Regulation of CRE-dependent transcription by presenilins: prospects for therapy of Alzheimer's disease.
Alzheimer's disease (AD) is the most common neurodegenerative disorder and is characterized by memory loss and other cognitive disabilities. Mutations in the presenilin genes are the major cause of familial AD. Analysis of conditional knockout mice has shown that inactivation of presenilins results in progressive memory impairment and age-dependent neurodegeneration, suggesting that reduced presenilin activity might represent an important pathogenic mechanism. Presenilins positively regulate the transcription of cAMP response element (CRE)-containing genes, some of which are known to be important for memory formation and neuronal survival. Phosphodiesterase 4 and histone deacetylase inhibitors, which can enhance CRE-dependent gene expression, have been shown to ameliorate memory deficits and neurodegeneration in animal models. Thus, modulation of CRE-dependent transcription might be beneficial for the treatment of dementia in AD.
Beglopoulos
Vassilios
V
Center for Neurologic Diseases, Brigham and Women's Hospital, Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA.
Shen
Jie
J
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000502:physiology; D000818:Animals; D002470:Cell Survival; D000242:Cyclic AMP / Q000494:pharmacology*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D008568:Memory; D009154:Mutation; D009474:Neurons / Q000502:physiology; D053764:Presenilin-1; D053766:Presenilin-2; D020218:Response Elements / Q000502:physiology*; D015398:Signal Transduction; D014158:Transcription, Genetic
D016229:Amyloid beta-Peptides; D008565:Membrane Proteins; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4