Intracellular accumulation of tau inhibits autophagosome formation by activating TIA1-amino acid-mTORC1 signaling

Background:Autophagy dysfunction plays a crucial role in tau accumulation and neurodegeneration in Alzheimer’s disease(AD).This study aimed to investigate whether and how the accumulating tau may in turn affect autophagy.Methods:The primary hippocampal neurons,N2a and HEK293T cells with tau overexpression were respectively starved and treated with vinblastine to study the effects of tau on the initiating steps of autophagy,which was analysed by Student’s two-tailed t-test.The rapamycin and concanamycin A were employed to inhibit the mammalian target of rapamycin kinase complex 1(mTORC1)activity and the vacuolar H+-ATPase(v-ATPase)activity,respectively,which were analysed by One-way ANOVA with post hoc tests.The Western blotting,co-immunoprecipitation and immunofuorescence staining were conducted to gain insight into the mechanisms underlying the tau effects of mTORC1 signaling alterations,as analysed by Student’s two-tailed t-test or One-way ANOVA with post hoc tests.The autophagosome formation was detected by immunofuorescence staining and transmission electron microscopy.The amino acids(AA)levels were detected by high performance liquid chromatography(HPLC).Results:We observed that overexpressing human full-length wild-type tau to mimic AD-like tau accumulation induced autophagy deficits.Further studies revealed that the increased tau could bind to the prion-related domain of T cell intracellular antigen 1(PRD-TIA1)and this association significantly increased the intercellular level of amino acids(Leucine,P=0.0038;Glutamic acid,P=0.0348;Alanine,P=0.0037;Glycine,P=0.0104),with concordant upregulation of mTORC1 activity[phosphorylated eukaryotic translation initiation factor 4E-binding protein 1(p-4EBP1),P<0.0001;phosphorylated 70 kD ribosomal protein S6 kinase 1(p-p70S6K1),P=0.0001,phosphorylated unc-51-like autophagyactivating kinase 1(p-ULK1),P=0.0015]and inhibition of autophagosome formation[microtubuleassociated protein light chain 3 II(LC3 II),P=0.0073;LC3 puncta,P<0.0001].As expected,this tau-induced deficit of autophagosome formation in turn aggravated tau accumulation.Importantly,we also found that blocking TIA1 and tau interaction by overexpressing PRD-TIA1,downregulating the endogenous TIA1 expression by shRNA,or downregulating tau protein level by a small proteolysis targeting chimera(PROTAC)could remarkably attenuate tau-induced autophagy impairment.Conclusions:Our findings reveal that AD-like tau accumulation inhibits autophagosome formation and induces autophagy deficits by activating the TIA1/amino acid/mTORC1 pathway,and thus this work reveals new insight into tau-associated neurodegeneration and provides evidence supporting the use of new therapeutic targets for AD treat-ment and that of related tauopathies.

Inactivation of ERK1/2-CREB Pathway Is Implicated in MK801-induced Cognitive Impairment

Objective Schizophrenia(SZ)is associated with cognitive impairment,and it is known that the activity of cAMP response element binding protein(CREB)decreases in the brain of SZ patients.The previous study conducted by the investigators revealed that the upregulation of CREB improves the MK801-related SZ cognitive deficit.The present study further investigates the mechanism on how CREB deficiency is associated with SZ-related cognitive impairment.Methods MK-801 was used to induce SZ in rats.Western blotting and immunofluorescence were performed to investigate CREB and the CREB-related pathway implicated in MK801 rats.The long-term potentiation and behavioral tests were performed to assess the synaptic plasticity and cognitive impairment,respectively.Results The phosphorylation of CREB at Ser133 decreased in the hippocampus of SZ rats.Interestingly,among the upstream kinases of CREB,merely ERK1/2 was downregulated,while CaMKII and PKA remained unchanged in the brain of MK801-related SZ rats.The inhibition of ERK1/2 by PD98059 reduced the phosphorylation of CREB-Ser133,and induced synaptic dysfunction in primary hippocampal neurons.Conversely,the activation of CREB attenuated the ERK1/2 inhibitor-induced synaptic and cognitive impairment.Conclusion These present findings partially suggest that the deficiency of the ERK1/2-CREB pathway is involved in MK801-related SZ cognitive impairment.The activation of the ERK1/2-CREB pathway may be therapeutically useful for treating SZ cognitive deficits.

