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Waltham, MA, United States

Sewal A.S.,U.S. National Institute on Aging | Sewal A.S.,Mount Sinai School of Medicine | Patzke H.,FORUM Pharmaceuticals | Perez E.J.,U.S. National Institute on Aging | And 7 more authors.
Journal of Neuroscience | Year: 2015

The therapeutic potential of histone deacetylase inhibitor (HDACi) treatment has attracted considerable attention in the emerging area of cognitive neuroepigenetics. The possibility that ongoing cognitive experience importantly regulates the cell biological effects of HDACi administration, however, has not been systematically examined. In an initial experiment addressing this issue, we tested whether water maze training influences the gene expression response to acute systemic HDACi administration in the young adult rat hippocampus. Training powerfully modulated the response to HDACi treatment, increasing the total number of genes regulated to nearly 3000, including many not typically linked to neural plasticity, compared with < 300 following HDACi administration alone. Although water maze training itself also regulated nearly 1800 genes, the specificmRNAs,gene networks, and biological pathways involved were largely distinct when the same experience was provided together with HDACi administration. Next, we tested whether the synaptic protein response to HDACi treatment is similarly dependent on recent cognitive experience, and whether this plasticity is altered in aged rats with memory impairment. Whereas synaptic protein labeling in the young hippocampus was selectively increased when HDACi administration was provided in conjunction with water maze training, combined treatment had no effect on synaptic proteins in the aged hippocampus. Our findings indicate that ongoing experience potently regulates the molecular consequences of HDACi treatment and that the interaction of recent cognitive experience with histone acetylation dynamics is disrupted in the aged hippocampus. © 2015 the authors.

Soares H.D.,Bristol Myers Squibb | Gasior M.,Teva Pharmaceuticals | Toyn J.H.,Bristol Myers Squibb | Wang J.-S.,GSK Consumer Healthcare | And 17 more authors.
Journal of Pharmacology and Experimental Therapeutics | Year: 2016

The pharmacokinetics, pharmacodynamics, safety, and tolerability of BMS-932481, a γ-secretase modulator (GSM), were tested in healthy young and elderly volunteers after single and multiple doses. BMS-932481 was orally absorbed, showed dose proportionality after a single dose administration, and had approximately 3-fold accumulation after multiple dosing. High-fat/caloric meals doubled the Cmax and area under the curve and prolonged Tmax by 1.5 hours. Consistent with the preclinical pharmacology of GSMs, BMS-932481 decreased cerebrospinal fluid (CSF) Aβ39, Aβ40, and Aβ42 while increasing Aβ37 and Aβ38, thereby providing evidence of γ-secretase enzyme modulation rather than inhibition. In plasma, reductions in Aβ40 and Aβ42 were observed with no change in total Ab; in CSF, modest decreases in total Ab were observed at higher dose levels. Increases in liver enzymes were observed at exposures associated with greater than 70%CSF Aβ42 lowering after multiple dosing. Although further development was halted due to an insufficient safety margin to test the hypothesis for efficacy of Ab lowering in Alzheimer's disease, this study demonstrates that γ-secretase modulation is achievable in healthy human volunteers and supports further efforts to discover well tolerated GSMs for testing in Alzheimer's disease and other indications.

Toyn J.H.,Yale University | Boy K.M.,Bristol Myers Squibb | Raybon J.,Bristol Myers Squibb | Meredith J.E.,Bristol Myers Squibb | And 29 more authors.
Journal of Pharmacology and Experimental Therapeutics | Year: 2016

The amyloid-b peptide Aβ-in particular, the 42-amino acid form, Aβ1-42-is thought to play a key role in the pathogenesis of Alzheimer's disease (AD). Thus, several therapeutic modalities aiming to inhibit Ab synthesis or increase the clearance of Aβ have entered clinical trials, including γ-secretase inhibitors, anti-Aβ antibodies, and amyloid-β precursor protein cleaving enzyme inhibitors. A unique class of small molecules, γ-secretase modulators (GSMs), selectively reduce Aβ1-42 production, and may also decrease Aβ1-40 while simultaneously increasing one or more shorter Aβ peptides, such as Aβ1-38 and Aβ1-37. GSMs are particularly attractive because they do not alter the total amount of Aβ peptides produced by γ-secretase activity; they spare the processing of other γ-secretase substrates, such as Notch; and they do not cause accumulation of the potentially toxic processing intermediate, β-C-terminal fragment. This report describes the translation of pharmacological activity across species for two novel GSMs, (S)-7-(4-fluorophenyl)-N2-(3-methoxy-4-(3- methyl-1H-1, 2, 4-triazol-1-yl)phenyl)-N4-methyl-6, 7-dihydro- 5H-cyclopenta[d]pyrimidine-2, 4-diamine (BMS-932481) and (S, Z)-17-(4-chloro-2-fluorophenyl)-34-(3-methyl-1H-1, 2, 4-triazol-1-yl)- 16, 17-dihydro-15H-4-oxa-2, 9-diaza-1(2, 4)-cyclopenta[d]pyrimidina-3 (1, 3)-benzenacyclononaphan-6-ene (BMS-986133). These GSMs are highly potent in vitro, exhibit dose- and time-dependent activity in vivo, and have consistent levels of pharmacological effect across rats, dogs, monkeys, and human subjects. In rats, the two GSMs exhibit similar pharmacokinetics/pharmacodynamics between the brain and cerebrospinal fluid. In all species, GSM treatment decreased Aβ1-42 and Aβ1-40 levels while increasing Aβ1-38 and Aβ1-37 by a corresponding amount. Thus, the GSM mechanism and central activity translate across preclinical species and humans, thereby validating this therapeutic modality for potential utility in AD. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Lui H.,University of California at San Francisco | Zhang J.,University of California at San Francisco | Makinson S.R.,University of California at San Francisco | Cahill M.K.,University of California at San Francisco | And 23 more authors.
Cell | Year: 2016

Microglia maintain homeostasis in the brain, but whether aberrant microglial activation can cause neurodegeneration remains controversial. Here, we use transcriptome profiling to demonstrate that deficiency in frontotemporal dementia (FTD) gene progranulin (Grn) leads to an age-dependent, progressive upregulation of lysosomal and innate immunity genes, increased complement production, and enhanced synaptic pruning in microglia. During aging, Grn -/- mice show profound microglia infiltration and preferential elimination of inhibitory synapses in the ventral thalamus, which lead to hyperexcitability in the thalamocortical circuits and obsessive-compulsive disorder (OCD)-like grooming behaviors. Remarkably, deleting C1qa gene significantly reduces synaptic pruning by Grn -/- microglia and mitigates neurodegeneration, behavioral phenotypes, and premature mortality in Grn -/- mice. Together, our results uncover a previously unrecognized role of progranulin in suppressing aberrant microglia activation during aging. These results represent an important conceptual advance that complement activation and microglia-mediated synaptic pruning are major drivers, rather than consequences, of neurodegeneration caused by progranulin deficiency. Loss of progranulin, which occurs in patients with frontotemporal dementia, causes lysosomal defects and excessive complement production, triggering selective synaptic pruning by microglia and behavioral deficits that can be rescued by blocking complement activation. © 2016 Elsevier Inc.

Forum Pharmaceuticals | Date: 2014-05-07

Pharmaceuticals. Pharmaceutical research.

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