- Email: [email protected]
URSODEOXYCHOLIC ACID FOR THE TREATMENT OF TAUOPATHIES
P1270
Poster Presentations: Wednesday, July 19, 2017
pathogenesis. They also support the use of drugs restoring DNA methylation levels as a treatment for AD.
P4-036
THE NOVEL AMPA RECEPTOR POSITIVE ALLOSTERIC MODULATOR S 47445 RESCUES IN VIVO CA3-CA1 LONG-TERM POTENTIATION AND STRUCTURAL SYNAPTIC CHANGES IN MIDDLE-AGED MICE Gomez-Climent5, Sylvie Bretin1, Albert Giralt2,3,4, Marıa Angeles 2,4,6 7 Rafael Alcala , Jose Maria Delgado-Garcia , Esther Perez-Navarro2,4,6, Jordi Alberch2,4,6, Agnes Gruart7, 1Institut de Recherches Internationales Servier, Suresnes, France; 2Facultat de Medicina, Institut de Neurociencies, Universitat de Barcelona, Barcelona, Spain; 3(3) Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; 4Centro de Investigaci on Biomedica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; 5Pablo de Olavide University, Seville, Spain; 6 Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; 7University Pablo de Olavide, Seville, Spain. Contact e-mail: [email protected] Background: Positive allosteric modulators of AMPA receptors
(AMPA-PAMs) are small molecules that keep the AMPA receptor in an active state by decreasing deactivation or desensitization. They have been proposed to treat cognitive decline in dementias and Alzheimer disease (AD). S 47445 is a novel AMPA-PAM. Here, the mechanisms by which S 47445 could improve synaptic strengthen and connectivity were studied and compared between young (3-months old) and middle-aged freely moving mice (14months old). Methods: LTP was evoked at the CA3-CA1 synapse using high-frequency stimulation (HFS) protocol at two occasions on day 1 and on day 13 after the first administration of S 47445 (3mg/kg or 10mg/kg). Assessment of drug effect on LTP was performed after either acute or chronic treatment. The drug effect on micro-cytoarchitecture in hippocampal (CA1 and CA3) and cortical tissue (L2-3 and L5-6) was also evaluated by confocal microscopy by assessing number and size of positive particles for the presynaptic vesicular glutamate transporter VGlut1 and the postsynaptic protein spinophilin. Results: Middle-aged control mice displayed a marked significant deficit of LTP as compared to young control mice following the first presentation of the HFS protocol. After acute administration of S 47445 at 10mg/kg in middle-aged mice, a complete reversion of the LTP deficit was observed on day 1. Then, chronic treatment with S 47445 at 10mg/kg in middle-aged animals significantly counteracted the aged deficit of LTP. During the second HFS presentation, LTP was much smaller than during the previous acute experiment in each mice group, suggesting a loss of LTP-evoked phenomenon. Interestingly, the chronic administration of S 47445 at 10mg/kg in middle-aged mice induced significantly larger LTP values as compared to young control and middle-aged control mice. Moreover, chronic treatment with S 47445 at 10mg/kg significantly prevented the decrease in number and size of VGlut1 and spinophilin in CA1-CA3 and in the cortex of middle-aged mice. Conclusions: Collectively, by its different effects observed, S 47445 is able to modulate both the structure and function of hippocampal excitatory synapses known to be involved in learning and memory processes and could provide beneficial effects in dementias such as AD.