Advances in Drug Therapy for Alzheimer’s Disease

Alzheimer’s disease(AD)is a chronic neurodegenerative disease that mainly causes dementia.It is a serious threat to the health of the global elderly population.Considerable money and effort has been invested in the development of drug therapy for AD worldwide.Many drug therapies are currently under development or in clinical trials,based on two known mechanisms of AD,namely,Aβtoxicity and the abnormal Tau hyperphosphorylation.Numerous drugs are also being developed for other AD associated mechanisms such as neuroinflammation,neurotransmitter imbalance,oxidative damage and mitochondrial dysfunction,neuron loss and degeneration.Even so,the number of drugs that can successfully improve symptoms or delay the progression of the disease remains very limited.However,multi-drug combinations may provide a new avenue for drug therapy for AD.In addition,early diagnosis of AD and timely initiation of treatment may allow drugs that act on the early pathological processes of AD to help improve the symptoms and prevent the progression of the condition.

Correction:A positive feedback inhibition of isocitrate dehydrogenase 3β on paired-box gene 6 promotes Alzheimerlike pathology

After online publication of the article',the authors noticed that,owing to authors'oversight in layer placement within the illustration,Golgi staining images representing both the 5xFAD group and,the 5xFAD+IDH3β_group were unintentionally duplicated in Fig.7e;In Fig.8b,11-month-old mice were incorrectly written as 12-month-old.

A positive feedback inhibition of isocitrate dehydrogenase 3β on paired-box gene 6 promotes Alzheimer-like pathology

Impaired brain glucose metabolism is an early indicator of Alzheimer’s disease(AD);however,the fundamental mechanism is unknown.In this study,we found a substantial decline in isocitrate dehydrogenase 3β(IDH3β)levels,a critical tricarboxylic acid cycle enzyme,in AD patients and AD-transgenic mice’s brains.Further investigations demonstrated that the knockdown of IDH3βinduced oxidation-phosphorylation uncoupling,leading to reduced energy metabolism and lactate accumulation.The resulting increased lactate,a source of lactyl,was found to promote histone lactylation,thereby enhancing the expression of paired-box gene 6(PAX6).As an inhibitory transcription factor of IDH3β,the elevated PAX6 in turn inhibited the expression of IDH3β,leading to tau hyperphosphorylation,synapse impairment,and learning and memory deficits resembling those seen in AD.In AD-transgenic mice,upregulating IDH3βand downregulating PAX6 were found to improve cognitive functioning and reverse AD-like pathologies.Collectively,our data suggest that impaired oxidative phosphorylation accelerates AD progression via a positive feedback inhibition loop of IDH3β-lactate-PAX6-IDH3β.Breaking this loop by upregulating IDH3βor downregulating PAX6 attenuates AD neurodegeneration and cognitive impairments.

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.

A novel transgenic mouse line with hippocampus-dominant and inducible expression of truncated human tau

Background Intraneuronal accumulation of hyperphosphorylated tau is a defining hallmark of Alzheimer’s disease(AD).However,mouse models imitating AD-exclusive neuronal tau pathologies are lacking.Methods We generated a new tet-on transgenic mouse model expressing truncated human tau N1-368(termed hTau368),a tau fragment increased in the brains of AD patients and aged mouse brains.Doxycycline(dox)was administered in drinking water to induce hTau368 expression.Immunostaining and Western blotting were performed to measure the tau level.RNA sequencing was performed to evaluate gene expression,and several behavioral tests were conducted to evaluate mouse cognitive functions,emotion and locomotion.Results Dox treatment for 1-2 months at a young age induced overt and reversible human tau accumulation in the brains of hTau368 transgenic mice,predominantly in the hippocampus.Meanwhile,the transgenic mice exhibited AD-like high level of tau phosphorylation,glial activation,loss of mature neurons,impaired hippocampal neurogenesis,synaptic degeneration and cognitive deficits.Conclusions This study developed a well-characterized and easy-to-use tool for the investigations and drug development for AD and other tauopathies.

Tau hyperphosphorylation induces apoptotic escape and triggers neurodegeneration in Alzheimer's disease

Since abnormal post-translational modifications or gene mutations of tau have been detected in over twenty neurodegenerative disorders, tau has attracted widespread interest as a target protein. Among its various post-translational modifications, phosphorylation is the most extensively studied. It is recognized that tau hyperphosphorylation is the root cause of neurodegeneration in Alzheimer＇s disease （AD）; however, it is not clear how it causes neurodegeneration. Based on the findings that tau hyperphosphorylation leads to the escape of neurons from acute apoptosis and simultaneously impairs the function of neurons, we have proposed that the nature of AD neurodegeneration is the consequence of aborted apoptosis induced by tau phosphorylation. Therefore, proper manipulation of tau hyperphosphorylation could be promising for arresting AD neurodegeneration. In this review, the neuroprotective and neurodegenerative effects of tau hyperphosphorylation and our thoughts regarding their relationship are presented.

