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Experimental Gerontology 40 (2005) 774–783
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Mini review
The senescence-accelerated prone mouse (SAMP8): A model of
age-related cognitive decline with relevance to alterations of the gene
expression and protein abnormalities in Alzheimer’s disease
D. Allan Butterfield*, H. Fai Poon
Department of Chemistry, Center of Membrane Sciences and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40506-0055, USA
Received 12 April 2005; received in revised form 6 May 2005; accepted 12 May 2005
Available online 18 July 2005
Abstract
The senescence-accelerated mouse (SAM) is an accelerated aging model that was established through phenotypic selection from a
common genetic pool of AKR/J strain of mice. The SAM model was established in 1981, including nine major senescence-accelerated mouse
prone (SAMP) substrains and three major senescence-accelerated mouse resistant (SAMR) substrains, each of which exhibits characteristic
disorders. Recently, SAMP8 have drawn attention in gerontological research due to its characteristic learning and memory deficits at old age.
Many recent reports provide insight into mechanisms of the cognitive impairment and pathological changes in SAMP8. Therefore, this mini
review examines the recent findings of SAMP8 mice abnormalities at the gene and protein levels. The genes and proteins described in this
review are functionally categorized into neuroprotection, signal transduction, protein folding/degradation, cytoskeleton/transport, immune
response and reactive oxygen species (ROS) production. All of these processes are involved in learning and memory. Although these studies
provide insight into the mechanisms that contribute to the learning and memory decline in aged SAMP8 mice, higher throughput techniques
of proteomics and genomics are necessary to study the alterations of gene expression and protein abnormalities in SAMP8 mice brain in order
to more completely understand the central nervous system dysfunction in this mouse model. The SAMP8 is a good animal model to
investigate the fundamental mechanisms of age-related learning and memory deficits at the gene and protein levels.
q 2005 Elsevier Inc. All rights reserved.
1. Introduction
The senescence-accelerated mouse (SAM) is a model of
accelerated senescence that was established through
phenotypic selection from a common genetic pool of
AKR/J strain of mice (Takeda et al., 1981). In 1975, certain
littermates of AKR/J mice were noticed to become senile at
an early age and had a shorter life span. Five of these litters
with early senescence were selected as the progenitors of the
senescence-accelerated-prone mice (SAMP). Three litters
with normal aging process were also selected as the
progenitors of senescence-accelerated-resistant mice
(SAMR) (Takeda et al., 1981; Miyamoto, 1997). Thereafter,
selective inbreeding was applied based on the degree of
senescence, the lifespan, and the age-associated pathologic
* Corresponding author. Tel.: C1 859 257 3184; fax: C1 859 257 5876.
E-mail address: [email protected] (D.A. Butterfield).
0531-5565/$ - see front matter q 2005 Elsevier Inc. All rights reserved.
doi:10.1016/j.exger.2005.05.007
phenotypes (Hosokawa et al., 1997). In 1981, the SAM
model was established, including nine major SAMP
substrains and three major SAMR substrains, each of
which exhibits characteristic disorders. The characteristics
of the SAMP substrains are summarized in Table 1. It
should be noted that other strains were also derived from
these major substrains (Takeda, 1999).
Recently, SAMP8 mice have drawn attention in
gerontological research of dementia due to its characteristic
learning and memory deficits at old age (Flood and Morley,
1998). The life span of ARK/J mice is approximately 10
months. Depending on the microbiological condition of
housing, the life span of SAMP8 mice ranges from 10
months to 17 months. Such life span is shorter than that of
SAMR1, which ranges from 19 months to 21 months (Flood
and Morley, 1998). The unique characteristic of SAMP8
mice is that it has low incidence of other phenotypic aging
alterations when its deficits in learning and memory are
developed (Flood and Morley, 1998). Therefore, it is a good
rodent model for cognitive impairment in aged subjects.
