Publications by authors named "Keqiang Ye"

188 Publications

ApoE4 inhibition of VMAT2 in the locus coeruleus exacerbates Tau pathology in Alzheimer's disease.

Acta Neuropathol 2021 Apr 25. Epub 2021 Apr 25.

Department of Pathology and Laboratory Medicine, Emory University School of Medicine, 615 Michael St. Whitehead BLDG Room #141, Atlanta, GA, 30322, USA.

ApoE4 enhances Tau neurotoxicity and promotes the early onset of AD. Pretangle Tau in the noradrenergic locus coeruleus (LC) is the earliest detectable AD-like pathology in the human brain. However, a direct relationship between ApoE4 and Tau in the LC has not been identified. Here we show that ApoE4 selectively binds to the vesicular monoamine transporter 2 (VMAT2) and inhibits neurotransmitter uptake. The exclusion of norepinephrine (NE) from synaptic vesicles leads to its oxidation into the toxic metabolite 3,4-dihydroxyphenyl glycolaldehyde (DOPEGAL), which subsequently activates cleavage of Tau at N368 by asparagine endopeptidase (AEP) and triggers LC neurodegeneration. Our data reveal that ApoE4 boosts Tau neurotoxicity via VMAT2 inhibition, reduces hippocampal volume, and induces cognitive dysfunction in an AEP- and Tau N368-dependent manner, while conversely ApoE3 binds Tau and protects it from cleavage. Thus, ApoE4 exacerbates Tau neurotoxicity by increasing VMAT2 vesicle leakage and facilitating AEP-mediated Tau proteolytic cleavage in the LC via DOPEGAL.
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http://dx.doi.org/10.1007/s00401-021-02315-1DOI Listing
April 2021

A delta-secretase-truncated APP fragment activates CEBPB, mediating Alzheimer's disease pathologies.

Brain 2021 Apr 20. Epub 2021 Apr 20.

Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.

Amyloid-β precursor protein (APP) is sequentially cleaved by secretases and generates amyloid-β, the major components in senile plaques in Alzheimer's disease. APP is upregulated in human Alzheimer's disease brains. However, the molecular mechanism of how APP contributes to Alzheimer's disease pathogenesis remains incompletely understood. Here we show that truncated APP C586-695 fragment generated by δ-secretase directly binds to CCAAT/enhancer-binding protein beta (CEBPB), an inflammatory transcription factor, and enhances its transcriptional activity, escalating Alzheimer's disease-related gene expression and pathogenesis. The APP C586-695 fragment, but not full-length APP, strongly associates with CEBPB and elicits its nuclear translocation and augments the transcriptional activities on APP itself, MAPT (microtubule-associated protein tau), δ-secretase and inflammatory cytokine mRNA expression, finally triggering Alzheimer's disease pathology and cognitive disorder in a viral overexpression mouse model. Blockade of δ-secretase cleavage of APP by mutating the cleavage sites reduces its stimulatory effect on CEBPB, alleviating amyloid pathology and cognitive dysfunctions. Clearance of APP C586-695 from 5xFAD mice by antibody administration mitigates Alzheimer's disease pathologies and restores cognitive functions. Thus, in addition to the sequestration of amyloid-β, APP implicates in Alzheimer's disease pathology by activating CEBPB upon δ-secretase cleavage.
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http://dx.doi.org/10.1093/brain/awab062DOI Listing
April 2021

Netrin-1 receptor UNC5C cleavage by active δ-secretase enhances neurodegeneration, promoting Alzheimer's disease pathologies.

Sci Adv 2021 Apr 16;7(16). Epub 2021 Apr 16.

Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.

Netrin-1, a family member of laminin-related secreted proteins, mediates axon guidance and cell migration during neural development. T835M mutation in netrin receptor UNC5C predisposes to the late-onset Alzheimer's disease (AD) and increases neuronal cell death. However, it remains unclear how this receptor is molecularly regulated in AD. Here, we show that δ-secretase selectively cleaves UNC5C and escalates its proapoptotic activity, facilitating neurodegeneration in AD. Netrin deficiency activates δ-secretase that specifically cuts UNC5C at N467 and N547 residues and enhances subsequent caspase-3 activation, additively augmenting neuronal cell death. Blockade of δ-secretase cleavage of UNC5C diminishes T835M mutant's proapoptotic activity. Viral expression of δ-secretase-truncated UNC5C fragments into APP/PS1 mice strongly accelerates AD pathologies, impairing learning and memory. Conversely, deletion of UNC5C from netrin-1-depleted mice attenuates AD pathologies and rescues cognitive disorders. Hence, δ-secretase truncates UNC5C and elevates its neurotoxicity, contributing to AD pathogenesis.
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http://dx.doi.org/10.1126/sciadv.abe4499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8051868PMC
April 2021

ApoE4 activates C/EBPβ/δ-secretase with 27-hydroxycholesterol, driving the pathogenesis of Alzheimer's disease.

Prog Neurobiol 2021 Mar 11:102032. Epub 2021 Mar 11.

Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, 30322, USA. Electronic address:

ApoE4, an apolipoprotein implicated in cholesterol transport and amyloid-β (Aβ) metabolism, is a major genetic risk determinant for Alzheimer's Disease (AD) and drives its pathogenesis via Aβ-dependent and -independent pathways. C/EBPβ, a proinflammatory cytokines-activated transcription factor, is upregulated in AD and mediates cytokines and δ-secretase expression. However, how ApoE4 contributes to AD pathogenesis remains incompletely understood. Here we show that ApoE4 and 27-hydroxycholesterol (27-OHC) co-activate C/EBPβ/δ-secretase signaling in neurons, mediating AD pathogenesis, and this effect is dependent on neuronal secreted Aβ and inflammatory cytokines. Inhibition of cholesterol metabolism with lovastatin diminishes neuronal ApoE4's stimulatory effects. Furthermore, ApoE4 and 27-OHC also mediate lysosomal δ-secretase leakage, activation, secretion and endocytosis. Notably, 27-OHC strongly activates C/EBPβ/δ-secretase pathway in human ApoE4-TR mice and triggers AD pathologies and cognitive deficits, which is blocked by C/EBPβ depletion. Hence, our findings demonstrate that ApoE4 and 27-OHC additively trigger AD pathogenesis via activating C/EBPβ/δ-secretase pathway. Lowering cholesterol levels with statins should benefit the ApoE4 AD carriers.
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http://dx.doi.org/10.1016/j.pneurobio.2021.102032DOI Listing
March 2021

Asparagine endopeptidase cleaves synaptojanin 1 and triggers synaptic dysfunction in Parkinson's disease.

