Publications by authors named "Jason D Ulrich"

35 Publications

Neuronal VCP loss of function recapitulates FTLD-TDP pathology.

Cell Rep 2021 Jul;36(3):109399

Department of Neurology, Hope Center for Neurological Diseases, Washington University School of Medicine, St. Louis, MO, USA. Electronic address:

The pathogenic mechanism by which dominant mutations in VCP cause multisystem proteinopathy (MSP), a rare neurodegenerative disease that presents as fronto-temporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), remains unclear. To explore this, we inactivate VCP in murine postnatal forebrain neurons (VCP conditional knockout [cKO]). VCP cKO mice have cortical brain atrophy, neuronal loss, autophago-lysosomal dysfunction, and TDP-43 inclusions resembling FTLD-TDP pathology. Conditional expression of a single disease-associated mutation, VCP-R155C, in a VCP null background similarly recapitulates features of VCP inactivation and FTLD-TDP, suggesting that this MSP mutation is hypomorphic. Comparison of transcriptomic and proteomic datasets from genetically defined patients with FTLD-TDP reveal that progranulin deficiency and VCP insufficiency result in similar profiles. These data identify a loss of VCP-dependent functions as a mediator of FTLD-TDP and reveal an unexpected biochemical similarity with progranulin deficiency.
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http://dx.doi.org/10.1016/j.celrep.2021.109399DOI Listing
July 2021

Overexpressing low-density lipoprotein receptor reduces tau-associated neurodegeneration in relation to apoE-linked mechanisms.

Neuron 2021 Jun 10. Epub 2021 Jun 10.

Department of Neurology, Washington University, St. Louis, MO 63110, USA. Electronic address:

APOE is the strongest genetic risk factor for late-onset Alzheimer's disease. ApoE exacerbates tau-associated neurodegeneration by driving microglial activation. However, how apoE regulates microglial activation and whether targeting apoE is therapeutically beneficial in tauopathy is unclear. Here, we show that overexpressing an apoE metabolic receptor, LDLR (low-density lipoprotein receptor), in P301S tauopathy mice markedly reduces brain apoE and ameliorates tau pathology and neurodegeneration. LDLR overexpression (OX) in microglia cell-autonomously downregulates microglial Apoe expression and is associated with suppressed microglial activation as in apoE-deficient microglia. ApoE deficiency and LDLR OX strongly drive microglial immunometabolism toward enhanced catabolism over anabolism, whereas LDLR-overexpressing microglia also uniquely upregulate specific ion channels and neurotransmitter receptors upon activation. ApoE-deficient and LDLR-overexpressing mice harbor enlarged pools of oligodendrocyte progenitor cells (OPCs) and show greater preservation of myelin integrity under neurodegenerative conditions. They also show less reactive astrocyte activation in the setting of tauopathy.
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http://dx.doi.org/10.1016/j.neuron.2021.05.034DOI Listing
June 2021

C9orf72 deficiency promotes microglial-mediated synaptic loss in aging and amyloid accumulation.

Neuron 2021 07 15;109(14):2275-2291.e8. Epub 2021 Jun 15.

Center for Neural Science and Medicine, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA; Department of Neurology, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA. Electronic address:

C9orf72 repeat expansions cause inherited amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD) and result in both loss of C9orf72 protein expression and production of potentially toxic RNA and dipeptide repeat proteins. In addition to ALS/FTD, C9orf72 repeat expansions have been reported in a broad array of neurodegenerative syndromes, including Alzheimer's disease. Here we show that C9orf72 deficiency promotes a change in the homeostatic signature in microglia and a transition to an inflammatory state characterized by an enhanced type I IFN signature. Furthermore, C9orf72-depleted microglia trigger age-dependent neuronal defects, in particular enhanced cortical synaptic pruning, leading to altered learning and memory behaviors in mice. Interestingly, C9orf72-deficient microglia promote enhanced synapse loss and neuronal deficits in a mouse model of amyloid accumulation while paradoxically improving plaque clearance. These findings suggest that altered microglial function due to decreased C9orf72 expression directly contributes to neurodegeneration in repeat expansion carriers independent of gain-of-function toxicities.
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http://dx.doi.org/10.1016/j.neuron.2021.05.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8298293PMC
July 2021

Activated microglia mitigate Aβ-associated tau seeding and spreading.

J Exp Med 2021 Aug 8;218(8). Epub 2021 Jun 8.

Department of Neurology, Washington University School of Medicine, St. Louis, MO.

In Alzheimer's disease (AD) models, AD risk variants in the microglial-expressed TREM2 gene decrease Aβ plaque-associated microgliosis and increase neuritic dystrophy as well as plaque-associated seeding and spreading of tau aggregates. Whether this Aβ-enhanced tau seeding/spreading is due to loss of microglial function or a toxic gain of function in TREM2-deficient microglia is unclear. Depletion of microglia in mice with established brain amyloid has no effect on amyloid but results in less spine and neuronal loss. Microglial repopulation in aged mice improved cognitive and neuronal deficits. In the context of AD pathology, we asked whether microglial removal and repopulation decreased Aβ-driven tau seeding and spreading. We show that both TREM2KO and microglial ablation dramatically enhance tau seeding and spreading around plaques. Interestingly, although repopulated microglia clustered around plaques, they had a reduction in disease-associated microglia (DAM) gene expression and elevated tau seeding/spreading. Together, these data suggest that TREM2-dependent activation of the DAM phenotype is essential in delaying Aβ-induced pathological tau propagation.
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http://dx.doi.org/10.1084/jem.20210542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190588PMC
August 2021

Selective removal of astrocytic APOE4 strongly protects against tau-mediated neurodegeneration and decreases synaptic phagocytosis by microglia.

