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Amyloid Suppresses Induction of Genes Critical for Memory Consolidation in APP+PS1 Transgenic Mice
Chad A. Dickey1, Marcia N. Gordon1, Jerimiah E. Mason1, Nedda J. Wilson1, David M. Diamond2, John F. Guzowski3 & Dave Morgan1
1 Alzheimer’s Disease Research Laboratory, Department of Pharmacology, University of South Florida, College of Medicine 12901 Bruce B. Downs Blvd, MDC 9, Tampa, Fl 33612
2 Departments of Psychology and Pharmacology, College of Arts and Sciences, University of South Florida, and Medical Research, Veterans Hospital, 4202 E. Fowler Ave. Tampa, FL 33620
3 Department of Neurosciences, Basic Medical Sciences Building, Room 145, University of New Mexico, Health Sciences Center, Albuquerque, NM 87131
2. Different Sensitivity to Amyloid Accumulation by Age in APP+PS1 Mice
Gene Expression Profiling Reveals Reductions in
Several Plasticity Related Genes in Memory Deficient
APP+PS1 Mice
Immediate-early Genes
Plasticity Related Genes
150
*
*
*
50
*
**
Zif268
Nur77
Arc
Synaptophysin
100
*
0
0
0
5
10
15
Months of Age
Amyloid
Containing
Reductions are Age-Dependent
Expression is Further Reduced with Increasing Amyloid
Load
Induction by Environmental Novelty is Repressed in
APP+PS1 Mice
Protein Function Loss follows mRNA Reductions
*
Plasticity-Related
Genes
Immediate-Early
Genes
*
*
50
5
10
15
20
0
5
10
15
Non-Tg Basal
*
*
200
Non-Tg Induced
APP+PS1 Basal
100
APP+PS1 Induced
20
Months of Age
Relative expression is derived from dividing target mRNA by 18S rRNA following qRT-PCR. % relative
expression was determined by dividing each transgenic value by an average of the non-transgenic values.
* indicates p-value is <0.05.
0
Non-Tg APP+PS1
Arc
Non-Tg
APP+PS1
Nur77
Non-Tg
APP+PS1
Zif268
Relative expression is derived from dividing target mRNA by 18S rRNA following qRT-PCR. % relative
expression was determined by dividing each transgenic value by an average of the non-transgenic noninduced values. * indicates p-value is <0.05 between non-tg induced and APP+PS1 induced.
3. Contributions of Individual Transgenes to mRNA Reduction in
APP+PS1 Mice
Significant reductions of immediate-early gene expression were seen in both APP only and APP+PS1 mice,
however significant reductions in other plasticity related genes were only observed in the doubly transgenic
mice. PS1 only mice maintain expression similar to non-transgenic mice.
150
Plasticity-Related Genes
Immediate-Early Genes
100
*
*
*
*
*
†
*
†
*
Non-Changing
Synaptic Genes
†
*
PS1 only
APP only
*
6. Conclusions
We have presented strong evidence that A itself causes specific
reductions in gene expression critically linked to proper memory function in
APP+PS1 mice
There is a variable sensitivity of these genes to A
50
APP+PS1
Zif268
Arc
Na, K
ATPase
CaMKII 
GluR1
GAP43
IEGs are reduced in response to lower levels of A, prior to detectable memory
dysfunction
Synaptophysin
4. Differential Expression in APP+PS1 Mice in Regions with Different
Amyloid Load and Composition
Significant reductions of immediate-early gene expression were seen in hippocampus, cortex and caudate
nucleus with reductions in other plasticity related genes seeming predominantly exclusive to the hippocampus of
18-month old APP+PS1 mice.
150
Relative Expression ± SEM
(% of Non-Tg Control)
to
Non-Changing
Synaptic Genes
100
Months of Age
Reductions in Plasticity Related Genes are Confirmed
and Extended by qRT-PCR
Restricted
300
0
0
20
Nur77
are
Na, K ATPase
GluR1
CaMKII
**
*
50
0
Reductions
Regions
Summary
Relative Expression ± SEM
(% of Non-Tg Control)
Relative Expression ± SEM
(% of Non-Tg Control)
Gap43
100
After a five minute exposure to a novel enriched environment, IEG induction was significantly
impaired in APP+PS1 mice compared to non-transgenic littermates.
150
150
Relative Expression ± SEM
(% of Non-Tg Control)
1. Question: What Mechanisms Account for Memory
Loss in APP+PS1 Mice?
No Significant Neuron Loss
No Significant Synapse Loss
Changes in Gene Expression?
Early significant reductions of immediate-early gene expression were seen at 6 months followed by significant
reductions in other plasticity related genes by 18-months, when memory deficits were detectable by radial arm
water maze.
Relative Expression ± SEM
(% of Non-Tg Control)
Mice transgenic for mutated forms of the amyloid precursor protein (APP) plus
presenilin-1 (PS-1) genes gradually develop amyloid pathology as they age
resulting in reliable memory deficits by 15 months. Several genes critical for
learning and memory are down-regulated in memory deficient transgenic mice
compared to non-transgenic littermates. The down-regulation of these genes is
strongly linked to the presence of amyloid, as gene expression is normal in
APP+PS1 mice at an age prior to amyloid deposition, and the extent of gene
repression worsens as amyloid deposits accumulate. We have also found that while
18 month old singly transgenic PS1 mice do not exhibit reductions in expression of
any of the mRNAs we investigated, singly transgenic APP mice have less
repression of gene expression than doubly transgenic APP+PS1 mice, consistent
with their differences in amyloid deposition. We also find that some of the repressed
genes, typically in the immediate early gene (IEG) category, are more sensitive to
the presence of amyloid than the constitutively expressed synaptic genes that are
critical for neural plasticity. Lastly, using a novel environment to stimulate IEG
expression, we demonstrate that the abundance of several IEG mRNAs in the
APP+PS1 mice are reduced during induction and not at the basal expression level.
Therefore, an inability to induce expression as robustly as non-transgenic
littermates may preclude the APP+PS1 mice from having adequate memory
function. These data imply that amyloid deposition can lead to repression of multiple
genes linked to synaptic plasticity and that the repression of these genes and the
loss of their dynamic nature may account for the memory loss characteristic of early
stage Alzheimer's disease.
5. Induction of Immediate Early Gene Expression is Impaired in
APP+PS1 Mice
Relative Expression ± SEM
(% of Non-Tg Control)
Abstract
Immediate-Early Genes
Plasticity-Related Genes
†
†
100
* * * ** * * *
*
50
*
Non-Changing
Synaptic Genes
*
*
These reductions are not ascribed to transgene over-expression
Caudate Nucleus
Posterior Cortex
*
Other plasticity related genes are reduced only at the time when memory loss is
detectable
It is the induction of the IEGs that is reduced, not the low-level basal
expression
Hippocampus
0
Nur77
Zif268
Arc
Na, K
ATPase
GluR1 CaMKII 
GAP43
Synaptophysin
Relative expression is derived from dividing target mRNA by 18S rRNA following qRT-PCR. % relative
expression was determined by dividing each transgenic value by an average of the non-transgenic values.
* indicates p-value is <0.05 between transgenic and non-transgenic. † indicates significance p-value is <0.05
between APP only and APP+PS1 mice (3) or cortex and hippocampus (4).
This work was supported by the National Institute of Aging (NIA) &
National Institutes of Health (NIH) AG18478