Neurobiol Dis 2021 Jul 4;154:105326. Epub 2021 Mar 4.

Department of Neurology, Renmin Hospital of Wuhan University, Wuhan 430060, China. Electronic address:

Parkinson's disease (PD) is one of the most common neurodegenerative diseases, which is characterized by the loss of dopaminergic neurons in the nigrostriatal pathway. Synaptic dysfunction impairs dopamine turnover and contributes to the degeneration of dopaminergic neurons. However, the molecular mechanisms underlying synaptic dysfunction and dopaminergic neuronal vulnerability in PD are not clear. Here, we report that synaptojanin 1 (SYNJ1), a polyphosphoinositide phosphatase concentrated at nerve terminals, is a substrate of a cysteine proteinase, asparagine endopeptidase (AEP). SYNJ1 is cleaved by the cysteine proteinase AEP at N599 in the brains of PD patients. AEP-mediated cleavage of SYNJ1 disrupts neuronal phosphoinositide homeostasis and causes synaptic dysfunction. Overexpression of the AEP-generated fragments of SYNJ1 triggers synaptic dysfunction and the degeneration of dopaminergic neurons, inducing motor defects in the α-synuclein transgenic mice. Blockage of AEP-mediated cleavage of SYJN1 alleviates the pathological and behavioral defects in a mouse model of PD. Our results demonstrate that the fragmentation of SYNJ1 by AEP mediates synaptic dysfunction and dopaminergic neuronal degeneration in PD.
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http://dx.doi.org/10.1016/j.nbd.2021.105326DOI Listing
July 2021

Crosstalk between the muscular estrogen receptor α and BDNF/TrkB signaling alleviates metabolic syndrome via 7,8-dihydroxyflavone in female mice.

Mol Metab 2021 03 19;45:101149. Epub 2020 Dec 19.

Department of Food Science and Nutrition, School of Biosystems Engineering and Food Science, Zhejiang Key Laboratory for Agro-Food Processing, Zhejiang Engineering Center for Food Technology and Equipment, Zhejiang University, Hangzhou 310058, China. Electronic address:

Objective: 7,8-Dihydroxyflavone (7,8-DHF), a small molecular mimetic of brain-derived neurotrophic factor (BDNF), alleviates high-fat diet-induced obesity in female mice in a sex-specific manner by activating muscular tropomyosin-related kinase B (TrkB). However, the underlying molecular mechanism for this sex difference is unknown. Moreover, muscular estrogen receptor α (ERα) plays a critical role in metabolic diseases. Impaired ERα action is often accompanied by metabolic syndrome (MetS) in postmenopausal women. This study investigated whether muscular ERα is involved in the metabolic effects of 7,8-DHF.

Methods: For the in vivo studies, 72 female C57BL/6J mice were given a low-fat diet or high-fat diet, and both received daily intragastric administration of vehicle or 7,8-DHF for 24 weeks. The hypothalamic-pituitary-ovarian (HPO) axis function was assessed by investigating typical sex-related serum hormones and the ovarian reserve. Indicators of menopausal MetS, including lipid metabolism, insulin sensitivity, bone density, and serum inflammatory cytokines, were also evaluated. The expression levels of ERα and other relevant signaling molecules were also examined. In vitro, the molecular mechanism involved in the interplay of ERα and TrkB receptors was verified in differentiated C2C12 myotubes using several inhibitors and a lentivirus short hairpin RNA-knockdown strategy.

Results: Long-term oral administration of 7,8-DHF acted as a protective factor for the female HPO axis function, protecting against ovarian failure, earlier menopause, and sex hormone disorders, which was paralleled by the alleviation of MetS coupled with the production of ERα-rich, TrkB-activated, and uncoupling protein 1 (UCP1) high thermogenic skeletal muscle tissues. 7,8-DHF-stimulated transactivation of ERα at serine 118 (S118) and tyrosine 537 (Y537), which was crucial to activate the BDNF/TrkB signaling cascades. In turn, activation of BDNF/TrkB signaling was also required for the ligand-independent activation of ERα, especially at the Y537 phosphorylation site. In addition, Src family kinases played a core role in the interplay of ERα and TrkB, synergistically activating the signaling pathways related to energy metabolism.

Conclusions: These findings revealed a novel role of 7,8-DHF in protecting the function of the female HPO axis and activating tissue-specific ERα, which improves our understanding of this sex difference in 7,8-DHF-mediated maintenance of metabolic homeostasis and provides new therapeutic strategies for managing MetS in women.
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http://dx.doi.org/10.1016/j.molmet.2020.101149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811170PMC
March 2021

Netrin-1 and its receptor DCC modulate survival and death of dopamine neurons and Parkinson's disease features.

EMBO J 2021 Feb 22;40(3):e105537. Epub 2020 Dec 22.

Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.

The netrin-1/DCC ligand/receptor pair has key roles in central nervous system (CNS) development, mediating axonal, and neuronal navigation. Although expression of netrin-1 and DCC is maintained in the adult brain, little is known about their role in mature neurons. Notably, netrin-1 is highly expressed in the adult substantia nigra, leading us to investigate a role of the netrin-1/DCC pair in adult nigral neuron fate. Here, we show that silencing netrin-1 in the adult substantia nigra of mice induces DCC cleavage and a significant loss of dopamine neurons, resulting in motor deficits. Because loss of adult dopamine neurons and motor impairments are features of Parkinson's disease (PD), we studied the potential impact of netrin-1 in different animal models of PD. We demonstrate that both overexpression of netrin-1 and brain administration of recombinant netrin-1 are neuroprotective and neurorestorative in mouse and rat models of PD. Of interest, we observed that netrin-1 levels are significantly reduced in PD patient brain samples. These results highlight the key role of netrin-1 in adult dopamine neuron fate, and the therapeutic potential of targeting netrin-1 signaling in PD.
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http://dx.doi.org/10.15252/embj.2020105537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849168PMC
February 2021

C/EBPβ is a key transcription factor for APOE and preferentially mediates ApoE4 expression in Alzheimer's disease.

