Abstract

The demonstration that the drugs rolipram and forskalin reverse the inhibition of LTP induced by alpha beta in hippocampal slices and that exposure of cultured hippocampal neurons to alpha beta causes changes in expression of genes involved in the switch from early to late LTP suggests that the cAMP signaling pathway may be an early target of damage in Alzheimer's disease as well as a therapeutic target, The first portion of work proposed will examine the role of alpha beta on the regulation of cAMP levels and investigate the mechanism of alpha beta Down regulation of PKA activity. Emphasis will be on the regulation of levels of the regulatory subunits of PKA. Experiments of APP Tg mice will examine the mechanism of LTP inhibition in the animals and determine if rolipram and forskalin reverse this inhibition. The second portion of the application examines the role of caspase 2 in cellular responses to alpha beta and will explore the issue of whether caspase 2 is necessary for the synaptic loss in APP Tg mice by crossing these animals with caspase 2 null mice.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS015076-27
Application #
7217287
Study Section
Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Sieber, Beth-Anne
Project Start
1989-06-01
Project End
2009-03-31
Budget Start
2007-04-01
Budget End
2009-03-31
Support Year
27
Fiscal Year
2007
Total Cost
$455,093
Indirect Cost

  Institution

Name
Columbia University (N.Y.)
Department
Pathology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032

  Publications

Padmanabhan, Jaya; Brown, Kristy R; Padilla, Amelia et al. (2015) Functional role of RNA polymerase II and P70 S6 kinase in KCl withdrawal-induced cerebellar granule neuron apoptosis. J Biol Chem 290:5267-79
Pozueta, Julio; Lefort, Roger; Ribe, Elena M et al. (2013) Caspase-2 is required for dendritic spine and behavioural alterations in J20 APP transgenic mice. Nat Commun 4:1939
Gong, Bing; Chen, Fei; Pan, Yong et al. (2010) SCFFbx2-E3-ligase-mediated degradation of BACE1 attenuates Alzheimer's disease amyloidosis and improves synaptic function. Aging Cell 9:1018-31
Vitolo, Ottavio; Gong, Bing; Cao, Zixuan et al. (2009) Protection against beta-amyloid induced abnormal synaptic function and cell death by Ginkgolide J. Neurobiol Aging 30:257-65
Smith, Donna L; Pozueta, Julio; Gong, Bing et al. (2009) Reversal of long-term dendritic spine alterations in Alzheimer disease models. Proc Natl Acad Sci U S A 106:16877-82
Lopez-Toledano, Miguel A; Shelanski, Michael L (2007) Increased neurogenesis in young transgenic mice overexpressing human APP(Sw, Ind). J Alzheimers Dis 12:229-40
Padmanabhan, Jaya; Brown, Kristy; Shelanski, Michael L (2007) Cell cycle inhibition and retinoblastoma protein overexpression prevent Purkinje cell death in organotypic slice cultures. Dev Neurobiol 67:818-26
Gong, Bing; Cao, Zixuan; Zheng, Ping et al. (2006) Ubiquitin hydrolase Uch-L1 rescues beta-amyloid-induced decreases in synaptic function and contextual memory. Cell 126:775-88
Shrestha, Brikha R; Vitolo, Ottavio V; Joshi, Powrnima et al. (2006) Amyloid beta peptide adversely affects spine number and motility in hippocampal neurons. Mol Cell Neurosci 33:274-82
Puzzo, Daniela; Vitolo, Ottavio; Trinchese, Fabrizio et al. (2005) Amyloid-beta peptide inhibits activation of the nitric oxide/cGMP/cAMP-responsive element-binding protein pathway during hippocampal synaptic plasticity. J Neurosci 25:6887-97

Showing the most recent 10 out of 32 publications