- Email: [email protected]
MicroRNA-132 loss is associated with tau exon 10 inclusion in progressive supranuclear palsy
Developing Topics that critically regulate Aß transport at the BBB and that may be influenced by vascular challenges. Methods: Transverse aortic coarctation (TAC) was performed in mice to induce chronic hypertension. RAGE activation was analyzed at different time points after TAC and then we used mice with genetic ablation of this receptor to disclose whether the phenotype of hypertensive mice recapitulating AD traits was dependent on RAGE activation. Cognitive performance was evaluated by Morris Water Maze and brains were analyzed for Aß deposition. Results: We found that the hypertensive challenge had an early and sustained effect of up-regulation of RAGE expression in cortex and hippocampus, almost exclusively localized in brain vessels. The increased expression of RAGE was preceded by a peak in circulating Advanced Glycation End-products (AGEs) in TAC mice at early time points. Furthermore, a daily oral treatment an inhibitor of AGEs, during the hypertensive challenge, prevented both the early and the sustained increase in RAGE expression. Interestingly, RAGE ablation protected mice from memory impairment and parenchymal Aß deposition. However, a striking characteristic showed by hypertensive mice lacking RAGE was a strong Aß accumulation confined to cerebral blood vessels. These results also suggest that RAGE deficiency modulate equilibrium of Aß between vasculature and cerebral parenchyma via facilitating efflux of Aß from the brain. Conclusions: Overall we demonstrate that RAGE activation is a crucial pathogenetic event in vascular-related AD, thus suggesting that this therapeutic target could be more successful in the subset of AD patients with vascular related pathology.
O4-06-06
48-WEEK EFFICACY AND TOLERABILITY OF TREATMENT WITH SB-742457, A NOVEL 5HT6 RECEPTOR ANTAGONIST, WHEN ADDED ON TO DONEPEZIL IN SUBJECTS WITH MILD-TOMODERATE ALZHEIMER’S DISEASE (AD)
Gareth Maher-Edwards1, John Ascher2, Carolyn Watson1, Marina Zvartau-Hind1, Carly Donovan1, John Davies1, Beth Safirstein3, Orazio Zanetti4, Manuel Fernandez5, Michael Gold6, 1GlaxoSmithKline, Stockley Park, Middlesex, United Kingdom; 2GlaxoSmithKline, Research Triangle Park, North Carolina, United States; 3MD Clinical, Hallandale Beach, Florida, United States; 4IRCCS S. Giovanni di Dio Fatebenefratelli Brescia, Brescia, Lombardia, Italy; 5Hospital de Cruces, Basque Country, Spain; 6Allon Therapeutics, Vancouver, British Columbia, Canada. Background: SB-742457 is a novel and potent 5-hydroxytryptamine-6 (5HT6) receptor antagonist. Methods: In this 48-week, double-blind, randomized study (AZ3110866), 684 subjects with mild/moderate AD (MMSE score 10-26) received placebo (n ¼ 226), SB-742457 15mg (n ¼ 221) or SB-742457 35mg (n ¼ 237) added to donepezil(D) 5-10mg for an initial 24 weeks and were allowed to continue for an additional 24 weeks of treatment. The co-primary efficacy measures were the Alzheimer’s disease Assessment Scale-cognitive subscale (ADAS-Cog) and Clinical Dementia Rating-Sum of Boxes (CDR-SB). The primary analysis was based on the change from baseline on the ADAS-Cog and CDR-SB at Week 24 using an intention-to-treat [ITT], mixed model repeated measures model (reported separately 2011 ICAD presentation #02-05-02). Efficacy data were also collected at Weeks 12, 36 and 48 (secondary). Other secondary measures included the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the Alzheimer’s