Amyloid suppresses induction of genes critical for memory consolidation in APP + PS1 transgenic mice.
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, CaMKIIalpha and Na-K- ATPase alphaIII) 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 Abeta 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 Abeta 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 Abeta-related inhibition of gene expression will have benefit in AD.
Dickey
Chad A
CA
Alzheimer's Disease Research Laboratory, Department of Pharmacology, University of South Florida, College of Medicine, Tampa, Florida 33612, USA.
Gordon
Marcia N
MN
Mason
Jerimiah E
JE
Wilson
Nedda J
NJ
Diamond
David M
DM
Guzowski
John F
JF
Morgan
Dave
D
D000682:Amyloid / Q000502:physiology*; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D000818:Animals; D015536:Down-Regulation / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology*; D017781:Genes, Immediate-Early / Q000502:physiology; D006624:Hippocampus / Q000378:metabolism; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics*; D008568:Memory / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D053764:Presenilin-1; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics
D000682:Amyloid; D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; D053764:Presenilin-1; D012333:RNA, Messenger