- Email: [email protected]
Anti-NMDA receptor encephalitis mimicking schizophrenia: diagnosis and treatment
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S.15. Inflammation in psychosis: diagnosis and treatment
The present results suggest sex and anxious features as important variables to be considered in pharmacogenetic studies. Additionally, a combined pharmacogenetic/epigenetic approach is expected to aid in establishing more robust biomarkers of treatment response and thereby to contribute to the development of a personalized treatment of major depression.
S.15. Inflammation in psychosis: diagnosis and treatment S.15.01 Imaging neuroinflammation in schizophrenia and depression with PET R. Mizrahi1 ° 1 Centre for Addiction and Mental Health, Research Imaging Centre, Toronto- Ontario, Canada The neuroinflammatory hypothesis of schizophrenia (SCZ) and major depressive disorder (MDE) is supported by several previous findings. These include, but are not limited to, immune activation, increased peripheral markers of inflammation frequently reported and some positive postmortem studies. However, a fundamental limitation of the neuroinflammatory hypothesis is a paucity of evidence of brain inflammation in-vivo in during SCZ and MDE. Translocator protein density measured by distribution volume (TSPO VT) is increased in activated microglia, an important marker of neuroinflammation. We will present work of Dr. Mizrahi’s lab and Dr. Meyer’s lab testing whether TSPO VT is elevated in-vivo in brain in SCZ and MDE. Together, we have scanned 18 untreated first episode of psychosis (FEP) and 20 MDE patients, who were compared to matched healthy volunteer (HV) samples. We used a novel 2nd generation TSPO radiotracer ([18 F]FEPPA) and incorporated the impact of TSPO genotype (rs 6971) on all analyses. Data was analyzed using the 2 tissue compartment model (2TCM) to obtain the validate outcome measure VT. First, we found no significant difference in [18 F]FEPPA VT in any ROIs between HV and untreated patients with FEP. However, in MDE, TSPO VT was significantly elevated in all ROIs examined (multivariate analysis of variance, F15,23 = 4.5 [P = 0.001]). The magnitude of TSPO VT elevation was 26% in prefrontal cortex and 32% in the ACC of MDE patients. Results from these studies suggest that neuroinflammation might be disease specific or that significant variation exists among patients or disease progression stages. References [1] Setiawan E, Wilson A, Mizrahi R, Rusjan P, Miler L, Rajkowska G, Suridjan I, Kennedy J, Rekkas P, Houle S, Meyer JH. 2015. Role of translocator protein density, a marker of neuroinflammation, in the brain during major depressive episodes. Jama Psychiatry 72, 268−75. [2] Kenk M, Selvanathan T, Rao N, Suridjan I, Rusjan P, Remington G, Meyer JH, Wilson A, Houle S, Mizrahi R. 2015. Imaging neuroinflammation in gray and white matter in schizophrenia: an in-vivo PET study with [18 F]-FEPPA. Schizophrenia Bulletin 41, 85−93. [3] Suridjan I, Rusjan P, Kenk M, Verhoeff N, Voineskos A, Rotenberg D, Wilson A, Meyer J, Houle S, Mizrahi R. 2014. Quantitative imaging of neuroinflammation in human white matter: a positron emission tomography study with translocator protein 18 kDa radioligand, [18 F]FEPPA, Synapse 68, 536−47.