P4-037
IDENTIFICATION OF NOVEL TARGETS FOR INHIBITING PRION-LIKE SEEDING AND PROPAGATION OF TAU PATHOLOGY IN VITRO AND IN VIVO
Ilse Dewachter1, Ilie-Cosmin Stancu1, Alexandre Vanoosthuyse1, Arjan Buist2, Bruno Vasconcelos1, Peng Wang1,3, Pascal KienlenCampard1, Jean-No€el Octave1, Diederik Moechars2, 1Universite Catholique de Louvain, Brussels, Belgium; 2Janssen Research and Development, a division of Janssen Pharmaceutica, Beerse, Belgium; 3Institute of NeuroScience, Brussels, Belgium. Contact e-mail: ilse.dewachter@ uclouvain.be Background: In AD, Tau pathology progresses in a stereotypic
spatiotemporal pattern, strongly correlating with progression of disease symptoms. Prion-like propagation of Tau-pathology, or propagation of Tau-misfolding between cells and functionally connected brain regions, provides a compelling mechanism for this stereotypic progression of Tau-pathology, and hence an attractive therapeutic target. Methods: To test and validate novel therapeutic targets capable of inhibiting prion-like progression of Tau-pathology, we have generated combined in vitro and in vivo models recapitulating prion-like seeding and propagation of Tau-pathology. Seeding of pre-aggregated Tau in Tau expressing primary neurons and Tau transgenic mice recapitultes strong induction of Tau-pathology and propagation to the contralateral side. Results: Using these models we have analysed and evaluated the modifying potential of different targets on Tau pathology and propagation of Tau pathology. Targets under evaluation encompass Tau-interactome based Tau interacting proteins, including OTUB1 and other identified Tau-interacting proteins, as well as hypothesis based analysis. Within this analysis we identified OTUB1 as Tau deubiquitinase, involved in the accumulation of pathological forms of Tau. We furthermore identified novel targets with modifying effect on prion-like seeding and propagation of Tau-pathology. Conclusions: We here present the identification of different targets with a modulatory effect in vitro and in vivo on Tau-pathology and prion-like propagation of Tau-pathology.
P4-038
URSODEOXYCHOLIC ACID FOR THE TREATMENT OF TAUOPATHIES
Joseph F. Quinn1,2, Christopher Harris2, Carly Gray2, Andrea Debarber2, Nora E. Gray2, Don Matthews2, Maya Caruso2, Amala Soumyanath2, 1VA Portland Health Care System, Portland, OR, USA; 2Oregon Health and Science University, Portland, OR, USA. Contact e-mail: [email protected] Background: Ursodeoxycholic acid (UDCA) is a bile salt which is currently FDA-approved for the treatment of gallstones, and has also been shown to have neuroprotectant properties in a number of model systems. One of its metabolites, tauroursodeoxycholic acid (TUDCA) has shown neuroprotectant properties in cell culture models of tau neurotoxicity. We evaluated the neuroprotective effects of UDCA in animal models of tau-opathy. Methods: In experiment 1, h-tau mice (n¼31 males and females) and wildtype C57Bl mice (wt, n¼ 27 males and 26 females) were fed chow containing 0.4% UDCA or vehicle for 6 weeks, starting at age 16 months. At the end of 6 weeks, spatial memory was tested in Morris Water Maze and then mice were euthanized with terminal harvest of plasma and brain tissue for determination of plasma and brain UDCA and TUDCA levels, as well as brain levels of
Poster Presentations: Wednesday, July 19, 2017
phosphorylated tau. In experiment 2, PS19 mice were fed chow containing 0.4% UDCA or vehicle beginning at age 3 months and continuing until behavioral testing and sacrifice at age 9 months. Results: Experiment 1: UDCA was well tolerated, with no significant effects on body weight or survival. UDCA treatment was associated with improved Morris Water Maze performance in male h-tau mice (on Probe Test at 72 hours after training, wt mice spent 37% of time in target quadrant, vehicle treated h-tau mice 25%, UDCA treated htau mice 34%). Plasma UDCA ¼ 7206794 ng/ml in UDCA treated mice (n¼12) and 33648 (p¼0.006) in vehicle treated mice (n¼12). Brain UDCA ¼ 41650 pg/mg tissue in UDCA treated mice vs 661 (p¼0.02) for vehicle. Plasma TUDCA ¼ 3846130 ng/ml in UDCA treated mice vs 20637 (p<0.00001) in vehicle, and brain TUDCA¼ 766 pg/mg tissue in UDCA treated mice vs 0 in vehicle treated mice (p¼0.0002). The ratio of hippocampal phosphorylated tau: total tau was reduced in UDCA treated htau mice compared to vehicle-treated mice on Western blot. Experiment 2: Long-term UDCA has been well tolerated in PS19 mice. Analysis of behavior and brain tissue is ongoing. Conclusions: UDCA is well tolerated with chronic treatment, bioavailable, CNS-penetrant, and demonstrated neuroprotectant properties in preliminary studies in mouse models of tau-opathy.
