title: Synaptic therapy in Alzheimer's disease: a CREB-centric approach.
abstract: Therapeutic attempts to cure Alzheimer's disease (AD) have failed, and new strategies are desperately needed. Motivated by this reality, many laboratories (including our own) have focused on synaptic dysfunction in AD because synaptic changes are highly correlated with the severity of clinical dementia. In particular, memory formation is accompanied by altered synaptic strength, and this phenomenon (and its dysfunction in AD) has been a recent focus for many laboratories. The molecule cyclic adenosine monophosphate response element-binding protein (CREB) is at a central converging point of pathways and mechanisms activated during the processes of synaptic strengthening and memory formation, as CREB phosphorylation leads to transcription of memory-associated genes. Disruption of these mechanisms in AD results in a reduction of CREB activation with accompanying memory impairment. Thus, it is likely that strategies aimed at these mechanisms will lead to future therapies for AD. In this review, we will summarize literature that investigates 5 possible therapeutic pathways for rescuing synaptic dysfunction in AD: 4 enzymatic pathways that lead to CREB phosphorylation (the cyclic adenosine monophosphate cascade, the serine/threonine kinases extracellular regulated kinases 1 and 2, the nitric oxide cascade, and the calpains), as well as histone acetyltransferases and histone deacetylases (2 enzymes that regulate the histone acetylation necessary for gene transcription).
authors.affiliation: Department of Pathology & Cell Biology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, 10032, USA.
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Teich
authors.forename: Russell E
authors.initials: RE
authors.lastname: Nicholls
authors.forename: Daniela
authors.initials: D
authors.lastname: Puzzo
authors.forename: Jole
authors.initials: J
authors.lastname: Fiorito
authors.forename: Rosa
authors.initials: R
authors.lastname: Purgatorio
authors.forename: Mauro
authors.initials: M
authors.lastname: Fa'
authors.forename: Ottavio
authors.initials: O
authors.lastname: Arancio
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D006801:Humans; D013569:Synapses / Q000378:metabolism / Q000473:pathology; D009435:Synaptic Transmission / Q000502:physiology*
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein