Amyloid Suppresses Induction of Genes Critical for Memory Consolidation in APP PS1 Transgenic Mice

1
Amyloid Suppresses Induction of Genes Critical
for Memory Consolidation in APPPS1 Transgenic
Mice Chad A. Dickey1, Marcia N. Gordon1,
Jerimiah E. Mason1, Nedda J. Wilson1, David M.
Diamond2, John F. Guzowski3 Dave Morgan1 1
Alzheimers 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 APPPS1 Mice 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.
5. Induction of Immediate Early Gene Expression
is Impaired in APPPS1 Mice After a five minute
exposure to a novel enriched environment, IEG
induction was significantly impaired in APPPS1
mice compared to non-transgenic littermates.
Abstract 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 APPPS1 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 APPPS1 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 APPPS1 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 APPPS1 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.
Plasticity Related Genes
Summary
Immediate-early Genes
Non-Tg Basal
Non-Tg Induced
APPPS1 Basal
APPPS1 Induced
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
lt0.05.
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 non-induced values. indicates
p-value is lt0.05 between non-tg induced and
APPPS1 induced.
3. Contributions of Individual Transgenes to mRNA
Reduction in APPPS1 Mice Significant reductions
of immediate-early gene expression were seen in
both APP only and APPPS1 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.
1. Question What Mechanisms Account for Memory
Loss in APPPS1 Mice?

• 6. Conclusions
• We have presented strong evidence that A? itself
  causes specific reductions in gene expression
  critically linked to proper memory function in
  APPPS1 mice
• There is a variable sensitivity of these genes to
  A?
• IEGs are reduced in response to lower levels of
  A?, prior to detectable memory dysfunction
• Other plasticity related genes are reduced only
  at the time when memory loss is detectable
• These reductions are not ascribed to transgene
  over-expression
• It is the induction of the IEGs that is reduced,
  not the low-level basal expression

• No Significant Neuron Loss
• No Significant Synapse Loss
• Changes in Gene Expression?
• Gene Expression Profiling Reveals Reductions in
  Several Plasticity Related Genes in Memory
  Deficient APPPS1 Mice
• Reductions in Plasticity Related Genes are
  Confirmed and Extended by qRT-PCR
• Reductions are Restricted to Amyloid Containing
  Regions
• Reductions are Age-Dependent
• Expression is Further Reduced with Increasing
  Amyloid Load
• Induction by Environmental Novelty is Repressed
  in APPPS1 Mice
• Protein Function Loss follows mRNA Reductions

PS1 only
APP only
APPPS1
4. Differential Expression in APPPS1 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 APPPS1 mice.
Caudate Nucleus
Posterior Cortex
Hippocampus
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
lt0.05 between transgenic and non-transgenic.
indicates significance p-value is lt0.05 between
APP only and APPPS1 mice (3) or cortex and
hippocampus (4).
This work was supported by the National Institute
of Aging (NIA) National Institutes of Health
(NIH) AG18478