Mol Psychiatry 2020 Dec 18. Epub 2020 Dec 18.

Department of Pathophysiology, Key Laboratory of Ministry of Education of Neurological Diseases, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

The apolipoprotein E ε4 (APOE4) allele is a major genetic risk factor for Alzheimer's disease (AD), and its protein product, ApoE4, exerts its deleterious effects mainly by influencing amyloid-β (Aβ) and Tau (neurofibrillary tangles, NFTs) deposition in the brain. However, the molecular mechanism dictating its expression during ageing and in AD remains incompletely clear. Here we show that C/EBPβ acts as a pivotal transcription factor for APOE and mediates its mRNA levels in an age-dependent manner. C/EBPβ binds the promoter of APOE and escalates its expression in the brain. Knockout of C/EBPβ in AD mouse models diminishes ApoE expression and Aβ pathologies, whereas overexpression of C/EBPβ accelerates AD pathologies, which can be attenuated by anti-ApoE monoclonal antibody or deletion of ApoE via its specific shRNA. Remarkably, C/EBPβ selectively promotes more ApoE4 expression versus ApoE3 in human neurons, correlating with higher activation of C/EBPβ in human AD brains with ApoE4/4 compared to ApoE3/3. Therefore, our data support that C/EBPβ is a crucial transcription factor for temporally regulating APOE gene expression, modulating ApoE4's role in AD pathogenesis.
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http://dx.doi.org/10.1038/s41380-020-00956-4DOI Listing
December 2020

Asparagine Endopeptidase (δ Secretase), an Enzyme Implicated in Alzheimer's Disease Pathology, Is an Inhibitor of Axon Regeneration in Peripheral Nerves.

eNeuro 2021 Jan-Feb;8(1). Epub 2021 Jan 15.

Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322.

Asparagine endopeptidase (AEP) is a lysosomal protease implicated in the pathology of Alzheimer's disease (AD). It is known to cleave the axonal microtubule associated protein, Tau, and amyloid precursor protein (APP), both of which might impede axon regeneration following peripheral nerve injury (PNI). Active AEP, AEP-cleaved fragments of Tau (Tau N368), and APP (APP N585) were found in injured peripheral nerves. In AEP null mice, elongation of regenerating axons after sciatic nerve transection and repair was increased relative to wild-type (WT) controls. Compound muscle action potentials (M responses) were restored in reinnervated muscles twice as fast after injury in AEP knock-out (KO) mice as WT controls. Neurite elongation in cultures of adult dorsal root ganglion (DRG) neurons derived from AEP KO mice was increased significantly relative to cultures from WT controls. In AEP KO mice exposed to 1 h of 20-Hz electrical stimulation (ES) at the time of nerve injury, no further enhancement of axon regeneration was observed. These findings support inhibition of AEP as a therapeutic target to enhance axon regeneration after PNI.
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http://dx.doi.org/10.1523/ENEURO.0155-20.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814480PMC
January 2021

Delta-secretase triggers Alzheimer's disease pathologies in wild-type hAPP/hMAPT double transgenic mice.

Cell Death Dis 2020 12 12;11(12):1058. Epub 2020 Dec 12.

Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA.

Alzheimer's disease (AD) is the most common neurodegenerative disease with multifactorial pathologies including Aβ containing senile plaques and neurofibrillary tangles (NFT) consisted of aggregated Tau. Most of the AD patients are sporadic and the familial mutation hereditary patients are composed only 1% of all cases. However, the current AD mouse models employ mutated APP, PS1, or even Tau mutant, in order to display a portion of AD pathologies. Delta-secretase (legumain, or asparaginyl endopeptidase, AEP) simultaneously cleaves both APP and Tau and augments Aβ production and Tau hyperphosphorylation and aggregation, contributing to AD pathogenesis. Here we show that δ-secretase is sufficient to promote prominent AD pathologies in wild-type hAPP/hMAPT double transgenic mice. We crossed hAPP l5 mice and hMAPT mice to generate double transgenic mouse model carrying both human wild-type APP and Tau. Compared to the single transgenic parents, these double transgenic mice demonstrated AD-related pathologies in one-year-old hAPP/hMAPT mice. Notably, overexpression of δ-secretase in hAPP/hMAPT double-transgenic mice evidently accelerated enormous senile plaques and NFT, associated with prominent synaptic defects and cognitive deficits. Hence, δ-secretase facilitates AD pathogenesis independent of any patient-derived mutation.
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http://dx.doi.org/10.1038/s41419-020-03270-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733592PMC
December 2020

Discovery of a dual inhibitor of NQO1 and GSTP1 for treating glioblastoma.

J Hematol Oncol 2020 10 21;13(1):141. Epub 2020 Oct 21.

Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.

Background: Glioblastoma (GBM) is a universally lethal tumor with frequently overexpressed or mutated epidermal growth factor receptor (EGFR). NADPH quinone oxidoreductase 1 (NQO1) and glutathione-S-transferase Pi 1 (GSTP1) are commonly upregulated in GBM. NQO1 and GSTP1 decrease the formation of reactive oxygen species (ROS), which mediates the oxidative stress and promotes GBM cell proliferation.

Methods: High-throughput screen was used for agents selectively active against GBM cells with EGFRvIII mutations. Co-crystal structures were revealed molecular details of target recognition. Pharmacological and gene knockdown/overexpression approaches were used to investigate the oxidative stress in vitro and in vivo.