Neuron 2021 05 7;109(10):1657-1674.e7. Epub 2021 Apr 7.

Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer Disease, Research Center, Washington University, St. Louis, MO 63110, USA. Electronic address:

The apolipoprotein E (APOE) gene is the strongest genetic risk factor for Alzheimer's disease and directly influences tauopathy and tau-mediated neurodegeneration. ApoE4 has strong deleterious effects on both parameters. In the brain, apoE is produced and secreted primarily by astrocytes and by activated microglia. The cell-specific role of each form of apoE in the setting of neurodegeneration has not been determined. We generated P301S Tau/Aldh1l1-CreERT2/apoE3 or Tau/Aldh1l1-CreERT2/apoE4 mice. At 5.5 months of age, after the onset of tau pathology, we administered tamoxifen or vehicle and compared mice at 9.5 months of age. Removing astrocytic APOE4 markedly reduced tau-mediated neurodegeneration and decreased phosphorylated tau (pTau) pathology. Single-nucleus RNA sequencing analysis revealed striking gene expression changes in all cell types, with astrocytic APOE4 removal decreasing disease-associated gene signatures in neurons, oligodendrocytes, astrocytes, and microglia. Removal of astrocytic APOE4 decreased tau-induced synaptic loss and microglial phagocytosis of synaptic elements, suggesting a key role for astrocytic apoE in synaptic degeneration.
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http://dx.doi.org/10.1016/j.neuron.2021.03.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141024PMC
May 2021

APOE immunotherapy reduces cerebral amyloid angiopathy and amyloid plaques while improving cerebrovascular function.

Sci Transl Med 2021 02;13(581)

Department of Neurology, Hope Center for Neurological Disorders, Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA.

The ε4 allele of the apolipoprotein E () gene is the strongest genetic risk factor for late-onset Alzheimer's disease (AD) and greatly influences the development of amyloid-β (Aβ) pathology. Our current study investigated the potential therapeutic effects of the anti-human APOE antibody HAE-4, which selectively recognizes human APOE that is co-deposited with Aβ in cerebral amyloid angiopathy (CAA) and parenchymal amyloid pathology. In addition, we tested whether HAE-4 provoked brain hemorrhages, a component of amyloid-related imaging abnormalities (ARIA). ARIA is an adverse effect secondary to treatment with anti-Aβ antibodies that can occur in blood vessels with CAA. We used 5XFAD mice expressing human (5XE4) that have prominent CAA and parenchymal plaque pathology to assess the efficacy of HAE-4 compared to an Aβ antibody that removes parenchymal Aβ but increases ARIA in humans. In chronically treated 5XE4 mice, HAE-4 reduced Aβ deposition including CAA compared to a control antibody, whereas the anti-Aβ antibody had no effect on CAA. Furthermore, the anti-Aβ antibody exacerbated microhemorrhage severity, which highly correlated with reactive astrocytes surrounding CAA. In contrast, HAE-4 did not stimulate microhemorrhages and instead rescued CAA-induced cerebrovascular dysfunction in leptomeningeal arteries in vivo. HAE-4 not only reduced amyloid but also dampened reactive microglial, astrocytic, and proinflammatory-associated genes in the cortex. These results suggest that targeting APOE in the core of both CAA and plaques could ameliorate amyloid pathology while protecting cerebrovascular integrity and function.
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http://dx.doi.org/10.1126/scitranslmed.abd7522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128342PMC
February 2021

Apolipoprotein E4 Reduction with Antisense Oligonucleotides Decreases Neurodegeneration in a Tauopathy Model.

Ann Neurol 2021 05 24;89(5):952-966. Epub 2021 Feb 24.

Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO.

Objective: Apolipoprotein E (ApoE) genotype is the strongest genetic risk factor for late-onset Alzheimer's disease, with the ε4 allele increasing risk in a dose-dependent fashion. In addition to ApoE4 playing a crucial role in amyloid-β deposition, recent evidence suggests that it also plays an important role in tau pathology and tau-mediated neurodegeneration. It is not known, however, whether therapeutic reduction of ApoE4 would exert protective effects on tau-mediated neurodegeneration.

Methods: Herein, we used antisense oligonucleotides (ASOs) against human APOE to reduce ApoE4 levels in the P301S/ApoE4 mouse model of tauopathy. We treated P301S/ApoE4 mice with ApoE or control ASOs via intracerebroventricular injection at 6 and 7.5 months of age and performed brain pathological assessments at 9 months of age.

Results: Our results indicate that treatment with ApoE ASOs reduced ApoE4 protein levels by ~50%, significantly protected against tau pathology and associated neurodegeneration, decreased neuroinflammation, and preserved synaptic density. These data were also corroborated by a significant reduction in levels of neurofilament light chain (NfL) protein in plasma of ASO-treated mice.

Interpretation: We conclude that reducing ApoE4 levels should be explored further as a therapeutic approach for APOE4 carriers with tauopathy including Alzheimer's disease. ANN NEUROL 2021;89:952-966.
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http://dx.doi.org/10.1002/ana.26043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260038PMC
May 2021

Impact of TREM2R47H variant on tau pathology-induced gliosis and neurodegeneration.

J Clin Invest 2020 09;130(9):4954-4968

Department of Neurology.