S.15.02 Targetting microglia activation in schizophrenia by minocycline treatment D. Mattei1 , A. Ivanov2 , G. Ferrai3 , P. Jordan1 , D. Guneykaya1 , W. Schaafsma4 , P. Przanowski5 , W. Deuther-Conrad6 , P. Brust6 , S. Hesse7 , B. Eggen4 , E. Bodekke4 , B. Kaminska5 , A. Pombo3 , H. Kettenmann1 , S.A. Wolf1 ° 1 Max-Delbr¨uckCenter of Molecular Medicine, Cellular Neuroscience, Berlin, Germany; 2 BIH, Bioinformatic Core facility, Berlin, Germany; 3 Max-Delbr¨uck-Center of Molecular Medicine, BIMSBI, Berlin, Germany; 4 University of Groningen, Neuroscience, Groningen, The Netherlands; 5 Nencki Institute, Neuroscience, Warszawa, Poland; 6 Helmholtz Zentrum Dresden Rossendorf- Forschungsstelle Leipzig, Neuroradiopharmaceutical, Leipzig, Germany; 7 University of Leipzig, NeuroradiologyNuclearmedicine, Leipzig, Germany The importance of the brain’s phagocyte − the microglia − came recently into focus as a novel therapeutic target in psychiatric disorders1. Dysregulations of microglia have been reported in post mortem tissue and also in vivo by increased radio ligand binding to the (phagocyte-specific) TSPO receptor in brains of schizophrenic patients2. The tetracycline minocycline that partially acts on microglia has been shown to improve mainly negative symptoms in a few clinical studies3. We here use an animal model of maternal immune activation to test its validity for clinical translation and investigate the pathways that are targeted by minocycline specific in microglia. Pregnant dams were injected intraperitoneally with the viral mimic PolyI:C or saline at gestational day 15 and the offspring was tested for behavioral deficits at postnatal day 60. Indeed, the offspring showed behavioral correlates of schizophrenia like decreased pre-pulse inhibition, sociability and cognitive performance along with an increased binding potential to the TSPO shown by autoradiography using [18 F]GE-180 on hippocampal slices. This was accompanied by a profoundly altered transcriptome signature in hippocampal microglia and decreased phagocytic activity. Thereafter, mice were treated for five weeks with minocycline (3 mg/kg/day). This treatment normalized the behavioral deficits, TSPO binding and phagocytic activity and restored the transcriptome signature towards control levels. Our findings indicate that minocycline is a potent drug to affect specific microglial functions and thereby attenuate symptoms of schizophrenia in an animal model. References [1] Frick, L.R., Williams, K., Pittenger, C., 2013. Microglial Dysregulation in Psychiatric Disease. Clinical and Developmental Immunology Article ID 608654, http://dx.doi.org/10.1155/2013/608654. [2] Cosenza-Nashat, M., Zhao, M.L., Suh, H.S., et al., 2009. Expression of the translocator protein of 18kDa by microglia, macrophages and astrocytes based on immunohistochemical localization in abnormal human brain. Neuropathol Appl Neurobiol. 35:306−32. [3] Chaudhry, I.B., 2012. Minocycline benefits negative symptoms in early schizophrenia: a randomised double-blind placebo-controlled clinical trial in patients on standard treatment J Psychopharmacol September 26: 1185–1193, first published on April 23, 2012.
S.15.03 Anti-NMDA receptor encephalitis mimicking schizophrenia: diagnosis and treatment M.J. Titulaer1 ° 1 Erasmus University Medical Center, Department of Neurology, Rotterdam, The Netherlands In the last years several novel autoimmune disorders were identified that associate with neuropsychiatric symptoms. These dis-
S.16. Junior Scientist symposium − Novel pathophysiological insights into the causes of brain disorders eases share the presence of antibodies against extracellular epitopes of neuronal cell surface proteins or synaptic receptors that are involved in neuronal transmission and excitability, like the NMDA receptor. These disorders affect patients of all ages and are severe but responsive to immunotherapy. Psychiatric symptoms are the first symptom in 65% of adult patients, and 44% of children [1]. Overall, 97% of patients will have any psychiatric involvement, comprising all types of psychotic behavior. Pure psychiatric forms of anti-NMDA receptor encephalitis have been described [2], and have raised serious interest in the psychiatric society. Unfortunately, studies using different clinical criteria, and different assays have caused confusion. Areas of concern consisted of inclusion of patients with clear neurological symptoms like tonic-clonic seizures, and the lack of robust laboratory checks to avoid false-positives. Serum testing can be both false-positive and false-negative [3]. Large-scale well-defined cohorts have shown that anti-NMDAR encephalitis mainly mimics 1st episode psychosis, and is rare in patients with clear schizophrenia [4,5]. Most patients will develop other neuropsychiatric symptoms within the first four weeks of disease [2]. Extrapyramidal side-effects of haloperidol are almost invariably present. Due to the low prior chance, antibody confirmation in cerebrospinal fluid is essential in patients with serum NMDARantibodies; similarly cerebrospinal fluid should be tested if serum tests negative and suspicion remains high. As treatment with immunotherapy is rewarding, the importance of diagnosing of anti-NMDA receptor encephalitis cannot be overestimated [1]. References [1] Titulaer MJ, McCracken L, Gabilondo I, et al., 2013. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurology 12, 157–165. [2] Kayser MS, Titulaer MJ, Gresa-Arribas N, Dalmau J, 2014. Frequency and characteristics of isolated psychiatric episodes in anti-N-methyl-Daspartate receptor encephalitis. JAMA Neurology 70, 1133–1139. [3] Gresa-Arribas N*, Titulaer MJ*, Torrents A, et al., 2014. Antibody titres at diagnosis and follow-up of anti-NMDA receptor encephalitis: a retrospective study. Lancet Neurology 13, 167–177. [4] Steiner J, Walter M, Glanz W, et al. 2013. Increased prevalence of diverse N-methyl-D-aspartate glutamate receptor antibodies in patients with an initial diagnosis of schizophrenia: specific relevance of IgG NR1a antibodies for distinction from N-methyl-D-aspartate glutamate receptor encephalitis. JAMA Psychiatry 70, 271–278. [5] De Witte LD, Hoffmann C, van Mierlo HC, Titulaer MJ, Kahn RS, Martinez-Martinez P, 2015. Absence of N-methyl-D-aspartate-receptor IgG autoantibodies in schizophrenia: the importance of cross-validation studies. JAMA Psychiatry 72:731–733. Disclosure statement: Dr. Titulaer has been supported by grants from the Netherlands Organisation for Scientific Research (NWO, Veni-incentive and Memorabel fellowship), the Dutch Epilepsy Foundations (NEF, project 14−19), and an ErasmusMC fellowship. Dr. Titulaer received received research funds for serving on a scientific advisory board of MedImmune LLC., and a travel grant for lecturing in India from Sun Pharma, India.