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.

Humanin attenuates Alzheimer-like cognitive deficits and pathological changes induced by amyloid β-peptide in rats

Amyloid β-peptide（Aβ） has been implicated as a key molecule in the neurodegenerative cascades of Alzheimer ’s disease（AD）. Humanin（HN） is a secretory peptide that inhibits the neurotoxicity of Aβ. However, the mechanism（s） by which HN exerts its neuroprotection against Aβ-induced ADlike pathological changes and memory deficits are yet to be completely defined. In the present study,we provided evidence that treatment of rats with HN increases the number of dendritic branches and the density of dendritic spines, and upregulates pre- and post-synaptic protein levels; these effects lead to enhanced long-term potentiation and amelioration of the memory deficits induced by Aβ1-42. HN also attenuated Aβ1-42-induced tau hyperphosphorylation,apparently by inhibiting the phosphorylation of Tyr307 on the inhibitory protein phosphatase-2A（PP2A）catalytic subunit and thereby activating PP2 A. HN also inhibited apoptosis and reduced the oxidativestress induced by Aβ1-42. These findings provide novel mechanisms of action for the ability of HN to protect against Aβ1-42-induced AD-like pathological changes and memory deficits.

Illuminating Neural Circuits in Alzheimer’s Disease

Alzheimer’s disease(AD)is the most common neurodegenerative disorder and there is currently no cure.Neural circuit dysfunction is the fundamental mechanism underlying the learning and memory deficits in patients with AD.Therefore,it is important to understand the structural features and mechanisms underlying the deregulated circuits during AD progression,by which new tools for intervention can be developed.Here,we briefly summarize the most recently established cutting-edge experimental approaches and key techniques that enable neural circuit tracing and manipulation of their activity.We also discuss the advantages and limitations of these approaches.Finally,we review the applications of these techniques in the discovery of circuit mechanisms underlyingβ-amyloid and tau pathologies during AD progression,and as well as the strategies for targeted AD treatments.

Tau-Induced Ca^(2+)/Calmodulin-Dependent Protein Kinase-IV Activation Aggravates Nuclear Tau Hyperphosphorylation

Hyperphosphorylated tau is the major protein component of neurofibrillary tangles in the brains of patients with Alzheimer’s disease(AD). However, the mechanism underlying tau hyperphosphorylation is not fully understood. Here, we demonstrated that exogenously expressed wild-type human tau40 was detectable in the phosphorylated form at multiple AD-associated sites in cytoplasmic and nuclear fractions from HEK293 cells.Among these sites, tau phosphorylated at Thr205 and Ser214 was almost exclusively found in the nuclear fraction at the conditions used in the present study. With the intracellular tau accumulation, the Ca2+concentration was significantly increased in both cytoplasmic and nuclear fractions. Further studies using site-specific mutagenesis and pharmacological treatment demonstrated that phosphorylation of tau at Thr205 increased nuclear Ca2+concentration with a simultaneous increase in the phosphorylation of Ca2+/calmodulin-dependent protein kinase IV(Ca MKIV) at Ser196. On the other hand, phosphorylation of tau at Ser214 did not significantly change the nuclear Ca2+/Ca MKIV signaling. Finally, expressing calmodulin-binding protein-4 that disrupts formation ofthe Ca2+/calmodulin complex abolished the okadaic acidinduced tau hyperphosphorylation in the nuclear fraction.We conclude that the intracellular accumulation of phosphorylated tau, as detected in the brains of AD patients, can trigger nuclear Ca2+/Ca MKIV signaling, which in turn aggravates tau hyperphosphorylation. Our findings provide new insights for tauopathies: hyperphosphorylation of intracellular tau and an increased Ca2+concentration may induce a self-perpetuating harmful loop to promote neurodegeneration.

Liraglutide Ameliorates Hyperhomocysteinemia-Induced Alzheimer-Like Pathology and Memory Deficits in Rats via Multi-molecular Targeting

Hyperhomocysteinemia(Hhcy)is an independent risk factor for Alzheimer's disease(AD),and insulinresistance is commonly seen in patients with Hhcy.Liraglutide(Lir),a glucagon-like peptide that increases the secretion and sensitivity of insulin,has a neurotrophic or neuroprotective effect.However,it is not known whether Lir ameliorates the AD-like pathology and memory deficit induced by Hhcy.By vena caudalis injection of homocysteine to produce the Hhcy model in rats,we found here that simultaneous administration of Lir for 2 weeks ameliorated the Hhcy-induced memory deficit,along with increased density of dendritic spines and up-regulation of synaptic proteins.Lir also attenuated the Hhcy-induced tau hyperphosphorylation and Aβ overproduction,and the molecular mechanisms involved the restoration of protein phosphatase-2 A activity and inhibition of β-and γ-secretases.Phosphorylated insulin receptor substrate-1 also decreased after treatment with Lir.Our data reveal that Lir improves the Hhcy-induced AD-like spatial memory deficit and the mechanisms involve the modulation of insulinresistance and the pathways generating abnormal tau and Aβ.