Alzheimer's disease (AD) is characterized by plaques containing amyloid-β (Aβ) and neurofibrillary tangles composed of aggregated, hyperphosphorylated tau. Beyond tau and Aβ, evidence suggests that microglia play an important role in AD pathogenesis. Rare variants in the microglia-expressed triggering receptor expressed on myeloid cells 2 (TREM2) gene increase AD risk 2- to 4-fold. It is likely that these TREM2 variants increase AD risk by decreasing the response of microglia to Aβ and its local toxicity. However, neocortical Aβ pathology occurs many years before neocortical tau pathology in AD. Thus, it will be important to understand the role of TREM2 in the context of tauopathy. We investigated the impact of the AD-associated TREM2 variant (R47H) on tau-mediated neuropathology in the PS19 mouse model of tauopathy. We assessed PS19 mice expressing human TREM2CV (common variant) or human TREM2R47H. PS19-TREM2R47H mice had significantly attenuated brain atrophy and synapse loss versus PS19-TREM2CV mice. Gene expression analyses and CD68 immunostaining revealed attenuated microglial reactivity in PS19-TREM2R47H versus PS19-TREM2CV mice. There was also a decrease in phagocytosis of postsynaptic elements by microglia expressing TREM2R47H in the PS19 mice and in human AD brains. These findings suggest that impaired TREM2 signaling reduces microglia-mediated neurodegeneration in the setting of tauopathy.
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http://dx.doi.org/10.1172/JCI138179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456230PMC
September 2020

genotype regulates pathology and disease progression in synucleinopathy.

Sci Transl Med 2020 02;12(529)

Hope Center for Neurologic Disease, Washington University, St. Louis, MO 63110, USA.

Apolipoprotein E () ε4 genotype is associated with increased risk of dementia in Parkinson's disease (PD), but the mechanism is not clear, because patients often have a mixture of α-synuclein (αSyn), amyloid-β (Aβ), and tau pathologies. ε4 exacerbates brain Aβ pathology, as well as tau pathology, but it is not clear whether genotype independently regulates αSyn pathology. In this study, we generated A53T αSyn transgenic mice (A53T) on knockout (A53T/EKO) or human knockin backgrounds (A53T/E2, E3, and E4). At 12 months of age, A53T/E4 mice accumulated higher amounts of brainstem detergent-insoluble phosphorylated αSyn compared to A53T/EKO and A53T/E3; detergent-insoluble αSyn in A53T/E2 mice was undetectable. By immunohistochemistry, A53T/E4 mice displayed a higher burden of phosphorylated αSyn and reactive gliosis compared to A53T/E2 mice. A53T/E2 mice exhibited increased survival and improved motor performance compared to other genotypes. In a complementary model of αSyn spreading, striatal injection of αSyn preformed fibrils induced greater accumulation of αSyn pathology in the substantia nigra of A53T/E4 mice compared to A53T/E2 and A53T/EKO mice. In two separate cohorts of human patients with PD, ε4/ε4 individuals showed the fastest rate of cognitive decline over time. Our results demonstrate that genotype directly regulates αSyn pathology independent of its established effects on Aβ and tau, corroborate the finding that ε4 exacerbates pathology, and suggest that ε2 may protect against αSyn aggregation and neurodegeneration in synucleinopathies.
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http://dx.doi.org/10.1126/scitranslmed.aay3069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289511PMC
February 2020

Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer's disease.

Nat Med 2020 01 13;26(1):131-142. Epub 2020 Jan 13.

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.

Glia have been implicated in Alzheimer's disease (AD) pathogenesis. Variants of the microglia receptor triggering receptor expressed on myeloid cells 2 (TREM2) increase AD risk, and activation of disease-associated microglia (DAM) is dependent on TREM2 in mouse models of AD. We surveyed gene-expression changes associated with AD pathology and TREM2 in 5XFAD mice and in human AD by single-nucleus RNA sequencing. We confirmed the presence of Trem2-dependent DAM and identified a previously undiscovered Serpina3nC4b reactive oligodendrocyte population in mice. Interestingly, remarkably different glial phenotypes were evident in human AD. Microglia signature was reminiscent of IRF8-driven reactive microglia in peripheral-nerve injury. Oligodendrocyte signatures suggested impaired axonal myelination and metabolic adaptation to neuronal degeneration. Astrocyte profiles indicated weakened metabolic coordination with neurons. Notably, the reactive phenotype of microglia was less evident in TREM2-R47H and TREM2-R62H carriers than in non-carriers, demonstrating a TREM2 requirement in both mouse and human AD, despite the marked species-specific differences.
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http://dx.doi.org/10.1038/s41591-019-0695-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6980793PMC
January 2020

Lack of hepatic apoE does not influence early Aβ deposition: observations from a new APOE knock-in model.

Mol Neurodegener 2019 10 17;14(1):37. Epub 2019 Oct 17.

Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA.

Background: The apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset Alzheimer disease (AD). ApoE is produced by both astrocytes and microglia in the brain, whereas hepatocytes produce the majority of apoE found in the periphery. Studies using APOE knock-in and transgenic mice have demonstrated a strong isoform-dependent effect of apoE on the accumulation of amyloid-β (Aβ) deposition in the brain in the form of both Aβ-containing amyloid plaques and cerebral amyloid angiopathy. However, the specific contributions of different apoE pools to AD pathogenesis remain unknown.