Results: We identified a small molecular inhibitor, "MNPC," that binds to both NQO1 and GSTP1 with high affinity and selectivity. MNPC inhibits NQO1 and GSTP1 enzymes and induces apoptosis in GBM, specifically inhibiting the growth of cell lines and primary GBM bearing the EGFRvIII mutation. Co-crystal structures between MNPC and NQO1, and molecular docking of MNPC with GSTP1 reveal that it binds the active sites and acts as a potent dual inhibitor. Inactivation of both NQO1 and GSTP1 with siRNA or MNPC results in imbalanced redox homeostasis, leading to apoptosis and mitigated cancer proliferation in vitro and in vivo.

Conclusions: Thus, MNPC, a dual inhibitor for both NQO1 and GSTP1, provides a novel lead compound for treating GBM via the exploitation of specific vulnerabilities created by mutant EGFR.
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http://dx.doi.org/10.1186/s13045-020-00979-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7579906PMC
October 2020

Netrin1 deficiency activates MST1 via UNC5B receptor, promoting dopaminergic apoptosis in Parkinson's disease.

Proc Natl Acad Sci U S A 2020 09 14;117(39):24503-24513. Epub 2020 Sep 14.

Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322

The Hippo (MST1/2) pathway plays a critical role in restricting tissue growth in adults and modulating cell proliferation, differentiation, and migration in developing organs. Netrin1, a secreted laminin-related protein, is essential for nervous system development. However, the mechanisms underlying MST1 regulation by the extrinsic signals remain unclear. Here, we demonstrate that Netrin1 reduction in Parkinson's disease (PD) activates MST1, which selectively binds and phosphorylates netrin receptor UNC5B on T428 residue, promoting its apoptotic activation and dopaminergic neuronal loss. Netrin1 deprivation stimulates MST1 activation and interaction with UNC5B, diminishing YAP levels and escalating cell deaths. Knockout of UNC5B abolishes netrin depletion-induced dopaminergic loss, whereas blockade of MST1 phosphorylating UNC5B suppresses neuronal apoptosis. Remarkably, Netrin1 is reduced in PD patient brains, associated with MST1 activation and UNC5B T428 phosphorylation, which is accompanied by YAP reduction and apoptotic activation. Hence, Netrin1 regulates Hippo (MST1) pathway in dopaminergic neuronal loss in PD via UNC5B receptor.
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http://dx.doi.org/10.1073/pnas.2004087117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7533679PMC
September 2020

BDNF and Netrin-1 repression by C/EBPβ in the gut triggers Parkinson's disease pathologies, associated with constipation and motor dysfunctions.

Prog Neurobiol 2021 Mar 7;198:101905. Epub 2020 Sep 7.

Department of Pathology and Laboratory Medicine, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322, USA. Electronic address:

Chronic constipation is one of the most prominent prodromal symptoms in Parkinson's disease (PD), and Lewy bodies, enriched with aggregated α-Synuclein (α-Syn), propagation from the gut into the brain has been proposed to play a key role in PD etiopathogenesis. BDNF (Brain-derived neurotrophic factor) and Netrin-1 promote both neuronal survival and regulate the gut functions. We hypothesize that C/EBPβ represses BDNF and Netrin-1 in peripheral nervous system and central nervous system, contributing to GI tract and brain malfunctions in PD. To test the hypothesis, we performed the studies in both human PD gut tissues and BDNF or Netrin-1 gut conditional KO mice models. Lewy bodies with α-Syn aggregation and neuro-inflammation were measured in the colon and brain samples from PD patients and healthy controls and rotenone or vehicle-treated WT and CEBPβ (+/-) mice. We show that both BDNF and Netrin-1 are strongly decreased in the brain and the gut of PD patients, and conditional KO of these trophic factors in the gut elicits dopaminergic neuronal loss, constipation and motor dysfunctions. Interestingly, the inflammation and oxidative stress-induced transcription factor C/EBPβ acts as a robust repressor for both BDNF and Netrin-1 and suppresses the expression of trophic factors, and its levels inversely correlate with BDNF and Netrin-1 in PD patients. Our findings support that gut inflammation induces C/EBPβ activation that leads to both BDNF and Netrin-1 reduction and triggers PD non-motor and motor symptoms. Possibly, C/EBPβ-mediated biological events might be early diagnostic biomarkers for PD.
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http://dx.doi.org/10.1016/j.pneurobio.2020.101905DOI Listing
March 2021

Delta-secretase cleavage of Tau mediates its pathology and propagation in Alzheimer's disease.

Exp Mol Med 2020 08 28;52(8):1275-1287. Epub 2020 Aug 28.

Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA.

Alzheimer's disease (AD) is a progressive neurodegenerative disease with age as a major risk factor. AD is the most common dementia with abnormal structures, including extracellular senile plaques and intraneuronal neurofibrillary tangles, as key neuropathologic hallmarks. The early feature of AD pathology is degeneration of the locus coeruleus (LC), which is the main source of norepinephrine (NE) supplying various cortical and subcortical areas that are affected in AD. The spread of Tau deposits is first initiated in the LC and is transported in a stepwise manner from the entorhinal cortex to the hippocampus and then to associative regions of the neocortex as the disease progresses. Most recently, we reported that the NE metabolite DOPEGAL activates delta-secretase (AEP, asparagine endopeptidase) and triggers pathological Tau aggregation in the LC, providing molecular insight into why LC neurons are selectively vulnerable to developing early Tau pathology and degenerating later in the disease and how δ-secretase mediates the spread of Tau pathology to the rest of the brain. This review summarizes our current understanding of the crucial role of δ-secretase in driving and spreading AD pathologies by cleaving multiple critical players, including APP and Tau, supporting that blockade of δ-secretase may provide an innovative disease-modifying therapeutic strategy for treating AD.
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http://dx.doi.org/10.1038/s12276-020-00494-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080617PMC
August 2020

Gut dysbiosis contributes to amyloid pathology, associated with C/EBPβ/AEP signaling activation in Alzheimer's disease mouse model.

Sci Adv 2020 Jul 29;6(31):eaba0466. Epub 2020 Jul 29.