Freestanding strontium vanadate/carbon nanotube films for long-life aqueous zinc-ion batteries

Aqueous rechargeable zinc-ion battery(ZIB)is considered to be a potential energy storage system for large-scale applications due to its environmental friendliness,high safety,and low cost.However,it remains challenging to develop suitable cathode materials with high specific capacity and long-term cyclic stability.Herein,we have fabricated freestanding Sr0.19V2O51.3H2O/carbon nanotubes(SrVO/CNTs)composite films with different mass ratios by incorporating SrVO into CNTs network.The synthesized SrVO possesses a large interlayer spacing of 1.31 nm,which facilitates Zn(2+)diffusion.Furthermore,the SrVO/CNTs composite film with conductive network structure promotes electron transfer and ensures good contact between SrVO and CNTs during the long-term cycling process.As a result,the battery based on the SrVO/CNTs composite cathode with a mass ratio of 7:3 delivers a specific capacity of 326 mAh·g^(-1)at 0.1 A·g^(-1)and 145 mAh·g^(-1)at 5 A·g^(-1),demonstrating a high capacity and excellent rate capability.Remarkably,the assembled ZIB shows good capacity retention of 91%even after ultra-long cycling for 7500 cycles at a high current rate of 5 Ag^(-1).More importantly,the battery also delivers a high energy density and power density,as 290 Wh·kg^(-1)at 125 W·kg^(-1)(0.1 A·g^(-1)),or 115 Wh·kg^(-1)at 6078 W·kg^(-1)(5 Ag^(-1)).The results demonstrate that the SrVO/CNTs composite is a promising cathode toward large-scale energy storage applications.

The dual roles of cytokines in Alzheimer’s disease:update on interleukins, TNF-α,TGF-β and IFN-γ

Alzheimer’s disease(AD)is one of the most common neurodegenerative disorders in the elderly.Although the mechanisms underlying AD neurodegeneration are not fully understood,it is well recognized that inflammation plays a crucial role in the initiation and/or deterioration of AD neurodegeneration.Increasing evidence suggests that different cytokines,including interleukins,TNF-α,TGF-βand IFN-γ,are actively participated in AD pathogenesis and may serve as diagnostic or therapeutic targets for AD neurodegeneration.Here,we review the progress in understanding the important role that these cytokines or neuroinflammation has played in AD etiology and pathogenesis.

Folate/Vitamin B Alleviates Hyperhomocysteinemia-Induced Alzheimer-Like Pathologies in Rat Retina

Hyperhomocysteinemia(Hhcy) is an independent risk factor for Alzheimer's disease(AD). Visual dysfunction is commonly found and is positively correlated with the severity of cognitive defects in AD patients. Our previous study demonstrated that Hhcy induces memory deficits with AD-like tau and amyloid-b(Ab) pathologies in the hippocampus, and supplementation with folate and vitamin B12(FB) prevents the Hhcy-induced AD-like pathologies in the hippocampus. Here, we investigated whether Hhcy also induces AD-like pathologies in the retina and the effects of FB. An Hhcy rat model was produced by vena caudalis injection of homocysteine for14 days, and the effects of FB were assessed by simultaneous supplementation with FB in drinking water. We found that Hhcy induced vessel damage with Ab and taupathologies in the retina, while simultaneous supplementation with FB remarkably attenuated the Hhcy-induced tau hyperphosphorylation at multiple AD-related sites and Ab accumulation in the retina. The mechanisms involved downregulation of amyloid precursor protein(APP), presenilin-1, beta-site APP-cleaving enzyme 1, and protein phosphatase-2 A. Our data suggest that the retina may serve as a window for evaluating the effects of FB on hyperhomocysteinemia-induced Alzheimer-like pathologies.