P4-039
PAN-TAU ANTIBODY BIIB076 EXHIBITS PROMISING SAFETY AND BIOMARKER PROFILE IN CYNOMOLGUS MONKEY TOXICITY STUDY
Julie Czerkowicz1, Weiping Chen1, Qin Wang1, Chase Shen1, Carrie Wager1, Ivan Stone1, Chris Stebbins1, Martin Lamb1, John Setser2, Gina Cantone1, Danielle Graham1, 1Biogen, Cambridge, MA, USA; 2 Charles River Laboratories, Ashland, OH, USA. Contact e-mail: julie. [email protected] Background: BIIB076 (6C5 huIgG1/l) is a human anti-tau mono-
clonal antibody with the potential to be a disease-modifying treatment for mild to moderate Alzheimer’s disease (AD). BIIB076 binds with subnanomolar affinity to human and cynomolgus monkey recombinant tau. In addition, BIIB076 is known to bind monomeric and pre-formed fibrillar tau and human brain tau isolated from both healthy individuals and AD patients. The primary objective of this study was to evaluate the toxicity potential and toxicokinetic profile of BIIB076 in cynomolgus monkeys. The exploratory objective was to assess changes in CSF tau levels. Methods: Cynomolgus monkeys (24 male, 24 female) 2-4 years of age received BIIB076 on study days 0, 14 and 28, delivered either IV at approximately 2, 8 and 16-fold higher than the highest predicted efficacious dose, or SC at 16-fold over efficacious dose. One group of vehicle control treated monkeys was included. Forty animals were sacrificed at Day 42. Four animals in the vehicle group and highest IV dose group were sacrificed following a 10-week recovery period. Blood and CSF samples were taken during the study to measure drug and tau levels, respectively. Standard toxicology and histopathology evaluations were included. Serum drug concentrations were measured with an anti-idiotype immunoassay, and a novel bead-based assay was used to measure CSF tau levels. Both total tau and free tau (not bound to BIIB076) were measured.
P1271
Results: There were no adverse BIIB076-related toxicology changes or pathology related findings. Following IVadministration, BIIB076 exhibited dose dependent increases in serum exposures, which are nearly dose proportional. Exposure was observed with SC administration, with a bioavailability of 73-75%. CSF total and free tau levels were significantly reduced in the highest BIIB076 dose groups. Conclusions: These data have established a positive safety profile for BIIB076 for inclusion in a Phase 1, Single-Ascending Dose (SAD) clinical trial in healthy volunteers. In combination with the PK profile, we determined the safety margins over proposed doses in the SAD study. In addition, these data suggest that CSF tau will provide a useful endpoint to demonstrate biological activity in clinical trials.