Methods: We have begun to address these questions by generating new lines of APOE knock-in (APOE-KI) mice (ε2/ε2, ε3/ε3, and ε4/ε4) where the exons in the coding region of APOE are flanked by loxP sites, allowing for cell type-specific manipulation of gene expression. We assessed these mice both alone and after crossing them with mice with amyloid deposition in the brain. Using biochemical and histological methods. We also investigated how removal of APOE expression from hepatocytes affected cerebral amyloid deposition.

Results: As in other APOE knock-in mice, apoE protein was present predominantly in astrocytes in the brain under basal conditions and was also detected in reactive microglia surrounding amyloid plaques. Primary cultured astrocytes and microglia from the APOE-KI mice secreted apoE in lipoprotein particles of distinct size distribution upon native gel analysis with microglial particles being substantially smaller than the HDL-like particles secreted by astrocytes. Crossing of APP/PS1 transgenic mice to the different APOE-KI mice recapitulated the previously described isoform-specific effect (ε4 > ε3) on amyloid plaque and Aβ accumulation. Deletion of APOE in hepatocytes did not alter brain apoE levels but did lead to a marked decrease in plasma apoE levels and changes in plasma lipid profile. Despite these changes in peripheral apoE and on plasma lipids, cerebral accumulation of amyloid plaques in APP/PS1 mice was not affected.

Conclusions: Altogether, these new knock-in strains offer a novel and dynamic tool to study the role of APOE in AD pathogenesis in a spatially and temporally controlled manner.
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http://dx.doi.org/10.1186/s13024-019-0337-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6796484PMC
October 2019

TREM2 function impedes tau seeding in neuritic plaques.

Nat Neurosci 2019 08 24;22(8):1217-1222. Epub 2019 Jun 24.

Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.

Variants in the triggering receptor expressed on myeloid cells 2 (TREM2) have been associated with increased risk for sporadic, late-onset Alzheimer's disease. Here we show that germline knockout of Trem2 or the TREM2 variant reduces microgliosis around amyloid-β plaques and facilitates the seeding and spreading of neuritic plaque tau aggregates. These findings demonstrate a key role for TREM2 and microglia in limiting the development of peri-plaque tau pathologies.
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http://dx.doi.org/10.1038/s41593-019-0433-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6660358PMC
August 2019

High-affinity interactions and signal transduction between Aβ oligomers and TREM2.

EMBO Mol Med 2018 11;10(11)

Center for Translational Research in Neurodegenerative Disease, Department of Neuroscience, University of Florida, Gainesville, FL, USA

Rare coding variants in the triggering receptor expressed on myeloid cells 2 (TREM2) are associated with increased risk for Alzheimer's disease (AD), but how they confer this risk remains uncertain. We assessed binding of TREM2, AD-associated TREM2 variants to various forms of Aβ and APOE in multiple assays. TREM2 interacts directly with various forms of Aβ, with highest affinity interactions observed between TREM2 and soluble Aβ42 oligomers. High-affinity binding of TREM2 to Aβ oligomers is characterized by very slow dissociation. Pre-incubation with Aβ is shown to block the interaction of APOE In cellular assays, AD-associated variants of TREM2 reduced the amount of Aβ42 internalized, and in NFAT assay, the R47H and R62H variants decreased NFAT signaling activity in response to Aβ42. These studies demonstrate i) a high-affinity interaction between TREM2 and Aβ oligomers that can block interaction with another TREM2 ligand and ii) that AD-associated TREM2 variants bind Aβ with equivalent affinity but show loss of function in terms of signaling and Aβ internalization.
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http://dx.doi.org/10.15252/emmm.201809027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6220267PMC
November 2018

Targeting of nonlipidated, aggregated apoE with antibodies inhibits amyloid accumulation.

J Clin Invest 2018 05 30;128(5):2144-2155. Epub 2018 Mar 30.

Department of Neurology, Hope Center for Neurological Disorders, Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, Missouri, USA.

The apolipoprotein E E4 allele of the APOE gene is the strongest genetic factor for late-onset Alzheimer disease (LOAD). There is compelling evidence that apoE influences Alzheimer disease (AD) in large part by affecting amyloid β (Aβ) aggregation and clearance; however, the molecular mechanism underlying these findings remains largely unknown. Herein, we tested whether anti-human apoE antibodies can decrease Aβ pathology in mice producing both human Aβ and apoE4, and investigated the mechanism underlying these effects. We utilized APPPS1-21 mice crossed to apoE4-knockin mice expressing human apoE4 (APPPS1-21/APOE4). We discovered an anti-human apoE antibody, anti-human apoE 4 (HAE-4), that specifically recognizes human apoE4 and apoE3 and preferentially binds nonlipidated, aggregated apoE over the lipidated apoE found in circulation. HAE-4 also binds to apoE in amyloid plaques in unfixed brain sections and in living APPPS1-21/APOE4 mice. When delivered centrally or by peripheral injection, HAE-4 reduced Aβ deposition in APPPS1-21/APOE4 mice. Using adeno-associated virus to express 2 different full-length anti-apoE antibodies in the brain, we found that HAE antibodies decreased amyloid accumulation, which was dependent on Fcγ receptor function. These data support the hypothesis that a primary mechanism for apoE-mediated plaque formation may be a result of apoE aggregation, as preferentially targeting apoE aggregates with therapeutic antibodies reduces Aβ pathology and may represent a selective approach to treat AD.
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http://dx.doi.org/10.1172/JCI96429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5919821PMC
May 2018

ApoE facilitates the microglial response to amyloid plaque pathology.

J Exp Med 2018 04 26;215(4):1047-1058. Epub 2018 Feb 26.

