Alzheimer's disease (AD) patients manifest severe impairment of memory and learning disorder, the most important functions of the human brain. More than 10 million people suffer from this devastating disease. To elucidate its pathogenesis and develop specific therapy is an urgent issue. The beta amyloid peptide is a major constituent of senile plaques, one of the hallmarks of AD pathology, and has been implicated in its pathogenesis. This peptide is the cleavage product of a larger precursor, APP, which serves as a cell-surface receptor coupling to Go, a neuron-specific member of the signal-transducer G protein family. In familial AD (FAD), a point mutation occurs in the transmembrane domain of APP. Using a chemically defined system, my preliminary study has shown that the FAD-linked APPs (FAD-APPs) have constitutively active receptor functions to active Go. The long-term goal of the proposed project is to fully understand the role of FAD-APPs in the pathogenesis of AD.
Its specific aims are (i) to examine the hypothesis that FAD-APPs are receptors that activate Go and the Go-linked cascade, especially adenylate cyclase (AC)-cAMP response element (CRE) system in intact cells, in a constitutive manner, and (ii) to establish a system for observing the ligand-dependent activation of Go by APP in intact cells. This project is expected to provide valuable new insight into the intracellular pathophysiology occurring in AD. Dysregulation of AC and CRE by FAD-APP and Go will be given particular attention, because the CRE system is pivotal in long-term memory formation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29MH056036-03
Application #
2555915
Study Section
Neuropharmacology and Neurochemistry Review Committee (NPNC)
Project Start
1996-08-01
Project End
2001-04-30
Budget Start
1997-09-30
Budget End
1998-04-30
Support Year
3
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Type
DUNS #
017730458
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Flores, A I; Mallon, B S; Matsui, T et al. (2000) Akt-mediated survival of oligodendrocytes induced by neuregulins. J Neurosci 20:7622-30
Parolini, I; Sargiacomo, M; Galbiati, F et al. (1999) Expression of caveolin-1 is required for the transport of caveolin-2 to the plasma membrane. Retention of caveolin-2 at the level of the golgi complex. J Biol Chem 274:25718-25
Nishiyama, K; Trapp, B D; Ikezu, T et al. (1999) Caveolin-3 upregulation activates beta-secretase-mediated cleavage of the amyloid precursor protein in Alzheimer's disease. J Neurosci 19:6538-48
Ikezu, T; Yasuhara, S; Granneman, J G et al. (1999) A unique mechanism of desensitization to lipolysis mediated by beta(3)-adrenoceptor in rats with thermal injury. Am J Physiol 277:E316-24
Volonte, D; Galbiati, F; Li, S et al. (1999) Flotillins/cavatellins are differentially expressed in cells and tissues and form a hetero-oligomeric complex with caveolins in vivo. Characterization and epitope-mapping of a novel flotillin-1 monoclonal antibody probe. J Biol Chem 274:12702-9
Engelman, J A; Zhang, X; Galbiati, F et al. (1998) Molecular genetics of the caveolin gene family: implications for human cancers, diabetes, Alzheimer disease, and muscular dystrophy. Am J Hum Genet 63:1578-87
Ikezu, T; Ueda, H; Trapp, B D et al. (1998) Affinity-purification and characterization of caveolins from the brain: differential expression of caveolin-1, -2, and -3 in brain endothelial and astroglial cell types. Brain Res 804:177-92
Okamoto, T; Schlegel, A; Scherer, P E et al. (1998) Caveolins, a family of scaffolding proteins for organizing ""preassembled signaling complexes"" at the plasma membrane. J Biol Chem 273:5419-22
Ikezu, T; Trapp, B D; Song, K S et al. (1998) Caveolae, plasma membrane microdomains for alpha-secretase-mediated processing of the amyloid precursor protein. J Biol Chem 273:10485-95
Smine, A; Xu, X; Nishiyama, K et al. (1998) Regulation of brain G-protein go by Alzheimer's disease gene presenilin-1. J Biol Chem 273:16281-8

Showing the most recent 10 out of 13 publications