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S.16. Junior Scientist symposium − Novel pathophysiological insights into the causes of brain disorders S.16.01 The “stressed” autophagy: chronic stress exacerbates Tau pathology by blocking autophagy clearance system J. Silva1 ° , S. Rodrigues1 , M. Marques1 , C. Soares-Cunha1 , P. Ludovico1 , N. Sousa1 , I. Sotiropoulos1 1 Life and Health Sciences Research Institute ICVS/ ICVS/3B’s - PT Government Associate Laboratory, School of Health Sciences- University of Minho, Braga, Portugal Aggregation of the cytoskeletal protein Tau is a common neurodegenerative feature in Alzheimer’s disease (AD) and other Tauopathies. Consistent with suggestions that lifetime stress may be an important precipitating factor of AD pathology, triggering Tau accumulation and aggregation [1,2], we aimed to clarify the impact of chronic stress on autophagy clearance system using both animal and cellular models of Tau pathology expressing P301L-hTau [3]. We show that P301L-Tg mice exposed to chronic unpredictable stress (CUS) [2] exhibited deficits in behavioral flexibility and working memory, and anxious-like behavior. Further molecular analysis showed that CUS induced a blockage of autophagy clearance machinery, which was shown to be dependent on mTOR activation, as stress decreased levels of p-S6K, p-p38 and PI3K. The above stress-triggered autophagic blockage was accompanied by an increase in Sarkosyl-insoluble Tau protein levels and related cell loss in PFC of P301L-mice. As GC are responsible for many detrimental effects of chronic stress and thus, often used to clarify the stress molecular “signature”, we treated P301L-Tau-expressing SHSY5Y cells with Dexamethasone (DEX). DEX mimicked the stress-evoked blockage of autophagy leading to Tau accumulation and related cell death. Moreover, co-treatment with CCI-779 (Temsirolimus), established stimulator of autophagy, attenuated the DEX effects, normalizing Tau levels. Altogether, these findings demonstrate that chronic stress trigger Tau aggregation pathology through the blockage of autophagy, leading to neuronal loss in PFC and related cognitive and mood deficits. This work provides novel insights into the molecular mechanisms through which chronic stress and elevated GC may precipitate AD pathology. References [1] Sotiropoulos, I., Catania, C., Pinto, L.G., Silva, R., Pollerberg, G.E., Takashima, A., Sousa, N., Almeida, O.F.X., 2011. Stress acts cumulatively to precipitate Alzheimer’s disease-like Tau pathology and cognitive deficits. J Neurosci 31, 7840–7847. [2] Sotiropoulos, I., Silva, J., Kimura, T., Rodrigues, A.J., Costa, P., Almeida, O.F.X., Sousa, N., Takashima, A., 2015. Female hippocampus vulnerability to environmental stress as precipitating factor of Tau aggregation pathology. Journal of Alzheimer’s Disease 43(3):763−74. [3] Kimura, T., Fukuda, T., Sahara, N., Yamashita, S., Murayama, M., Mizoroki, T., Yoshiike, Y., Lee, B., Sotiropoulos, I., Maeda, S., Takashima, A., 2010. Aggregation of detergent-insoluble Tau is involved in neuronal loss but not in synaptic loss. J Biol Chem 285, 38692–38699.