Department of Neurology, Washington University School of Medicine, St. Louis, MO

One of the hallmarks of Alzheimer's disease is the presence of extracellular diffuse and fibrillar plaques predominantly consisting of the amyloid-β (Aβ) peptide. Apolipoprotein E (ApoE) influences the deposition of amyloid pathology through affecting the clearance and aggregation of monomeric Aβ in the brain. In addition to influencing Aβ metabolism, increasing evidence suggests that apoE influences microglial function in neurodegenerative diseases. Here, we characterize the impact that apoE has on amyloid pathology and the innate immune response in APPPS1ΔE9 and APPPS1-21 transgenic mice. We report that deficiency reduced fibrillar plaque deposition, consistent with previous studies. However, fibrillar plaques in -deficient mice exhibited a striking reduction in plaque compaction. Hyperspectral fluorescent imaging using luminescent conjugated oligothiophenes identified distinct Aβ morphotypes in -deficient mice. We also observed a significant reduction in fibrillar plaque-associated microgliosis and activated microglial gene expression in -deficient mice, along with significant increases in dystrophic neurites around fibrillar plaques. Our results suggest that apoE is critical in stimulating the innate immune response to amyloid pathology.
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http://dx.doi.org/10.1084/jem.20171265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5881464PMC
April 2018

Age-Dependent Effects of apoE Reduction Using Antisense Oligonucleotides in a Model of β-amyloidosis.

Neuron 2017 Dec;96(5):1013-1023.e4

Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address:

The apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset Alzheimer disease. Previous studies suggest that reduction of apoE levels through genetic manipulation can reduce Aβ pathology. However, it is not clear how reduction of apoE levels after birth would affect amyloid deposition. We utilize an antisense oligonucleotide (ASO) to reduce apoE expression in the brains of APP/PS1-21 mice homozygous for the APOE-ε4 or APOE-ε3 allele. ASO treatment starting after birth led to a significant decrease in Aβ pathology when assessed at 4 months. Interestingly, ASO treatment starting at the onset of amyloid deposition led to an increase in Aβ plaque size and a reduction in plaque-associated neuritic dystrophy with no change in overall plaque load. These results suggest that lowering apoE levels prior to plaque deposition can strongly affect the initiation of Aβ pathology while lowering apoE after Aβ seeding modulates plaque size and toxicity.
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http://dx.doi.org/10.1016/j.neuron.2017.11.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5728673PMC
December 2017

TREM2 deficiency attenuates neuroinflammation and protects against neurodegeneration in a mouse model of tauopathy.

Proc Natl Acad Sci U S A 2017 10 9;114(43):11524-11529. Epub 2017 Oct 9.

Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110;

Variants in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2) were recently found to increase the risk for developing Alzheimer's disease (AD). In the brain, TREM2 is predominately expressed on microglia, and its association with AD adds to increasing evidence implicating a role for the innate immune system in AD initiation and progression. Thus far, studies have found TREM2 is protective in the response to amyloid pathology while variants leading to a loss of TREM2 function impair microglial signaling and are deleterious. However, the potential role of TREM2 in the context of tau pathology has not yet been characterized. In this study, we crossed (T2) and (T2) mice to the PS19 human tau transgenic line (PS) to investigate whether loss of TREM2 function affected tau pathology, the microglial response to tau pathology, or neurodegeneration. Strikingly, by 9 mo of age, T2PS mice exhibited significantly less brain atrophy as quantified by ventricular enlargement and preserved cortical volume in the entorhinal and piriform regions compared with T2PS mice. However, no TREM2-dependent differences were observed for phosphorylated tau staining or insoluble tau levels. Rather, T2PS mice exhibited significantly reduced microgliosis in the hippocampus and piriform cortex compared with T2PS mice. Gene expression analyses and immunostaining revealed microglial activation was significantly attenuated in T2PS mice, and there were lower levels of inflammatory cytokines and astrogliosis. These unexpected findings suggest that impairing microglial TREM2 signaling reduces neuroinflammation and is protective against neurodegeneration in the setting of pure tauopathy.
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http://dx.doi.org/10.1073/pnas.1710311114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5663386PMC
October 2017

Behavioral and transcriptomic analysis of Trem2-null mice: not all knockout mice are created equal.

Hum Mol Genet 2018 01;27(2):211-223

Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.

It is clear that innate immune system status is altered in numerous neurodegenerative diseases. Human genetic studies have demonstrated that triggering receptor expressed in myeloid cells 2 (TREM2) coding variants have a strong association with Alzheimer's disease (AD) and other neurodegenerative diseases. To more thoroughly understand the impact of TREM2 in vivo, we studied the behavioral and cognitive functions of wild-type (WT) and Trem2-/- (KO) mice during basal conditions and brain function in the context of innate immune stimulation with peripherally administered lipopolysaccharide (LPS). Early markers of neuroinflammation preceded Aif1 and Trem2 upregulation that occurred at later stages (24-48 h post-LPS). We performed a transcriptomic study of these cohorts and found numerous transcripts and pathways that were altered in Trem2-/- mice both at baseline and 48 h after LPS challenge. Importantly, our transcriptome analysis revealed that our Trem2-/- mouse line (Velocigene allele) results in exaggerated Treml1 upregulation. In contrast, aberrantly high Treml1 expression was absent in the Trem2 knockout line generated by the Colonna lab and the Jackson Labs CRISPR/Cas9 Trem2 knockout line. Notably, removal of the floxed neomycin selection cassette ameliorated aberrant Treml1 expression, validating the artifactual nature of Treml1 expression in the original Trem2-/- Velocigene line. Clearly further studies are needed to decipher whether the Treml1 transcriptional artifact is functionally meaningful, but our data indicate that caution is warranted when interpreting functional studies with this particular line. Additionally, our results indicate that other Velocigene alleles or targeting strategies with strong heterologous promoters need to carefully consider downstream genes.
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http://dx.doi.org/10.1093/hmg/ddx366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5886290PMC
January 2018

The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases.