A novel dephosphorylation targeting chimera selectively promoting tau removal in tauopathies

Intraneuronal accumulation of hyperphosphorylated tau is a hallmark pathology shown in over twenty neurodegenerative disorders,collectively termed as tauopathies,including the most common Alzheimer's disease(AD).Therefore,selectively removing or reducing hyperphosphorylated tau is promising for therapies of AD and other tauopathies.Here,we designed and synthesized a novel DEPhosphorylation TArgeting Chimera(DEPTAC)to specifically facilitate the binding of tau to Ba-subunit-contalning protein phosphatase 2A(PP2A-Ba),the most active tau phosphatase in the brain.The DEPTAC exhibited high efficiency in dephosphorylating tau at multiple AD-associated sites and preventing tau accumulation both in vitro and in vivo.Further studies revealed that DEPTAC significantly improved microtubule assembly,neurite plasticity,and hippocampus-dependent learning and memory in transgenic mice with inducible overexpression of truncated and neurotoxic human tau N368.Our data provide a strategy for selective removal of the hyperphosphorylated tau,which sheds new light for the targeted therapy of AD and related-tauopathies.

Defective mitophagy and the etiopathogenesis of Alzheimer’s disease

Accumulation of impaired mitochondria and energy metabolism disorders are non-negligible features of both aging and age-related neurodegeneration,including Alzheimer’s disease(AD).A growing number of studies suggest that mitophagy disorders play an important role in AD occurrence and development.The interaction between mitophagy deficits and Aβor Tau pathology may form a vicious cycle and cause neuronal damage and death.Elucidating the molecular mechanism of mitophagy and its role in AD may provide insights into the etiology and mechanisms of AD.Defective mitophagy is a potential target for AD prevention and treatment.

Zinc binds to and directly inhibits protein phosphatase 2A in vitro

Zinc induces protein phosphatase 2A （PP2A） inactivation and tau hyperphosphorylation through PP2A （tyrosine 307） phosphorylation in cells and the brain, but whether Zn2＋ has a direct inhibitory effect on PP2A is not clear. Here we explored the effect of Zn2＋ on PP2A and their direct interaction in vitro. The results showed that Zn2＋ mimicked the inhibitory effect of okadaic acid on protein phosphatase and prevented tau dephosphorylation in N2a cell lysates. PP2A activity assays indicated that a low concentration （10 pmol/L） of Zn2＋ inhibited PP2A directly. Further Zn2＋-IDA-agarose affinity binding assays showed that Zn2＋ bound to and inhibited PP2Ac（51l-270） but not PP2Ac（1.50） or PP2Ac（27.309）. Taken together, Zn2＋ inhibits PP2A directly through binding to PP2Ac（51-270） in vitro.

Enriched gestation activates the IGF pathway to evoke embryo-adult benefits to prevent Alzheimer’s disease

Background:Building brain reserves before dementia onset could represent a promising strategy to prevent Alzheimer’s disease(AD),while how to initiate early cognitive stimulation is unclear.Given that the immature brain is more sensitive to environmental stimuli and that brain dynamics decrease with ageing,we reasoned that it would be effective to initiate cognitive stimulation against AD as early as the fetal period.Methods:After conception,maternal AD transgenic mice(3×Tg AD)were exposed to gestational environment enrichment(GEE)until the day of delivery.The cognitive capacity of the offspring was assessed by the Morris water maze and contextual fear-conditioning tests when the offspring were raised in a standard environment to 7 months of age.Western blotting,immunohistochemistry,real-time PCR,immunoprecipitation,chromatin immunoprecipitation(ChIP)assay,electrophysiology,Golgi staining,activity assays and sandwich ELISA were employed to gain insight into the mechanisms underlying the beneficial effects of GEE on embryos and 7–10-month-old adult offspring.Results:We found that GEE markedly preserved synaptic plasticity and memory capacity with amelioration of hallmark pathologies in 7–10-m-old AD offspring.The beneficial effects of GEE were accompanied by global histone hyperacetylation,including those at bdnf promoter-binding regions,with robust BDNF mRNA and protein expression in both embryo and progeny hippocampus.GEE increased insulin-like growth factor 1(IGF1)and activated its receptor(IGF1R),which phosphorylates Ca^(2+)/calmodulin-dependent kinase IV(CaMKIV)at tyrosine sites and triggers its nuclear translocation,subsequently upregulating histone acetyltransferase(HAT)and BDNF transcription.The upregulation of IGF1 mimicked the effects of GEE,while IGF1R or HAT inhibition during pregnancy abolished the GEE-induced CaMKIV-dependent histone hyperacetylation and BDNF upregulation.Conclusions:These findings suggest that activation of IGF1R/CaMKIV/HAT/BDNF signaling by gestational environment enrichment may serve as a promising strategy to delay AD progression.