P4-040
ROLE OF MICRORNAS IN ALZHEIMER’S DISEASE (AD)
Salil Sharma1, Yousuf Omar Ali1, Ines Khadimallah2, Adam Corya Williamson1, Hui-Chen Lu1, 1Indiana University, Bloomington, IN, USA; 2University of Lausanne, Lausanne, Switzerland. Contact e-mail: [email protected] Background: MicroRNAs (miRs) are small non-coding RNA
molecules that regulate gene expression. Circulating miRs in the plasma are very stable and are being explored as early-onset biomarkers to detect AD. Indeed, several studies have shown miR changes in AD patients (J Alzheimers Dis.2008May;14(1):27-41) Methods: rTg4510 mouse line overexpressing human P301L Tau only in the forebrain is a great animal model to examine miR changes resulting from forebrain Tau overexpression. RNA Deep Sequencing using Illumina platform (LC Sciences) was performed on hippocampus tissue and plasma samples at presymptomatic (2M: 3 littermate-pairs) and symptomatic (6M: 2 ctrls and 4 Tau) age. Bioinformatics analysis including differential miR expression, target analysis using Targetscan, miRanda and PITA, and pathway analysis was performed by AccuraScience. qPCR was performed using Taqman assays (Life Technologies). mRNA deep sequencing was performed on hippocampus tissue (2M: 3littermate-pairs) at IUSM. Results: For plasma, at 2M, 3 miRs were significantly upregulated and 5 miRs were downregulated and at 6M, 7 were significantly upregulated and 8 were downregulated (Tau vs Ctrl, P value <0.05). In the hippocampus, at 2M, 34 miRs were significantly upregulated and 101 miRs were downregulated and at 6M, 42 were significantly upregulated and 52 were downregulated (Tau vs Ctrl, P value <0.05). Target prediction by Targetscan, miRanda and PITA for differentially regulated miRs shows for plasma (2M: 463 up, 626 down; 6M: 112 up, 2501 down) and for hippocampus (2M: 34 up, 220 down; 6M: 399 up, 335 down). Several miRs identified by deep sequencing including miR219-5p and miR150 were validated at additional time points (Postnatalday 15, 1M, 2M and 6M) and increased animal number (n¼6-9) with qPCR. Several predicted target changes were also confirmed with qPCR. Currently, we are analyzing the expression of in-silico targets of altered miRs in 2M hippocampi of Tau mice by mRNA deep sequencing. Pathway/network analysis will be conducted using DAVID and Diana-miRPath. Conclusions: New pathways were identified from target prediction of miRs including chemokine signaling pathway. More information will be acquired with mRNA
Poster Presentations: Wednesday, July 19, 2017
pathogenesis. They also support the use of drugs restoring DNA methylation levels as a treatment for AD.
P4-036
THE NOVEL AMPA RECEPTOR POSITIVE ALLOSTERIC MODULATOR S 47445 RESCUES IN VIVO CA3-CA1 LONG-TERM POTENTIATION AND STRUCTURAL SYNAPTIC CHANGES IN MIDDLE-AGED MICE Gomez-Climent5, Sylvie Bretin1, Albert Giralt2,3,4, Marıa Angeles 2,4,6 7 Rafael Alcala , Jose Maria Delgado-Garcia , Esther Perez-Navarro2,4,6, Jordi Alberch2,4,6, Agnes Gruart7, 1Institut de Recherches Internationales Servier, Suresnes, France; 2Facultat de Medicina, Institut de Neurociencies, Universitat de Barcelona, Barcelona, Spain; 3(3) Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; 4Centro de Investigaci on Biomedica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; 5Pablo de Olavide University, Seville, Spain; 6 Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; 7University Pablo de Olavide, Seville, Spain. Contact e-mail: [email protected] Background: Positive allosteric modulators of AMPA receptors