Immunity 2017 09;47(3):566-581.e9

Department of Pharmacology and Experimental Therapeutics and Department of Neurology, Boston University School of Medicine, MA, USA.

Microglia play a pivotal role in the maintenance of brain homeostasis but lose homeostatic function during neurodegenerative disorders. We identified a specific apolipoprotein E (APOE)-dependent molecular signature in microglia from models of amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), and Alzheimer's disease (AD) and in microglia surrounding neuritic β-amyloid (Aβ)-plaques in the brains of people with AD. The APOE pathway mediated a switch from a homeostatic to a neurodegenerative microglia phenotype after phagocytosis of apoptotic neurons. TREM2 (triggering receptor expressed on myeloid cells 2) induced APOE signaling, and targeting the TREM2-APOE pathway restored the homeostatic signature of microglia in ALS and AD mouse models and prevented neuronal loss in an acute model of neurodegeneration. APOE-mediated neurodegenerative microglia had lost their tolerogenic function. Our work identifies the TREM2-APOE pathway as a major regulator of microglial functional phenotype in neurodegenerative diseases and serves as a novel target that could aid in the restoration of homeostatic microglia.
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http://dx.doi.org/10.1016/j.immuni.2017.08.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5719893PMC
September 2017

TREM2 Maintains Microglial Metabolic Fitness in Alzheimer's Disease.

Cell 2017 Aug;170(4):649-663.e13

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address:

Elevated risk of developing Alzheimer's disease (AD) is associated with hypomorphic variants of TREM2, a surface receptor required for microglial responses to neurodegeneration, including proliferation, survival, clustering, and phagocytosis. How TREM2 promotes such diverse responses is unknown. Here, we find that microglia in AD patients carrying TREM2 risk variants and TREM2-deficient mice with AD-like pathology have abundant autophagic vesicles, as do TREM2-deficient macrophages under growth-factor limitation or endoplasmic reticulum (ER) stress. Combined metabolomics and RNA sequencing (RNA-seq) linked this anomalous autophagy to defective mammalian target of rapamycin (mTOR) signaling, which affects ATP levels and biosynthetic pathways. Metabolic derailment and autophagy were offset in vitro through Dectin-1, a receptor that elicits TREM2-like intracellular signals, and cyclocreatine, a creatine analog that can supply ATP. Dietary cyclocreatine tempered autophagy, restored microglial clustering around plaques, and decreased plaque-adjacent neuronal dystrophy in TREM2-deficient mice with amyloid-β pathology. Thus, TREM2 enables microglial responses during AD by sustaining cellular energetic and biosynthetic metabolism.
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http://dx.doi.org/10.1016/j.cell.2017.07.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5573224PMC
August 2017

Elucidating the Role of TREM2 in Alzheimer's Disease.

Neuron 2017 Apr;94(2):237-248

Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA; Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address:

Alzheimer's disease (AD) is the sixth leading cause of death in the United States and the most common cause of dementia in the elderly. Genetic factors, such as rare variants in the microglial-expressed gene TREM2, strongly impact the lifetime risk of developing AD. Several recent studies have described dramatic TREM2-dependent phenotypes in mouse models of amyloidosis that point to an important role for TREM2 in regulating the response of the innate immune system to Aβ pathology. Furthermore, elevations in the CSF levels of soluble TREM2 fragments implicate changes in inflammatory pathways as occurring coincident with markers of neuronal damage and the onset of clinical dementia in AD. Here, we review the rapidly developing literature surrounding TREM2 in AD that may provide novel insight into the broader role of the innate immune system in neurodegenerative disease.
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http://dx.doi.org/10.1016/j.neuron.2017.02.042DOI Listing
April 2017

Anti-tau antibody administration increases plasma tau in transgenic mice and patients with tauopathy.

Sci Transl Med 2017 04;9(386)

Hope Center for Neurological Disorders and Knight Alzheimer's Disease Research Center, Department of Neurology, Washington University, St. Louis, MO 63110,USA.

Tauopathies are a group of disorders in which the cytosolic protein tau aggregates and accumulates in cells within the brain, resulting in neurodegeneration. A promising treatment being explored for tauopathies is passive immunization with anti-tau antibodies. We previously found that administration of an anti-tau antibody to human tau transgenic mice increased the concentration of plasma tau. We further explored the effects of administering an anti-tau antibody on plasma tau. After peripheral administration of an anti-tau antibody to human patients with tauopathy and to mice expressing human tau in the central nervous system, there was a dose-dependent increase in plasma tau. In mouse plasma, we found that tau had a short half-life of 8 min that increased to more than 3 hours after administration of anti-tau antibody. As tau transgenic mice accumulated insoluble tau in the brain, brain soluble and interstitial fluid tau decreased. Administration of anti-tau antibody to tau transgenic mice that had decreased brain soluble tau and interstitial fluid tau resulted in an increase in plasma tau, but this increase was less than that observed in tau transgenic mice without these brain changes. Tau transgenic mice subjected to acute neuronal injury using 3-nitropropionic acid showed increased interstitial fluid tau and plasma tau. These data suggest that peripheral administration of an anti-tau antibody results in increased plasma tau, which correlates with the concentration of extracellular and soluble tau in the brain.
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http://dx.doi.org/10.1126/scitranslmed.aal2029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727571PMC
April 2017

Apolipoprotein E and Alzheimer's disease: the influence of apolipoprotein E on amyloid-β and other amyloidogenic proteins.