S.15. Inflammation in psychosis: diagnosis and treatment
The present results suggest sex and anxious features as important variables to be considered in pharmacogenetic studies. Additionally, a combined pharmacogenetic/epigenetic approach is expected to aid in establishing more robust biomarkers of treatment response and thereby to contribute to the development of a personalized treatment of major depression.
S.15. Inflammation in psychosis: diagnosis and treatment S.15.01 Imaging neuroinflammation in schizophrenia and depression with PET R. Mizrahi1 ° 1 Centre for Addiction and Mental Health, Research Imaging Centre, Toronto- Ontario, Canada The neuroinflammatory hypothesis of schizophrenia (SCZ) and major depressive disorder (MDE) is supported by several previous findings. These include, but are not limited to, immune activation, increased peripheral markers of inflammation frequently reported and some positive postmortem studies. However, a fundamental limitation of the neuroinflammatory hypothesis is a paucity of evidence of brain inflammation in-vivo in during SCZ and MDE. Translocator protein density measured by distribution volume (TSPO VT) is increased in activated microglia, an important marker of neuroinflammation. We will present work of Dr. Mizrahi’s lab and Dr. Meyer’s lab testing whether TSPO VT is elevated in-vivo in brain in SCZ and MDE. Together, we have scanned 18 untreated first episode of psychosis (FEP) and 20 MDE patients, who were compared to matched healthy volunteer (HV) samples. We used a novel 2nd generation TSPO radiotracer ([18 F]FEPPA) and incorporated the impact of TSPO genotype (rs 6971) on all analyses. Data was analyzed using the 2 tissue compartment model (2TCM) to obtain the validate outcome measure VT. First, we found no significant difference in [18 F]FEPPA VT in any ROIs between HV and untreated patients with FEP. However, in MDE, TSPO VT was significantly elevated in all ROIs examined (multivariate analysis of variance, F15,23 = 4.5 [P = 0.001]). The magnitude of TSPO VT elevation was 26% in prefrontal cortex and 32% in the ACC of MDE patients. Results from these studies suggest that neuroinflammation might be disease specific or that significant variation exists among patients or disease progression stages. References [1] Setiawan E, Wilson A, Mizrahi R, Rusjan P, Miler L, Rajkowska G, Suridjan I, Kennedy J, Rekkas P, Houle S, Meyer JH. 2015. Role of translocator protein density, a marker of neuroinflammation, in the brain during major depressive episodes. Jama Psychiatry 72, 268−75. [2] Kenk M, Selvanathan T, Rao N, Suridjan I, Rusjan P, Remington G, Meyer JH, Wilson A, Houle S, Mizrahi R. 2015. Imaging neuroinflammation in gray and white matter in schizophrenia: an in-vivo PET study with [18 F]-FEPPA. Schizophrenia Bulletin 41, 85−93. [3] Suridjan I, Rusjan P, Kenk M, Verhoeff N, Voineskos A, Rotenberg D, Wilson A, Meyer J, Houle S, Mizrahi R. 2014. Quantitative imaging of neuroinflammation in human white matter: a positron emission tomography study with translocator protein 18 kDa radioligand, [18 F]FEPPA, Synapse 68, 536−47.