Disease Co-operative Study Group-Activities of Daily Living Inventory (ADCS-ADL) measured at Weeks 12, 24, 36 and 48. Safety and tolerability were assessed. No alpha adjustment was made for co-primary endpoints. Results: 67%, 67% and 73% of subjects completed Week 48 for placebo, SB-742457 15mg and SB-742457 35mg, respectively. As previously reported at Week 24, statistically significant treatment differences were observed for SB-742457 35mg vs. placebo for ADAS-Cog and ADCS-ADL but not for the CDR-SB or RBANS. Treatment differences at Week 48 were similar and remained statistically significant for ADAS-Cog (p ¼ 0.024) but not for ADCS-ADL (p ¼ 0.088). No significant difference was seen for CDR-SB or RBANS total scores at Week 48. No statistically significant treatment differences were observed between SB-742457 15mg and pla-
e5
cebo. All treatments were generally safe and well tolerated over 48 weeks. The proportion of subjects reporting adverse events (AEs) were 56%, 62% and 62% for placebo, SB-742457 15mg and SB-742457 35mg, respectively. The most commonly reported AEs were nasopharyngitis and urinary tract infection. Conclusions: Compared with donepezil alone, treatment with SB-742457 35mg added to stable donepezil demonstrated improvements in cognitive and functional status after 24 weeks which were largely maintained at 48 weeks. The combination was well tolerated. Further investigation into the effects of SB-742457 as an adjunct therapy is warranted.
O4-08-01
MICRORNA-132 LOSS IS ASSOCIATED WITH TAU EXON 10 INCLUSION IN PROGRESSIVE SUPRANUCLEAR PALSY
Pascal Smith1, Charlotte Delay1, Emmanuel Planel1, Nicolas Sergeant2, Luc Buee2, Sebastien Hebert1, 1Laval University, CRCHUQ (CHUL), Quebec, Quebec, Canada; 2Inserm University of Lille, Lille, France. Background: Mutations affecting tau exon 10 splicing, leading to an imbalance between three-repeat (3R) and four-repeat (4R) tau isoforms, can cause rare forms of frontotemporal dementia linked with parkinsonism at chromosome 17 (FTDP-17). Despite certain advances in the identification of cis- an trans-regulators of tau exon 10 splicing in vitro, little is know about the physiological mechanisms affecting tau splicing in sporadic tauopathies. The past years have witnessed an explosion of papers linking microRNA dysregulation to human disease, including neurodegenerative disorders. In addition, accumulating data point to a role for microRNAs in the regulation of pre-mRNA alternative splicing. Methods: In attempt to identify novel factors involved in tau exon 10 alternative splicing regulation, we performed global microRNA expression profiling from progressive supranuclear palsy (PSP) patients, a major 4R-tau tauopathy. Results: Our screens identified neuronal miR-132 to be specifically down-regulated in disease. Using bioinformatics and functional assays in cells, we show that miR-132 targets the neuronal splicing factor PTBP2/ nPTB, which was up-regulated in PSP brain. miR-132 overexpression or PTBP2 knockdown affected similarly tau exon 10 splicing and 4R:3Rtau ratios at endogenous levels of expression in neuronal cells. Finally, we demonstrate that miR-132 is inversely correlated with PTBP2 during post-natal brain development at the time when 4R-tau becomes expressed. Conclusions: Taken together, our results provide strong evidence that the miR-132/PTBP2 pathway is involved in tau exon 10 splicing regulation in neurons, and support the idea that changes in the microRNA network may contribute to sporadic tauopathic brain.