J Lipid Res 2017 05 27;58(5):824-836. Epub 2017 Feb 27.

Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University, St. Louis, MO 63110

Alzheimer's disease (AD) is one of the fastest-growing causes of death and disability in persons 65 years of age or older, affecting more than 5 million Americans alone. Clinical manifestations of AD include progressive decline in memory, executive function, language, and other cognitive domains. Research efforts within the last three decades have identified as the most significant genetic risk factor for late-onset AD, which accounts for >99% of cases. The apoE protein is hypothesized to affect AD pathogenesis through a variety of mechanisms, from its effects on the blood-brain barrier, the innate immune system, and synaptic function to the accumulation of amyloid-β (Aβ). Here, we discuss the role of apoE on the biophysical properties and metabolism of the Aβ peptide, the principal component of amyloid plaques and cerebral amyloid angiopathy (CAA). CAA is characterized by the deposition of amyloid proteins (including Aβ) in the leptomeningeal medium and small arteries, which is found in most AD cases but sometimes occurs as an independent entity. Accumulation of these pathologies in the brain is one of the pathological hallmarks of AD. Beyond Aβ, we will extend the discussion to the potential role of apoE on other amyloidogenic proteins found in AD, and also a number of diverse neurodegenerative diseases.
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http://dx.doi.org/10.1194/jlr.R075481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5408619PMC
May 2017

Novel allele-dependent role for APOE in controlling the rate of synapse pruning by astrocytes.

Proc Natl Acad Sci U S A 2016 09 24;113(36):10186-91. Epub 2016 Aug 24.

Department of Neurobiology, School of Medicine, Stanford University, Stanford, CA 94305;

The strongest genetic risk factor influencing susceptibility to late-onset Alzheimer's disease (AD) is apolipoprotein E (APOE) genotype. APOE has three common isoforms in humans, E2, E3, and E4. The presence of two copies of the E4 allele increases risk by ∼12-fold whereas E2 allele is associated with an ∼twofold decreased risk for AD. These data put APOE central to AD pathophysiology, but it is not yet clear how APOE alleles modify AD risk. Recently we found that astrocytes, a major central nervous system cell type that produces APOE, are highly phagocytic and participate in normal synapse pruning and turnover. Here, we report a novel role for APOE in controlling the phagocytic capacity of astrocytes that is highly dependent on APOE isoform. APOE2 enhances the rate of phagocytosis of synapses by astrocytes, whereas APO4 decreases it. We also found that the amount of C1q protein accumulation in hippocampus, which may represent the accumulation of senescent synapses with enhanced vulnerability to complement-mediated degeneration, is highly dependent on APOE alleles: C1q accumulation was significantly reduced in APOE2 knock-in (KI) animals and was significantly increased in APOE4 KI animals compared with APOE3 KI animals. These studies reveal a novel allele-dependent role for APOE in regulating the rate of synapse pruning by astrocytes. They also suggest the hypothesis that AD susceptibility of APOE4 may originate in part from defective phagocytic capacity of astrocytes which accelerates the rate of accumulation of C1q-coated senescent synapses, enhancing synaptic vulnerability to classical-complement-cascade mediated neurodegeneration.
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http://dx.doi.org/10.1073/pnas.1609896113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5018780PMC
September 2016

TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques.

J Exp Med 2016 05 18;213(5):667-75. Epub 2016 Apr 18.

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110

Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial receptor that recognizes changes in the lipid microenvironment, which may occur during amyloid β (Aβ) accumulation and neuronal degeneration in Alzheimer's disease (AD). Rare TREM2 variants that affect TREM2 function lead to an increased risk of developing AD. In murine models of AD, TREM2 deficiency prevents microglial clustering around Aβ deposits. However, the origin of myeloid cells surrounding amyloid and the impact of TREM2 on Aβ accumulation are a matter of debate. Using parabiosis, we found that amyloid-associated myeloid cells derive from brain-resident microglia rather than from recruitment of peripheral blood monocytes. To determine the impact of TREM2 deficiency on Aβ accumulation, we examined Aβ plaques in the 5XFAD model of AD at the onset of Aβ-related pathology. At this early time point, Aβ accumulation was similar in TREM2-deficient and -sufficient 5XFAD mice. However, in the absence of TREM2, Aβ plaques were not fully enclosed by microglia; they were more diffuse, less dense, and were associated with significantly greater neuritic damage. Thus, TREM2 protects from AD by enabling microglia to surround and alter Aβ plaque structure, thereby limiting neuritic damage.
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http://dx.doi.org/10.1084/jem.20151948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4854736PMC
May 2016

TREM2 Function in Alzheimer's Disease and Neurodegeneration.

ACS Chem Neurosci 2016 Apr 19;7(4):420-7. Epub 2016 Feb 19.

Department of Neurology, Knight Alzheimer's Disease Research Center, and Hope Center for Neurological Disorders, Washington University School of Medicine , St. Louis, Missouri 63110, United States.

Alzheimer's disease (AD), the most common cause of dementia in the elderly, is a complex neurodegenerative disease marked by the appearance of amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles. Alzheimer's disease has a strong genetic component, and recent advances in genome technology have unearthed novel variants in several genes, which could provide insight into the pathogenic mechanisms that contribute to AD. Particularly interesting are variants in the microglial-expressed receptor TREM2 which are associated with a 2-4-fold increased risk of developing AD. Since the discovery of a link between TREM2 and AD, multiple studies have emerged testing whether partial or complete loss of TREM2 function contributed to Aβ deposition or Aβ-associated microgliosis. Although some confounding conflicting data have emerged from these studies regarding the role of TREM2 in regulating Aβ deposition within the hippocampus, the most consistent and striking observation is a strong decrease in microgliosis surrounding Aβ plaques in TREM2 haploinsufficient and TREM2 deficient mice. Interestingly, a similar impairment in microgliosis has been reported in mouse models of prion disease, stroke, and multiple sclerosis, suggesting a critical role for TREM2 in supporting microgliosis in response to pathology in the central nervous system. In this Review, we summarize recent reports on the role of TREM2 in AD pathology and hypothesized mechanisms by which TREM2 function could influence AD-induced microgliosis.
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http://dx.doi.org/10.1021/acschemneuro.5b00313DOI Listing
April 2016

Re-evaluation of the Blood-Brain Barrier in the Presence of Alzheimer's Disease Pathology.

Neuron 2015 Oct;88(2):237-9

Department of Neurology, Washington University, 660 South Euclid Avenue, Box 8111, St. Louis, MO 63110, USA; Hope Center for Neurological Disorders, Washington University, 660 South Euclid Avenue, Box 8111, St. Louis, MO 63110, USA; The Knight Alzheimer's Disease Research Center, Washington University, 660 South Euclid Avenue, Box 8111, St. Louis, MO 63110, USA. Electronic address:

Blood-brain barrier disruption is believed to occur in Alzheimer's disease, which could influence the bioavailability of drugs within the brain. However, in this issue of Neuron, Bien-Ly et al. (2015) report no evidence of widespread blood-brain barrier dysfunction.
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http://dx.doi.org/10.1016/j.neuron.2015.10.008DOI Listing
October 2015

TREM2 lipid sensing sustains the microglial response in an Alzheimer's disease model.

Cell 2015 Mar 26;160(6):1061-71. Epub 2015 Feb 26.

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address:

Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial surface receptor that triggers intracellular protein tyrosine phosphorylation. Recent genome-wide association studies have shown that a rare R47H mutation of TREM2 correlates with a substantial increase in the risk of developing Alzheimer's disease (AD). To address the basis for this genetic association, we studied TREM2 deficiency in the 5XFAD mouse model of AD. We found that TREM2 deficiency and haploinsufficiency augment β-amyloid (Aβ) accumulation due to a dysfunctional response of microglia, which fail to cluster around Aβ plaques and become apoptotic. We further demonstrate that TREM2 senses a broad array of anionic and zwitterionic lipids known to associate with fibrillar Aβ in lipid membranes and to be exposed on the surface of damaged neurons. Remarkably, the R47H mutation impairs TREM2 detection of lipid ligands. Thus, TREM2 detects damage-associated lipid patterns associated with neurodegeneration, sustaining the microglial response to Aβ accumulation.
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http://dx.doi.org/10.1016/j.cell.2015.01.049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4477963PMC
March 2015

Nerve growth factor (NGF) regulates activity of nuclear factor of activated T-cells (NFAT) in neurons via the phosphatidylinositol 3-kinase (PI3K)-Akt-glycogen synthase kinase 3β (GSK3β) pathway.

J Biol Chem 2014 Nov 17;289(45):31349-60. Epub 2014 Sep 17.

From the Department of Pharmacology, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242 and

The Ca(2+)/calcineurin-dependent transcription factor nuclear factor of activated T-cells (NFAT) plays an important role in regulating many neuronal functions, including excitability, axonal growth, synaptogenesis, and neuronal survival. NFAT can be activated by action potential firing or depolarization that leads to Ca(2+)/calcineurin-dependent dephosphorylation of NFAT and its translocation to the nucleus. Recent data suggest that NFAT and NFAT-dependent functions in neurons can also be potently regulated by NGF and other neurotrophins. However, the mechanisms of NFAT regulation by neurotrophins are not well understood. Here, we show that in dorsal root ganglion sensory neurons, NGF markedly facilitates NFAT-mediated gene expression induced by mild depolarization. The effects of NGF were not associated with changes in [Ca(2+)]i and were independent of phospholipase C activity. Instead, the facilitatory effect of NGF depended on activation of the PI3K/Akt pathway downstream of the TrkA receptor and on inhibition of glycogen synthase kinase 3β (GSK3β), a protein kinase known to phosphorylate NFAT and promote its nuclear export. Knockdown or knockout of NFATc3 eliminated this facilitatory effect. Simultaneous monitoring of EGFP-NFATc3 nuclear translocation and [Ca(2+)]i changes in dorsal root ganglion neurons indicated that NGF slowed the rate of NFATc3 nuclear export but did not affect its nuclear import rate. Collectively, our data suggest that NGF facilitates depolarization-induced NFAT activation by stimulating PI3K/Akt signaling, inactivating GSK3β, and thereby slowing NFATc3 export from the nucleus. We propose that NFAT serves as an integrator of neurotrophin action and depolarization-driven calcium signaling to regulate neuronal gene expression.
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http://dx.doi.org/10.1074/jbc.M114.587188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4223335PMC
November 2014
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