S.15.02 Targetting microglia activation in schizophrenia by minocycline treatment D. Mattei1 , A. Ivanov2 , G. Ferrai3 , P. Jordan1 , D. Guneykaya1 , W. Schaafsma4 , P. Przanowski5 , W. Deuther-Conrad6 , P. Brust6 , S. Hesse7 , B. Eggen4 , E. Bodekke4 , B. Kaminska5 , A. Pombo3 , H. Kettenmann1 , S.A. Wolf1 ° 1 Max-Delbr¨uckCenter of Molecular Medicine, Cellular Neuroscience, Berlin, Germany; 2 BIH, Bioinformatic Core facility, Berlin, Germany; 3 Max-Delbr¨uck-Center of Molecular Medicine, BIMSBI, Berlin, Germany; 4 University of Groningen, Neuroscience, Groningen, The Netherlands; 5 Nencki Institute, Neuroscience, Warszawa, Poland; 6 Helmholtz Zentrum Dresden Rossendorf- Forschungsstelle Leipzig, Neuroradiopharmaceutical, Leipzig, Germany; 7 University of Leipzig, NeuroradiologyNuclearmedicine, Leipzig, Germany The importance of the brain’s phagocyte − the microglia − came recently into focus as a novel therapeutic target in psychiatric disorders1. Dysregulations of microglia have been reported in post mortem tissue and also in vivo by increased radio ligand binding to the (phagocyte-specific) TSPO receptor in brains of schizophrenic patients2. The tetracycline minocycline that partially acts on microglia has been shown to improve mainly negative symptoms in a few clinical studies3. We here use an animal model of maternal immune activation to test its validity for clinical translation and investigate the pathways that are targeted by minocycline specific in microglia. Pregnant dams were injected intraperitoneally with the viral mimic PolyI:C or saline at gestational day 15 and the offspring was tested for behavioral deficits at postnatal day 60. Indeed, the offspring showed behavioral correlates of schizophrenia like decreased pre-pulse inhibition, sociability and cognitive performance along with an increased binding potential to the TSPO shown by autoradiography using [18 F]GE-180 on hippocampal slices. This was accompanied by a profoundly altered transcriptome signature in hippocampal microglia and decreased phagocytic activity. Thereafter, mice were treated for five weeks with minocycline (3 mg/kg/day). This treatment normalized the behavioral deficits, TSPO binding and phagocytic activity and restored the transcriptome signature towards control levels. Our findings indicate that minocycline is a potent drug to affect specific microglial functions and thereby attenuate symptoms of schizophrenia in an animal model. References [1] Frick, L.R., Williams, K., Pittenger, C., 2013. Microglial Dysregulation in Psychiatric Disease. Clinical and Developmental Immunology Article ID 608654, http://dx.doi.org/10.1155/2013/608654. [2] Cosenza-Nashat, M., Zhao, M.L., Suh, H.S., et al., 2009. Expression of the translocator protein of 18kDa by microglia, macrophages and astrocytes based on immunohistochemical localization in abnormal human brain. Neuropathol Appl Neurobiol. 35:306−32. [3] Chaudhry, I.B., 2012. Minocycline benefits negative symptoms in early schizophrenia: a randomised double-blind placebo-controlled clinical trial in patients on standard treatment J Psychopharmacol September 26: 1185–1193, first published on April 23, 2012.
S.15.03 Anti-NMDA receptor encephalitis mimicking schizophrenia: diagnosis and treatment M.J. Titulaer1 ° 1 Erasmus University Medical Center, Department of Neurology, Rotterdam, The Netherlands In the last years several novel autoimmune disorders were identified that associate with neuropsychiatric symptoms. These dis-
S.16. Junior Scientist symposium − Novel pathophysiological insights into the causes of brain disorders eases share the presence of antibodies against extracellular epitopes of neuronal cell surface proteins or synaptic receptors that are involved in neuronal transmission and excitability, like the NMDA receptor. These disorders affect patients of all ages and are severe but responsive to immunotherapy. Psychiatric symptoms are the first symptom in 65% of adult patients, and 44% of children [1]. Overall, 97% of patients will have any psychiatric involvement, comprising all types of psychotic behavior. Pure psychiatric forms of anti-NMDA receptor encephalitis have been described [2], and have raised serious interest in the psychiatric society. Unfortunately, studies using different clinical criteria, and different assays have caused confusion. Areas of concern consisted of inclusion of patients with clear neurological symptoms like tonic-clonic seizures, and the lack of robust laboratory checks to avoid false-positives. Serum testing can be both false-positive and false-negative [3]. Large-scale well-defined cohorts have shown that anti-NMDAR encephalitis mainly mimics 1st episode psychosis, and is rare in patients with clear schizophrenia [4,5]. Most patients will develop other neuropsychiatric symptoms within the first four weeks of disease [2]. Extrapyramidal side-effects of haloperidol are almost invariably present. Due to the low prior chance, antibody confirmation in cerebrospinal fluid is essential in patients with serum NMDARantibodies; similarly cerebrospinal fluid should be tested if serum tests negative and suspicion remains high. As treatment with immunotherapy is rewarding, the importance of diagnosing of anti-NMDA receptor encephalitis cannot be overestimated [1]. References [1] Titulaer MJ, McCracken L, Gabilondo I, et al., 2013. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurology 12, 157–165. [2] Kayser MS, Titulaer MJ, Gresa-Arribas N, Dalmau J, 2014. Frequency and characteristics of isolated psychiatric episodes in anti-N-methyl-Daspartate receptor encephalitis. JAMA Neurology 70, 1133–1139. [3] Gresa-Arribas N*, Titulaer MJ*, Torrents A, et al., 2014. Antibody titres at diagnosis and follow-up of anti-NMDA receptor encephalitis: a retrospective study. Lancet Neurology 13, 167–177. [4] Steiner J, Walter M, Glanz W, et al. 2013. Increased prevalence of diverse N-methyl-D-aspartate glutamate receptor antibodies in patients with an initial diagnosis of schizophrenia: specific relevance of IgG NR1a antibodies for distinction from N-methyl-D-aspartate glutamate receptor encephalitis. JAMA Psychiatry 70, 271–278. [5] De Witte LD, Hoffmann C, van Mierlo HC, Titulaer MJ, Kahn RS, Martinez-Martinez P, 2015. Absence of N-methyl-D-aspartate-receptor IgG autoantibodies in schizophrenia: the importance of cross-validation studies. JAMA Psychiatry 72:731–733. Disclosure statement: Dr. Titulaer has been supported by grants from the Netherlands Organisation for Scientific Research (NWO, Veni-incentive and Memorabel fellowship), the Dutch Epilepsy Foundations (NEF, project 14−19), and an ErasmusMC fellowship. Dr. Titulaer received received research funds for serving on a scientific advisory board of MedImmune LLC., and a travel grant for lecturing in India from Sun Pharma, India.
