Amyloid suppresses induction of genes critical for memory consolidation in APP + PS1 transgenic mice
Article first published online: 23 DEC 2003
Journal of Neurochemistry
Volume 88, Issue 2, pages 434–442, January 2004
How to Cite
Dickey, C. A., Gordon, M. N., Mason, J. E., Wilson, N. J., Diamond, D. M., Guzowski, J. F. and Morgan, D. (2004), Amyloid suppresses induction of genes critical for memory consolidation in APP + PS1 transgenic mice. Journal of Neurochemistry, 88: 434–442. doi: 10.1111/j.1471-4159.2004.02185.x
- Issue published online: 23 DEC 2003
- Article first published online: 23 DEC 2003
- Received August 14, 2003; revised manuscript received September 25, 2003; accepted September 26, 2003.
- immediate-early genes;
Mice transgenic for mutated forms of the amyloid precursor protein (APP) plus presenilin-1 (PS1) genes (APP + PS1 mice) gradually develop memory deficits which correlate with the extent of amyloid deposition. The expression of several immediate-early genes (IEGs: Arc, Nur77 and Zif268) and several other plasticity-related genes (GluR1, CaMKIIα and Na-K- ATPase αIII) critical for learning and memory was normal in young APP + PS1 mice preceding amyloid deposition, but declined as mice grew older and amyloid deposits accumulated. Gene repression was less in APP + PS1 mouse brain regions that contain less Aβ and in APP mice compared with APP + PS1 mice, further linking the extent of amyloid deposition and the extent of gene repression. Critically, we demonstrated that amyloid deposition led specifically to impaired induction of the IEGs with no effects on basal expression using exposure to a novel environment 30 min prior to being killed to induce IEGs. These data imply that Aβ deposition can selectively reduce expression of multiple genes linked to synaptic plasticity, and provide a molecular basis for memory deficiencies found in transgenic APP mice and, most likely, in early stage Alzheimer's disease (AD). Presumably, pharmacological agents blocking the Aβ-related inhibition of gene expression will have benefit in AD.