Department of Pathology and Laboratory Medicine, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322, USA.

The gut-brain axis is bidirectional, and gut microbiota influence brain disorders including Alzheimer's disease (AD). CCAAT/enhancer binding protein β/asparagine endopeptidase (C/EBPβ/AEP) signaling spatiotemporally mediates AD pathologies in the brain via cleaving both β-amyloid precursor protein and Tau. We show that gut dysbiosis occurs in 5xFAD mice, and is associated with escalation of the C/EBPβ/AEP pathway in the gut with age. Unlike that of aged wild-type mice, the microbiota of aged 3xTg mice accelerate AD pathology in young 3xTg mice, accompanied by active C/EBPβ/AEP signaling in the brain. Antibiotic treatment diminishes this signaling and attenuates amyloidogenic processes in 5xFAD, improving cognitive functions. The prebiotic R13 inhibits this pathway and suppresses amyloid aggregates in the gut. R13-induced antagonizes the C/EBPβ/AEP axis, mitigating gut leakage and oxidative stress. Our findings support the hypothesis that C/EBPβ/AEP signaling is activated by gut dysbiosis, implicated in AD pathologies in the gut.
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http://dx.doi.org/10.1126/sciadv.aba0466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7439296PMC
July 2020

TrkB receptor cleavage by delta-secretase abolishes its phosphorylation of APP, aggravating Alzheimer's disease pathologies.

Mol Psychiatry 2020 Aug 11. Epub 2020 Aug 11.

Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA.

Neurotrophins promote neuronal survival and synaptic plasticity via activating the tropomyosin receptor kinases. BDNF and its high-affinity receptor TrkB are reduced in Alzheimer's disease (AD), contributing to progressive cognitive decline. However, how the signaling mediates AD pathologies remains incompletely understood. Here we show that the TrkB receptor binds and phosphorylates APP, reducing amyloid-β production, which are abrogated by δ-secretase cleavage of TrkB in AD. Remarkably, BDNF stimulates TrkB to phosphorylate APP Y687 residue that accumulates APP in the TGN (Trans-Golgi Network) and diminishes its amyloidogenic cleavage. Delta-secretase cleaves TrkB at N365 and N486/489 residues and abolishes its neurotrophic activity, decreasing p-APP Y687 and altering its subcellular trafficking. Notably, both TrkB and APP are robustly cleaved by δ-secretase in AD brains, accompanied by mitigated TrkB signaling and reduced p-Y687. Blockade of TrkB cleavage attenuates AD pathologies in 5xFAD mice, rescuing the learning and memory. Viral expression of TrkB 1-486 fragment in the hippocampus of APP/PS1 mice facilitates amyloid pathology and mitigates cognitive functions. Hence, δ-secretase cleaves TrkB and blunts its phosphorylation of APP, facilitating AD pathogenesis.
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http://dx.doi.org/10.1038/s41380-020-00863-8DOI Listing
August 2020

C/EBPβ mediates NQO1 and GSTP1 anti-oxidative reductases expression in glioblastoma, promoting brain tumor proliferation.

Redox Biol 2020 07 21;34:101578. Epub 2020 May 21.

Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA. Electronic address:

Glioblastoma (GBM) is the most common and most aggressive brain tumor, associated with high levels of reactive oxidative species (ROS) due to metabolic and signaling aberrations. High ROS levels are detrimental to cells, but it remains incompletely understood how cancer cells cope with the adverse effects. Here we show that C/EBPβ, a ROS responsive transcription factor, regulates the transcription of NQO1 and GSTP1, two antioxidative reductases, which neutralize ROS in the GBM and mediates their proliferation. C/EBPβ is upregulated in EGFR overexpressed GBM cells, inversely correlated with the survival rates of brain tumor patients. Interestingly, C/EBPβ binds the promoters of NQO1 and GSTP1 and escalates their expression. Overexpression of C/EBPβ selectively decreases the ROS in EGFR-overexpressed U87MG cells and promotes cell proliferation via upregulating NQO1 and GSTP1; whereas knocking down C/EBPβ elevates the ROS and reduces proliferation by repressing the reductases. Accordingly, C/EBPβ mediates the brain tumor growth in vivo, coupling with NQO1 and GSTP1 expression and ROS levels. Hence, C/EBPβ regulates the expression of antioxidative reductases and balances the ROS, promoting brain tumor proliferation.
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http://dx.doi.org/10.1016/j.redox.2020.101578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287278PMC
July 2020

C/EBPβ/δ-secretase signaling mediates Parkinson's disease pathogenesis via regulating transcription and proteolytic cleavage of α-synuclein and MAOB.

Mol Psychiatry 2021 02 21;26(2):568-585. Epub 2020 Feb 21.

Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA.

Parkinson's disease (PD) is characterized by dopaminergic neuronal loss and the presence of intra-neuronal Lewy body (LB) inclusions with aggregated α-synuclein (α-Syn) as the major component. MAOB, a crucial monoamine oxidase for dopamine metabolism, triggers oxidative stress in dopaminergic neurons and α-Syn aggregation. However, the key molecular mechanism that mediates PD pathogenesis remains elusive. Here we show that C/EBPβ acts as an age-dependent transcription factor for both α-Syn and MAOB, and initiates the PD pathologies by upregulating these two pivotal players, in addition to escalating δ-secretase activity to cleave α-Syn and promotes its neurotoxicity. Overexpression of C/EBPβ in human wild-type α-Syn transgenic mice facilitates PD pathologies and elicits motor disorders associated with augmentation of δ-secretase, α-Syn, and MAOB. In contrast, depletion of C/EBPβ from human α-Syn Tg mice abolishes rotenone-elicited PD pathologies and motor impairments via downregulating the expression of these key factors. Hence, our study supports that C/EBPβ/δ-secretase signaling mediates PD pathogenesis via regulating the expression and cleavage of α-Syn and MAOB.
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http://dx.doi.org/10.1038/s41380-020-0687-7DOI Listing
February 2021

δ-secretase in neurodegenerative diseases: mechanisms, regulators and therapeutic opportunities.

Transl Neurodegener 2020 6;9. Epub 2020 Jan 6.

2Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322 USA.

Mammalian asparagine endopeptidase (AEP) is a cysteine protease that cleaves its protein substrates on the C-terminal side of asparagine residues. Converging lines of evidence indicate that AEP may be involved in the pathogenesis of several neurological diseases, including Alzheimer's disease, Parkinson's disease, and frontotemporal dementia. AEP is activated in the aging brain, cleaves amyloid precursor protein (APP) and promotes the production of amyloid-β (Aβ). We renamed AEP to δ-secretase to emphasize its role in APP fragmentation and Aβ production. AEP also cleaves other substrates, such as tau, α-synuclein, SET, and TAR DNA-binding protein 43, generating neurotoxic fragments and disturbing their physiological functions. The activity of δ-secretase is tightly regulated at both the transcriptional and posttranslational levels. Here, we review the recent advances in the role of δ-secretase in neurodegenerative diseases, with a focus on its biochemical properties and the transcriptional and posttranslational regulation of its activity, and discuss the clinical implications of δ-secretase as a diagnostic biomarker and therapeutic target for neurodegenerative diseases.
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http://dx.doi.org/10.1186/s40035-019-0179-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943888PMC
January 2020

Cerebrospinal fluid tau fragment correlates with tau PET: a candidate biomarker for tangle pathology.

Brain 2020 02;143(2):650-660

Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.

To date, there is no validated fluid biomarker for tau pathology in Alzheimer's disease, with contradictory results from studies evaluating the correlation between phosphorylated tau in CSF with tau PET imaging. Tau protein is subjected to proteolytic processing into fragments before being secreted to the CSF. A recent study suggested that tau cleavage after amino acid 368 by asparagine endopeptidase (AEP) is upregulated in Alzheimer's disease. We used immunoprecipitation followed by mass spectrometric analyses to evaluate the presence of tau368 species in CSF. A novel Simoa® assay for quantification of tau368 in CSF was developed, while total tau (t-tau) was measured by ELISA and the presence of tau368 in tangles was evaluated using immunohistochemistry. The diagnostic utility of tau368 was first evaluated in a pilot study (Alzheimer's disease = 20, control = 20), then in a second cohort where the IWG-2 biomarker criteria were applied (Alzheimer's disease = 37, control = 45), and finally in a third cohort where the correlation with 18F-GTP1 tau PET was evaluated (Alzheimer's disease = 38, control = 11). The tau368/t-tau ratio was significantly decreased in Alzheimer's disease (P < 0.001) in all cohorts. Immunohistochemical staining demonstrated that tau fragments ending at 368 are present in tangles. There was a strong negative correlation between the CSF tau368/t-tau ratio and 18F-GTP1 retention. Our data suggest that tau368 is a tangle-enriched fragment and that the CSF ratio tau368/t-tau reflects tangle pathology. This novel tau biomarker could be used to improve diagnosis of Alzheimer's disease and to facilitate the development of drug candidates targeting tau pathology. Furthermore, future longitudinal studies will increase our understanding of tau pathophysiology in Alzheimer's disease and other tauopathies.
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http://dx.doi.org/10.1093/brain/awz346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7009597PMC
February 2020

Norepinephrine metabolite DOPEGAL activates AEP and pathological Tau aggregation in locus coeruleus.

J Clin Invest 2020 01;130(1):422-437

Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.

Aberrant Tau inclusions in the locus coeruleus (LC) are the earliest detectable Alzheimer's disease-like (AD-like) neuropathology in the human brain. However, why LC neurons are selectively vulnerable to developing early Tau pathology and degenerating later in disease and whether the LC might seed the stereotypical spread of Tau pathology to the rest of the brain remain unclear. Here, we show that 3,4-dihydroxyphenylglycolaldehyde, which is produced exclusively in noradrenergic neurons by monoamine oxidase A metabolism of norepinephrine, activated asparagine endopeptidase that cleaved Tau at residue N368 into aggregation- and propagation-prone forms, thus leading to LC degeneration and the spread of Tau pathology. Activation of asparagine endopeptidase-cleaved Tau aggregation in vitro and in intact cells was triggered by 3,4-dihydroxyphenylglycolaldehyde, resulting in LC neurotoxicity and propagation of pathology to the forebrain. Thus, our findings reveal that norepinephrine metabolism and Tau cleavage represent the specific molecular mechanism underlying the selective vulnerability of LC neurons in AD.
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http://dx.doi.org/10.1172/JCI130513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934194PMC
January 2020

Traumatic brain injury triggers APP and Tau cleavage by delta-secretase, mediating Alzheimer's disease pathology.

Prog Neurobiol 2020 02 25;185:101730. Epub 2019 Nov 25.

Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address:

Traumatic brain injury (TBI) is associated in some studies with clinical dementia, and neuropathological features, including amyloid plaque deposition and Tau neurofibrillary degeneration commonly identified in Alzheimer's disease (AD). However, the molecular mechanisms linking TBI to AD remain unclear. Here we show that TBI activates transcription factor CCAAT/Enhancer Binding Protein Beta (C/EBPβ), increasing delta-secretase (AEP) expression. Activated AEP cleaves both APP and Tau at APP N585 and Tau N368 sites, respectively, which mediate AD pathogenesis by promoting Aβ production and Tau hyperphosphorylation and inducing neuroinflammation and neurotoxicity. Knockout of AEP or C/EBPβ diminishes TBI-induced AD-like pathology and cognitive impairment in the 3xTg AD mouse model. Remarkably, viral expression of AEP-resistant Tau N368A in the hippocampus of 3xTg mice also ameliorates the pathological and cognitive consequences of TBI. Finally, clinical TBI activates C/EBPβ and escalates AEP expression, leading to APP N585 and Tau N368 proteolytic cleavage in TBI patient brains. Hence, our findings support a potential role for AEP in linking TBI exposure with AD pathogenesis.
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http://dx.doi.org/10.1016/j.pneurobio.2019.101730DOI Listing
February 2020

Author Correction: C/EBPβ regulates delta-secretase expression and mediates pathogenesis in mouse models of Alzheimer's disease.