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S.16. Junior Scientist symposium − Novel pathophysiological insights into the causes of brain disorders S.16.01 The “stressed” autophagy: chronic stress exacerbates Tau pathology by blocking autophagy clearance system J. Silva1 ° , S. Rodrigues1 , M. Marques1 , C. Soares-Cunha1 , P. Ludovico1 , N. Sousa1 , I. Sotiropoulos1 1 Life and Health Sciences Research Institute ICVS/ ICVS/3B’s - PT Government Associate Laboratory, School of Health Sciences- University of Minho, Braga, Portugal Aggregation of the cytoskeletal protein Tau is a common neurodegenerative feature in Alzheimer’s disease (AD) and other Tauopathies. Consistent with suggestions that lifetime stress may be an important precipitating factor of AD pathology, triggering Tau accumulation and aggregation [1,2], we aimed to clarify the impact of chronic stress on autophagy clearance system using both animal and cellular models of Tau pathology expressing P301L-hTau [3]. We show that P301L-Tg mice exposed to chronic unpredictable stress (CUS) [2] exhibited deficits in behavioral flexibility and working memory, and anxious-like behavior. Further molecular analysis showed that CUS induced a blockage of autophagy clearance machinery, which was shown to be dependent on mTOR activation, as stress decreased levels of p-S6K, p-p38 and PI3K. The above stress-triggered autophagic blockage was accompanied by an increase in Sarkosyl-insoluble Tau protein levels and related cell loss in PFC of P301L-mice. As GC are responsible for many detrimental effects of chronic stress and thus, often used to clarify the stress molecular “signature”, we treated P301L-Tau-expressing SHSY5Y cells with Dexamethasone (DEX). DEX mimicked the stress-evoked blockage of autophagy leading to Tau accumulation and related cell death. Moreover, co-treatment with CCI-779 (Temsirolimus), established stimulator of autophagy, attenuated the DEX effects, normalizing Tau levels. Altogether, these findings demonstrate that chronic stress trigger Tau aggregation pathology through the blockage of autophagy, leading to neuronal loss in PFC and related cognitive and mood deficits. This work provides novel insights into the molecular mechanisms through which chronic stress and elevated GC may precipitate AD pathology. References [1] Sotiropoulos, I., Catania, C., Pinto, L.G., Silva, R., Pollerberg, G.E., Takashima, A., Sousa, N., Almeida, O.F.X., 2011. Stress acts cumulatively to precipitate Alzheimer’s disease-like Tau pathology and cognitive deficits. J Neurosci 31, 7840–7847. [2] Sotiropoulos, I., Silva, J., Kimura, T., Rodrigues, A.J., Costa, P., Almeida, O.F.X., Sousa, N., Takashima, A., 2015. Female hippocampus vulnerability to environmental stress as precipitating factor of Tau aggregation pathology. Journal of Alzheimer’s Disease 43(3):763−74. [3] Kimura, T., Fukuda, T., Sahara, N., Yamashita, S., Murayama, M., Mizoroki, T., Yoshiike, Y., Lee, B., Sotiropoulos, I., Maeda, S., Takashima, A., 2010. Aggregation of detergent-insoluble Tau is involved in neuronal loss but not in synaptic loss. J Biol Chem 285, 38692–38699.