O4-08-02
SPECIFIC Ab OLIGOMERS AND THE TAU/Ab42 RATIO CORRELATE IN LUMBAR PUNCTURE CSF
Maureen Handoko1, Anders Wallin2, Kaj Blennow2, Karen Ashe1, 1N. Bud Grossman Center for Memory Research and Care, University of Minnesota, Minneapolis, Minnesota, United States; 2Sahlgrenska Academy at the University of Gothenburg, M€olndal, Sweden. Background: A growing body of evidence has led to the identification of a preclinical phase of Alzheimer’s disease (AD) wherein pathological processes occur prior to cognitive symptoms. Several potential biomarkers of AD have been described, and preliminary longitudinal studies suggest that AD-like biomarker profiles may predict future cognitive decline in asymptomatic elderly individuals. The amyloid cascade hypothesis initially posited that AD originates with Amyloid-ß (Aß) plaques, but recent advances instead implicate soluble Aß oligomers. The presence of Aß oligomers in cerebrospinal fluid (CSF) may thus represent an etiological biomarker for AD and identify individuals in the preclinical stage of disease. Methods: To test this hypothesis, we measured Aß56 (a 56-kDa Aß oligomer), low molecular weight (LMW) Aß oligomers, monomeric Aß, as well as soluble Amyloid Precursor Protein-a (sAPPa) in lumbar puncture CSF from clinically characterized individuals. Aß oligomers and sAPPa were
O4-06-06
48-WEEK EFFICACY AND TOLERABILITY OF TREATMENT WITH SB-742457, A NOVEL 5HT6 RECEPTOR ANTAGONIST, WHEN ADDED ON TO DONEPEZIL IN SUBJECTS WITH MILD-TOMODERATE ALZHEIMER’S DISEASE (AD)
Gareth Maher-Edwards1, John Ascher2, Carolyn Watson1, Marina Zvartau-Hind1, Carly Donovan1, John Davies1, Beth Safirstein3, Orazio Zanetti4, Manuel Fernandez5, Michael Gold6, 1GlaxoSmithKline, Stockley Park, Middlesex, United Kingdom; 2GlaxoSmithKline, Research Triangle Park, North Carolina, United States; 3MD Clinical, Hallandale Beach, Florida, United States; 4IRCCS S. Giovanni di Dio Fatebenefratelli Brescia, Brescia, Lombardia, Italy; 5Hospital de Cruces, Basque Country, Spain; 6Allon Therapeutics, Vancouver, British Columbia, Canada. Background: SB-742457 is a novel and potent 5-hydroxytryptamine-6 (5HT6) receptor antagonist. Methods: In this 48-week, double-blind, randomized study (AZ3110866), 684 subjects with mild/moderate AD (MMSE score 10-26) received placebo (n ¼ 226), SB-742457 15mg (n ¼ 221) or SB-742457 35mg (n ¼ 237) added to donepezil(D) 5-10mg for an initial 24 weeks and were allowed to continue for an additional 24 weeks of treatment. The co-primary efficacy measures were the Alzheimer’s disease Assessment Scale-cognitive subscale (ADAS-Cog) and Clinical Dementia Rating-Sum of Boxes (CDR-SB). The primary analysis was based on the change from baseline on the ADAS-Cog and CDR-SB at Week 24 using an intention-to-treat [ITT], mixed model repeated measures model (reported separately 2011 ICAD presentation #02-05-02). Efficacy data were also collected at Weeks 12, 36 and 48 (secondary). Other secondary measures included the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the Alzheimer’s Disease Co-operative Study Group-Activities of Daily Living Inventory (ADCS-ADL) measured at Weeks 12, 24, 36 and 48. Safety and tolerability were assessed. No alpha adjustment was made for co-primary endpoints. Results: 67%, 67% and 73% of subjects completed Week 48 for placebo, SB-742457 15mg and SB-742457 35mg, respectively. As previously reported at Week 24, statistically significant treatment differences were observed for SB-742457 35mg vs. placebo for ADAS-Cog and ADCS-ADL but not for the CDR-SB or RBANS. Treatment differences at Week 48 were similar and remained statistically significant for ADAS-Cog (p ¼ 0.024) but not for ADCS-ADL (p ¼ 0.088). No significant difference was seen for CDR-SB or RBANS total scores at Week 48. No statistically significant treatment differences were observed between SB-742457 15mg and pla-
e5
cebo. All treatments were generally safe and well tolerated over 48 weeks. The proportion of subjects reporting adverse events (AEs) were 56%, 62% and 62% for placebo, SB-742457 15mg and SB-742457 35mg, respectively. The most commonly reported AEs were nasopharyngitis and urinary tract infection. Conclusions: Compared with donepezil alone, treatment with SB-742457 35mg added to stable donepezil demonstrated improvements in cognitive and functional status after 24 weeks which were largely maintained at 48 weeks. The combination was well tolerated. Further investigation into the effects of SB-742457 as an adjunct therapy is warranted.