(AMPA-PAMs) are small molecules that keep the AMPA receptor in an active state by decreasing deactivation or desensitization. They have been proposed to treat cognitive decline in dementias and Alzheimer disease (AD). S 47445 is a novel AMPA-PAM. Here, the mechanisms by which S 47445 could improve synaptic strengthen and connectivity were studied and compared between young (3-months old) and middle-aged freely moving mice (14months old). Methods: LTP was evoked at the CA3-CA1 synapse using high-frequency stimulation (HFS) protocol at two occasions on day 1 and on day 13 after the first administration of S 47445 (3mg/kg or 10mg/kg). Assessment of drug effect on LTP was performed after either acute or chronic treatment. The drug effect on micro-cytoarchitecture in hippocampal (CA1 and CA3) and cortical tissue (L2-3 and L5-6) was also evaluated by confocal microscopy by assessing number and size of positive particles for the presynaptic vesicular glutamate transporter VGlut1 and the postsynaptic protein spinophilin. Results: Middle-aged control mice displayed a marked significant deficit of LTP as compared to young control mice following the first presentation of the HFS protocol. After acute administration of S 47445 at 10mg/kg in middle-aged mice, a complete reversion of the LTP deficit was observed on day 1. Then, chronic treatment with S 47445 at 10mg/kg in middle-aged animals significantly counteracted the aged deficit of LTP. During the second HFS presentation, LTP was much smaller than during the previous acute experiment in each mice group, suggesting a loss of LTP-evoked phenomenon. Interestingly, the chronic administration of S 47445 at 10mg/kg in middle-aged mice induced significantly larger LTP values as compared to young control and middle-aged control mice. Moreover, chronic treatment with S 47445 at 10mg/kg significantly prevented the decrease in number and size of VGlut1 and spinophilin in CA1-CA3 and in the cortex of middle-aged mice. Conclusions: Collectively, by its different effects observed, S 47445 is able to modulate both the structure and function of hippocampal excitatory synapses known to be involved in learning and memory processes and could provide beneficial effects in dementias such as AD.
P4-037
IDENTIFICATION OF NOVEL TARGETS FOR INHIBITING PRION-LIKE SEEDING AND PROPAGATION OF TAU PATHOLOGY IN VITRO AND IN VIVO
Ilse Dewachter1, Ilie-Cosmin Stancu1, Alexandre Vanoosthuyse1, Arjan Buist2, Bruno Vasconcelos1, Peng Wang1,3, Pascal KienlenCampard1, Jean-No€el Octave1, Diederik Moechars2, 1Universite Catholique de Louvain, Brussels, Belgium; 2Janssen Research and Development, a division of Janssen Pharmaceutica, Beerse, Belgium; 3Institute of NeuroScience, Brussels, Belgium. Contact e-mail: ilse.dewachter@ uclouvain.be Background: In AD, Tau pathology progresses in a stereotypic
spatiotemporal pattern, strongly correlating with progression of disease symptoms. Prion-like propagation of Tau-pathology, or propagation of Tau-misfolding between cells and functionally connected brain regions, provides a compelling mechanism for this stereotypic progression of Tau-pathology, and hence an attractive therapeutic target. Methods: To test and validate novel therapeutic targets capable of inhibiting prion-like progression of Tau-pathology, we have generated combined in vitro and in vivo models recapitulating prion-like seeding and propagation of Tau-pathology. Seeding of pre-aggregated Tau in Tau expressing primary neurons and Tau transgenic mice recapitultes strong induction of Tau-pathology and propagation to the contralateral side. Results: Using these models we have analysed and evaluated the modifying potential of different targets on Tau pathology and propagation of Tau pathology. Targets under evaluation encompass Tau-interactome based Tau interacting proteins, including OTUB1 and other identified Tau-interacting proteins, as well as hypothesis based analysis. Within this analysis we identified OTUB1 as Tau deubiquitinase, involved in the accumulation of pathological forms of Tau. We furthermore identified novel targets with modifying effect on prion-like seeding and propagation of Tau-pathology. Conclusions: We here present the identification of different targets with a modulatory effect in vitro and in vivo on Tau-pathology and prion-like propagation of Tau-pathology.