Nat Commun 2019 Nov 26;10(1):5452. Epub 2019 Nov 26.

Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41467-019-13553-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879502PMC
November 2019

Roles of ErbB3-binding protein 1 (EBP1) in embryonic development and gene-silencing control.

Proc Natl Acad Sci U S A 2019 12 20;116(49):24852-24860. Epub 2019 Nov 20.

Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, 16419 Suwon, Korea;

ErbB3-binding protein 1 (EBP1) is implicated in diverse cellular functions, including apoptosis, cell proliferation, and differentiation. Here, by generating genetic inactivation of mice, we identified the physiological roles of EBP1 in vivo. Loss of in mice caused aberrant organogenesis, including brain malformation, and death between E13.5 and 15.5 owing to severe hemorrhages, with massive apoptosis and cessation of cell proliferation. Specific ablation of Ebp1 in neurons caused structural abnormalities of brain with neuron loss in [Nestin-Cre; ] mice. Notably, global methylation increased with high levels of the gene-silencing unit Suv39H1/DNMT1 in -deficient mice. EBP1 repressed the transcription of by binding to its promoter region and interrupted DNMT1-mediated methylation at its target gene, promoter region. Reinstatement of EBP1 into embryo brain relived gene repression and rescued neuron death. Our findings uncover an essential role for EBP1 in embryonic development and implicate its function in transcriptional regulation.
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http://dx.doi.org/10.1073/pnas.1916306116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900500PMC
December 2019

Mcl-1 Interacts with Akt to Promote Lung Cancer Progression.

Cancer Res 2019 12 29;79(24):6126-6138. Epub 2019 Oct 29.

Department of Radiation Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, Georgia.

Mcl-1 is a unique antiapoptotic Bcl2 family protein that functions as a gatekeeper in manipulating apoptosis and survival in cancer cells. Akt is an oncogenic kinase that regulates multiple cellular functions and its activity is significantly elevated in human cancers. Here we discovered a cross-talk between Mcl-1 and Akt in promoting lung cancer cell growth. Depletion of endogenous Mcl-1 from human lung cancer cells using CRISPR/Cas9 or shRNA significantly decreased Akt activity, leading to suppression of lung cancer cell growth and in xenografts. Mechanistically, Mcl-1 directly interacted via its PEST domain with Akt at the pleckstrin homology (PH) domain. It is known that the interactions between the PH domain and kinase domain (KD) are important for maintaining Akt in an inactive state. The binding of Mcl-1/PH domain disrupted intramolecular PH/KD interactions to activate Akt. Intriguingly, Mcl-1 expression correlated with Akt activity in tumor tissues from patients with non-small cell lung cancer. Using the Mcl-1-binding PH domain of Akt as a docking site, we identified a novel small molecule, PH-687, that directly targets the PH domain and disrupts Mcl-1/Akt binding, leading to suppression of Akt activity and growth inhibition of lung cancer and . By targeting the Mcl-1/Akt interaction, this mechanism-driven agent provides a highly attractive strategy for the treatment of lung cancer. SIGNIFICANCE: These findings indicate that targeting Mcl-1/Akt interaction by employing small molecules such as PH-687 represents a potentially new and effective strategy for cancer treatment.
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http://dx.doi.org/10.1158/0008-5472.CAN-19-0950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6911632PMC
December 2019

Developing Insulin and BDNF Mimetics for Diabetes Therapy.

Curr Top Med Chem 2019 ;19(24):2188-2204

Department of Pathology and Laboratory Medicine, Emory University of School of Medicine, Atlanta, GA, United States.

Diabetes is a global public health concern nowadays. The majority of diabetes mellitus (DM) patients belong to type 2 diabetes mellitus (T2DM), which is highly associated with obesity. The general principle of current therapeutic strategies for patients with T2DM mainly focuses on restoring cellular insulin response by potentiating the insulin-induced signaling pathway. In late-stage T2DM, impaired insulin production requires the patients to receive insulin replacement therapy for maintaining their glucose homeostasis. T2DM patients also demonstrate a drop of brain-derived neurotrophic factor (BDNF) in their circulation, which suggests that replenishing BDNF or enhancing its downstream signaling pathway may be beneficial. Because of their protein nature, recombinant insulin or BDNF possess several limitations that hinder their clinical application in T2DM treatment. Thus, developing orally active "insulin pill" or "BDNF pill" is essential to provide a more convenient and effective therapy. This article reviews the current development of non-peptidyl chemicals that mimic insulin or BDNF and their potential as anti-diabetic agents.
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http://dx.doi.org/10.2174/1568026619666191010160643DOI Listing
December 2019

Initiation of Parkinson's disease from gut to brain by δ-secretase.

Cell Res 2020 01 24;30(1):70-87. Epub 2019 Oct 24.

Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA.

Lewy pathology, composed of α-Synuclein (α-Syn) inclusions, a hallmark of Parkinson's disease (PD), progressively spreads from the enteric nervous system (ENS) to the central nervous system (CNS). However, it remains unclear how this process is regulated at a molecular level. Here we show that δ-secretase (asparagine endopeptidase, AEP) cleaves both α-Syn at N103 and Tau at N368, and mediates their fibrillization and retrograde propagation from the gut to the brain, triggering nigra dopaminergic neuronal loss associated with Lewy bodies and motor dysfunction. α-Syn N103 and Tau N368 robustly interact with each other and are highly elevated in PD patients' gut and brain. Chronic oral administration of the neurotoxin rotenone induces AEP activation and α-Syn N103/Tau N368 complex formation in the gut, eliciting constipation and dopaminergic neuronal death in an AEP-dependent manner. Preformed fibrils (PFFs) of α-Syn N103/Tau N368 are more neurotoxic and compact, and aggregate more quickly along the vagus nerve than their FL/FL counterparts or the individual fragments' fibrils. Colonic injection of PFFs induces PD pathologies, motor dysfunctions, and cognitive impairments. Thus, δ-secretase plays a crucial role in initiating PD pathology progression from the ENS to the CNS.
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http://dx.doi.org/10.1038/s41422-019-0241-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6951265PMC
January 2020

Akt Phosphorylates NQO1 and Triggers its Degradation, Abolishing Its Antioxidative Activities in Parkinson's Disease.

