Blockade of gamma-secretase activity within the hippocampus enhances long-term memory.
The gamma-secretase complex, a membrane-bound aspartyl protease, hydrolyzes the transmembrane domains of several integral membrane proteins including the key signaling molecules amyloid precursor protein (APP), Notch, deleted in colorectal cancer (DCC), and N- and E-cadherins. The proteolysis processing of these proteins is critical for generation of signaling molecules that may participate in neuronal communication and plasticity. Using a potent gamma-secretase inhibitor, L-685,458, we examined if blockade of its activity in the hippocampus can influence contextual and spatial memory in rats. Surprisingly, we observed that post-training blockade of gamma-secretase activity leads to enhanced long-term memory in two hippocampus-dependent tasks. This suggests that a signaling molecule(s) generated by gamma-secretase activity may have a negative influence on long-term memory formation.
Dash
Pramod K
PK
The Vivian L. Smith Center for Neurologic Research and Department of Neurobiology and Anatomy, The University of Texas Medical School, P.O. Box 20708, Houston, TX 77225, USA. p.dash@uth.tmc.edu
Moore
Anthony N
AN
Orsi
Sara A
SA
D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D002219:Carbamates / Q000494:pharmacology*; D003214:Conditioning, Classical / Q000187:drug effects / Q000502:physiology*; D004151:Dipeptides / Q000494:pharmacology*; D010450:Endopeptidases / Q000187:drug effects / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology*; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D020318:Rats, Long-Evans
D002219:Carbamates; D004151:Dipeptides; C410009:L 685458; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases