In the early stages of iNPH,cognitive deficits occur primarily in the executive functions and working memory supported by frontostriatal circuits.As the disease progresses,cognition declines continuously and globally,leading to poor quality of life and daily functioning.In this review,we present recent advances in understanding the neurobiological mechanisms of cognitive impairment in iNPH,focusing on(1)abnormal CSF dynamics,(2)dysfunction of frontostriatal and entorhinal-hippocampal circuits and the default mode network,(3)abnormal neuromodulation,and(4)the presence of amyloid-βand tau pathologies.