J Neurosci 2019 09 29;39(37):7291-7305. Epub 2019 Jul 29.

Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30322,

The oxidative metabolism of dopamine and consequent oxidative stress are implicated in dopaminergic neuronal loss, mediating the pathogenesis of Parkinson's disease (PD). The inducible detoxifying antioxidative enzyme Quinone oxidoreductase (NQO1) (NAD(P)H: quinone oxidoreductase 1), neuroprotective to counteract reactive oxidative species, is most prominent in the active stage of the disease and virtually absent at the end stage of the disease. However, the molecular mechanism dictating NQO1 expression oscillation remains unclear. Here we show that Akt phosphorylates NQO1 at T128 residues and triggers its polyubiquitination and proteasomal degradation, abrogating its antioxidative effects in PD. Akt binds NQO1 in a phosphorylation-dependent manner. Interestingly, Akt, but not PINK1, provokes NQO1 phosphorylation and polyubiquitination with Parkin as an E3 ligase. Unphosphorylatable NQO1 mutant displays more robust neuroprotective activity than WT NQO1 in suppressing reactive oxidative species and against MPTP-induced dopaminergic cell death, rescuing the motor disorders in both α-synuclein transgenic transgenic male and female mice elicited by the neurotoxin. Thus, our findings demonstrate that blockade of Akt-mediated NQO1 degradation may ameliorate PD pathogenesis. Dopaminergic neurodegeneration in Parkinson's disease (PD) is associated with the imbalance of oxidative metabolism of dopamine. Quinone oxidoreductase (NQO1), a potent antioxidant system, its expression levels are prominently increased in the early and intermediate stages of PD and disappeared in the end-stage PD. The molecular modification behavior of NQO1 after it is upregulated by oxidative stress in the early stage of PD, however, remains unclear. This study shows that Akt binds and phosphorylates NQO1 at T128 residue and promotes its ubiquitination and degradation, and Parkin acts as an E3 ligase in this process, which affects the antioxidant capacity of NQO1. This finding provides a novel molecular mechanism for NQO1 oscillation in PD pathogenesis.
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http://dx.doi.org/10.1523/JNEUROSCI.0625-19.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759025PMC
September 2019

Deficiency in BDNF/TrkB Neurotrophic Activity Stimulates δ-Secretase by Upregulating C/EBPβ in Alzheimer's Disease.

Cell Rep 2019 07;28(3):655-669.e5

Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address:

BDNF/TrkB neurotrophic signaling regulates neuronal development, differentiation, and survival, and deficient BDNF/TrkB activity underlies neurodegeneration in Alzheimer's disease (AD). However, exactly how BDNF/TrkB participates in AD pathology remains unclear. Here, we show that deprivation of BDNF/TrkB increases inflammatory cytokines and activates the JAK2/STAT3 pathway, resulting in the upregulation of transcription factor C/EBPβ. This, in turn, results in increased expression of δ-secretase, leading to both APP and Tau fragmentation by δ-secretase and neuronal loss, which can be blocked by expression of STAT3 Y705F, knockdown of C/EBPβ, or the δ-secretase enzymatic-dead C189S mutant. Inhibition of this pathological cascade can also rescue impaired synaptic plasticity and cognitive dysfunctions. Importantly, reduction in BDNF/TrkB neurotrophic signaling is inversely coupled with an increase in JAK2/STAT3, C/EBPβ, and δ-secretase escalation in human AD brains. Therefore, our findings provide a mechanistic link between BDNF/TrkB reduction, C/EBPβ upregulation, δ-secretase activity, and Aβ and Tau alterations in murine brains.
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http://dx.doi.org/10.1016/j.celrep.2019.06.054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684282PMC
July 2019

Functional and Structural Impairments in the Perirhinal Cortex of a Mouse Model of CDKL5 Deficiency Disorder Are Rescued by a TrkB Agonist.

Front Cell Neurosci 2019 30;13:169. Epub 2019 Apr 30.

Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a severe X-linked neurodevelopmental encephalopathy caused by mutations in the gene and characterized by early-onset epilepsy and intellectual and motor impairments. No cure is currently available for CDD patients, as limited knowledge of the pathology has hindered the development of therapeutics. knockout (KO) mouse models, recently created to investigate the role of CDKL5 in the etiology of CDD, recapitulate various features of the disorder. Previous studies have shown alterations in synaptic plasticity and dendritic pattern in the cerebral cortex and in the hippocampus, but the knowledge of the molecular substrates underlying these alterations is still limited. Here, we have examined for the first time synaptic function and plasticity, dendritic morphology, and signal transduction pathways in the perirhinal cortex (PRC) of this mouse model. Being interconnected with a wide range of cortical and subcortical structures and involved in various cognitive processes, PRC provides a very interesting framework for examining how CDKL5 mutation leads to deficits at the synapse, circuit, and behavioral level. We found that long-term potentiation (LTP) was impaired, and that the TrkB/PLCγ1 pathway could be mechanistically involved in this alteration. PRC neurons in mutant mice showed a reduction in dendritic length, dendritic branches, PSD-95-positive puncta, GluA2-AMPA receptor levels, and spine density and maturation. These functional and structural deficits were associated with impairment in visual recognition memory. Interestingly, an treatment with a TrkB agonist (the 7,8-DHF prodrug R13) to trigger the TrkB/PLCγ1 pathway rescued defective LTP, dendritic pattern, PSD-95 and GluA2-AMPA receptor levels, and restored visual recognition memory in KO mice. Present findings demonstrate a critical role of TrkB signaling in the synaptic development alterations due to CDKL5 mutation, and suggest the possibility of TrkB-targeted pharmacological interventions.
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http://dx.doi.org/10.3389/fncel.2019.00169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6503158PMC
April 2019