O4-08-01
MICRORNA-132 LOSS IS ASSOCIATED WITH TAU EXON 10 INCLUSION IN PROGRESSIVE SUPRANUCLEAR PALSY
Pascal Smith1, Charlotte Delay1, Emmanuel Planel1, Nicolas Sergeant2, Luc Buee2, Sebastien Hebert1, 1Laval University, CRCHUQ (CHUL), Quebec, Quebec, Canada; 2Inserm University of Lille, Lille, France. Background: Mutations affecting tau exon 10 splicing, leading to an imbalance between three-repeat (3R) and four-repeat (4R) tau isoforms, can cause rare forms of frontotemporal dementia linked with parkinsonism at chromosome 17 (FTDP-17). Despite certain advances in the identification of cis- an trans-regulators of tau exon 10 splicing in vitro, little is know about the physiological mechanisms affecting tau splicing in sporadic tauopathies. The past years have witnessed an explosion of papers linking microRNA dysregulation to human disease, including neurodegenerative disorders. In addition, accumulating data point to a role for microRNAs in the regulation of pre-mRNA alternative splicing. Methods: In attempt to identify novel factors involved in tau exon 10 alternative splicing regulation, we performed global microRNA expression profiling from progressive supranuclear palsy (PSP) patients, a major 4R-tau tauopathy. Results: Our screens identified neuronal miR-132 to be specifically down-regulated in disease. Using bioinformatics and functional assays in cells, we show that miR-132 targets the neuronal splicing factor PTBP2/ nPTB, which was up-regulated in PSP brain. miR-132 overexpression or PTBP2 knockdown affected similarly tau exon 10 splicing and 4R:3Rtau ratios at endogenous levels of expression in neuronal cells. Finally, we demonstrate that miR-132 is inversely correlated with PTBP2 during post-natal brain development at the time when 4R-tau becomes expressed. Conclusions: Taken together, our results provide strong evidence that the miR-132/PTBP2 pathway is involved in tau exon 10 splicing regulation in neurons, and support the idea that changes in the microRNA network may contribute to sporadic tauopathic brain.
O4-08-02
SPECIFIC Ab OLIGOMERS AND THE TAU/Ab42 RATIO CORRELATE IN LUMBAR PUNCTURE CSF
Maureen Handoko1, Anders Wallin2, Kaj Blennow2, Karen Ashe1, 1N. Bud Grossman Center for Memory Research and Care, University of Minnesota, Minneapolis, Minnesota, United States; 2Sahlgrenska Academy at the University of Gothenburg, M€olndal, Sweden. Background: A growing body of evidence has led to the identification of a preclinical phase of Alzheimer’s disease (AD) wherein pathological processes occur prior to cognitive symptoms. Several potential biomarkers of AD have been described, and preliminary longitudinal studies suggest that AD-like biomarker profiles may predict future cognitive decline in asymptomatic elderly individuals. The amyloid cascade hypothesis initially posited that AD originates with Amyloid-ß (Aß) plaques, but recent advances instead implicate soluble Aß oligomers. The presence of Aß oligomers in cerebrospinal fluid (CSF) may thus represent an etiological biomarker for AD and identify individuals in the preclinical stage of disease. Methods: To test this hypothesis, we measured Aß56 (a 56-kDa Aß oligomer), low molecular weight (LMW) Aß oligomers, monomeric Aß, as well as soluble Amyloid Precursor Protein-a (sAPPa) in lumbar puncture CSF from clinically characterized individuals. Aß oligomers and sAPPa were