P4-038
URSODEOXYCHOLIC ACID FOR THE TREATMENT OF TAUOPATHIES
Joseph F. Quinn1,2, Christopher Harris2, Carly Gray2, Andrea Debarber2, Nora E. Gray2, Don Matthews2, Maya Caruso2, Amala Soumyanath2, 1VA Portland Health Care System, Portland, OR, USA; 2Oregon Health and Science University, Portland, OR, USA. Contact e-mail: [email protected] Background: Ursodeoxycholic acid (UDCA) is a bile salt which is currently FDA-approved for the treatment of gallstones, and has also been shown to have neuroprotectant properties in a number of model systems. One of its metabolites, tauroursodeoxycholic acid (TUDCA) has shown neuroprotectant properties in cell culture models of tau neurotoxicity. We evaluated the neuroprotective effects of UDCA in animal models of tau-opathy. Methods: In experiment 1, h-tau mice (n¼31 males and females) and wildtype C57Bl mice (wt, n¼ 27 males and 26 females) were fed chow containing 0.4% UDCA or vehicle for 6 weeks, starting at age 16 months. At the end of 6 weeks, spatial memory was tested in Morris Water Maze and then mice were euthanized with terminal harvest of plasma and brain tissue for determination of plasma and brain UDCA and TUDCA levels, as well as brain levels of
Poster Presentations: Wednesday, July 19, 2017
phosphorylated tau. In experiment 2, PS19 mice were fed chow containing 0.4% UDCA or vehicle beginning at age 3 months and continuing until behavioral testing and sacrifice at age 9 months. Results: Experiment 1: UDCA was well tolerated, with no significant effects on body weight or survival. UDCA treatment was associated with improved Morris Water Maze performance in male h-tau mice (on Probe Test at 72 hours after training, wt mice spent 37% of time in target quadrant, vehicle treated h-tau mice 25%, UDCA treated htau mice 34%). Plasma UDCA ¼ 7206794 ng/ml in UDCA treated mice (n¼12) and 33648 (p¼0.006) in vehicle treated mice (n¼12). Brain UDCA ¼ 41650 pg/mg tissue in UDCA treated mice vs 661 (p¼0.02) for vehicle. Plasma TUDCA ¼ 3846130 ng/ml in UDCA treated mice vs 20637 (p<0.00001) in vehicle, and brain TUDCA¼ 766 pg/mg tissue in UDCA treated mice vs 0 in vehicle treated mice (p¼0.0002). The ratio of hippocampal phosphorylated tau: total tau was reduced in UDCA treated htau mice compared to vehicle-treated mice on Western blot. Experiment 2: Long-term UDCA has been well tolerated in PS19 mice. Analysis of behavior and brain tissue is ongoing. Conclusions: UDCA is well tolerated with chronic treatment, bioavailable, CNS-penetrant, and demonstrated neuroprotectant properties in preliminary studies in mouse models of tau-opathy.
P4-039
PAN-TAU ANTIBODY BIIB076 EXHIBITS PROMISING SAFETY AND BIOMARKER PROFILE IN CYNOMOLGUS MONKEY TOXICITY STUDY
Julie Czerkowicz1, Weiping Chen1, Qin Wang1, Chase Shen1, Carrie Wager1, Ivan Stone1, Chris Stebbins1, Martin Lamb1, John Setser2, Gina Cantone1, Danielle Graham1, 1Biogen, Cambridge, MA, USA; 2 Charles River Laboratories, Ashland, OH, USA. Contact e-mail: julie. [email protected] Background: BIIB076 (6C5 huIgG1/l) is a human anti-tau mono-
clonal antibody with the potential to be a disease-modifying treatment for mild to moderate Alzheimer’s disease (AD). BIIB076 binds with subnanomolar affinity to human and cynomolgus monkey recombinant tau. In addition, BIIB076 is known to bind monomeric and pre-formed fibrillar tau and human brain tau isolated from both healthy individuals and AD patients. The primary objective of this study was to evaluate the toxicity potential and toxicokinetic profile of BIIB076 in cynomolgus monkeys. The exploratory objective was to assess changes in CSF tau levels. Methods: Cynomolgus monkeys (24 male, 24 female) 2-4 years of age received BIIB076 on study days 0, 14 and 28, delivered either IV at approximately 2, 8 and 16-fold higher than the highest predicted efficacious dose, or SC at 16-fold over efficacious dose. One group of vehicle control treated monkeys was included. Forty animals were sacrificed at Day 42. Four animals in the vehicle group and highest IV dose group were sacrificed following a 10-week recovery period. Blood and CSF samples were taken during the study to measure drug and tau levels, respectively. Standard toxicology and histopathology evaluations were included. Serum drug concentrations were measured with an anti-idiotype immunoassay, and a novel bead-based assay was used to measure CSF tau levels. Both total tau and free tau (not bound to BIIB076) were measured.
P1271
Results: There were no adverse BIIB076-related toxicology changes or pathology related findings. Following IVadministration, BIIB076 exhibited dose dependent increases in serum exposures, which are nearly dose proportional. Exposure was observed with SC administration, with a bioavailability of 73-75%. CSF total and free tau levels were significantly reduced in the highest BIIB076 dose groups. Conclusions: These data have established a positive safety profile for BIIB076 for inclusion in a Phase 1, Single-Ascending Dose (SAD) clinical trial in healthy volunteers. In combination with the PK profile, we determined the safety margins over proposed doses in the SAD study. In addition, these data suggest that CSF tau will provide a useful endpoint to demonstrate biological activity in clinical trials.
P4-040
ROLE OF MICRORNAS IN ALZHEIMER’S DISEASE (AD)
Salil Sharma1, Yousuf Omar Ali1, Ines Khadimallah2, Adam Corya Williamson1, Hui-Chen Lu1, 1Indiana University, Bloomington, IN, USA; 2University of Lausanne, Lausanne, Switzerland. Contact e-mail: [email protected] Background: MicroRNAs (miRs) are small non-coding RNA
molecules that regulate gene expression. Circulating miRs in the plasma are very stable and are being explored as early-onset biomarkers to detect AD. Indeed, several studies have shown miR changes in AD patients (J Alzheimers Dis.2008May;14(1):27-41) Methods: rTg4510 mouse line overexpressing human P301L Tau only in the forebrain is a great animal model to examine miR changes resulting from forebrain Tau overexpression. RNA Deep Sequencing using Illumina platform (LC Sciences) was performed on hippocampus tissue and plasma samples at presymptomatic (2M: 3 littermate-pairs) and symptomatic (6M: 2 ctrls and 4 Tau) age. Bioinformatics analysis including differential miR expression, target analysis using Targetscan, miRanda and PITA, and pathway analysis was performed by AccuraScience. qPCR was performed using Taqman assays (Life Technologies). mRNA deep sequencing was performed on hippocampus tissue (2M: 3littermate-pairs) at IUSM. Results: For plasma, at 2M, 3 miRs were significantly upregulated and 5 miRs were downregulated and at 6M, 7 were significantly upregulated and 8 were downregulated (Tau vs Ctrl, P value <0.05). In the hippocampus, at 2M, 34 miRs were significantly upregulated and 101 miRs were downregulated and at 6M, 42 were significantly upregulated and 52 were downregulated (Tau vs Ctrl, P value <0.05). Target prediction by Targetscan, miRanda and PITA for differentially regulated miRs shows for plasma (2M: 463 up, 626 down; 6M: 112 up, 2501 down) and for hippocampus (2M: 34 up, 220 down; 6M: 399 up, 335 down). Several miRs identified by deep sequencing including miR219-5p and miR150 were validated at additional time points (Postnatalday 15, 1M, 2M and 6M) and increased animal number (n¼6-9) with qPCR. Several predicted target changes were also confirmed with qPCR. Currently, we are analyzing the expression of in-silico targets of altered miRs in 2M hippocampi of Tau mice by mRNA deep sequencing. Pathway/network analysis will be conducted using DAVID and Diana-miRPath. Conclusions: New pathways were identified from target prediction of miRs including chemokine signaling pathway. More information will be acquired with mRNA