Moreover, in comparison with aged SAMR1 mice, the aged
D.A. Butterfield, H.F. Poon / Experimental Gerontology 40 (2005) 774–783
775
Table 1
Summary of the characteristics of different substrains of SAMP model
Strain
Characteristics
SAMP1
Senile amyloidosis, impaired immune system, impaired audiatory system, retinal atrophy, hypertensive vascular
disease, contracted kidney, pulmonary hyperinflation
Senile amyloidosis, impaired immue system
Degenerative arthrosis
Senile osteoporosis
Senile amyloidosis, thymoma
Age-related learning and memory deficits, anxiety, impaired immune system, age-dependent deposition of amyloid
b-peptide
Age-related cataracts
Brain atrophy, age-related learning and memory deficits, age-related depression
Age-relating thickening of tunic media of thoracic aorta, senile amyloidosis, contracted kidney
Normal aging with non-thymic lymphoma, histiocytic sarcoma and ovarian cysts
Normal aging with non-thymic lymphoma, histiocytic sarcoma, no ovarian cysts
Normal aging with colitis
SAMP2
SAMP3
SAMP6
SAMP7
SAMP8
SAMP9
SAMP 10
SAMP11
SAMR1
SAMR4.
SAMR5
SAMP8 mice show impairments in learning tasks, altered
emotion, abnormality of circadian rhythm (Miyamoto,
1997), and increased oxidative stress (Butterfield et al.,
1997). When compared to young SAMP8, aged SAMP8
mice also show clear age-related impairment in learning
assessed by foot shock avoidance (Flood and Morley, 1993),
which correlates with oxidative stress parameters (Farr
et al., 2003). These findings are consistent with the free
radical theory of aging that posits the oxidative modification
by reactive oxidative species (ROS) on biomolecules
contribute to the cellular dysfunction in aging (Harman,
1956).
Different paradigms were used to improve the agerelated learning and memory deficits in aged SAMP8 mice
(Farr et al., 2003; Kumar et al., 2000; Morley et al., 2002;
Yasui et al., 2002). These studies not only suggest potential
therapeutics for age-related dementia, but they also provide
insight into the mechanism underlying the learning and
memory deficits observed in aged SAMP8 mice. For
example, treating aged SAMP8 mice with antioxidants
decreased oxidative stress in aged SAMP8 brain and
improved their learning and memory, indicating that
oxidative stress contributes to the impairment of learning
and memory observed in the SAMP8 mice (Butterfield
et al., 1997; Farr et al., 2003; Yasui et al., 2002; Okatani
et al., 2002). Moreover, evidence strongly suggests that
abnormal expression of amyloid-b (Ab) contributes to the
cognitive decline in the aged SAMP8 mice, since reduction
of Ab by antibody or antisense oligonucleotides reduce
oxidative stress and improve learning and memory deficits
in aged SAMP8 mice (Kumar et al., 2000; Morley et al.,
2002; Morley et al., 2000; Poon et al., 2004). These studies
suggest that SAMP8 not only is a good model for studying
age-related learning and memory deficits, but may also
prove to be a useful model for studying Ab-mediated effects
in cognitive decline. Of course, the latter effects have
relevance to Alzheimer’s Disease (AD).
Many reports provide insights into the mechanism of the
cognitive impairment in SAMP8 mice. The neurochemical
alterations and pathological changes in SAMP8 were
previously reviewed (Takeda, 1999; Flood and Morley,
1998; Morley et al., 2001). Therefore, it is the intent of this
article to review the recent findings on alteration of gene
expression and protein abnormalities that are relevant to
age-related learning and memory deficits in SAMP8 mice
brain.
2. Gene expression alterations in SAMP8 mice
Cross breeding of a CD-1 dame and a SAMP8 sire
developed a series of paternal backcross strains. Siblings
from each backcross were then bred to establish strains with
different percentages of SAMP8 genes. It was demonstrated
that the age-related learning and memory impairment is
correlated to the percentage of SAMP8 genes (Morley et al.,
2001). Initial examination of the genetic profiles revealed
that at least one genotype in SAMP8 strain is different from
that in the AKR/J strain (Takeda, 1999). Moreover, a series
of Southern hybridization analyses of DNA isolated from
SAMP8 mice showed that: (1) the SAMP8 genome is
genetically distinguishable from that of other SAM mice;
(2) SAMP8 mice resemble other SAMP, but are clearly
different from the parental AKR/J strain; and (3) the level of
murine leukemia virus in SAMP8 mice is increased
(Takeda, 1999).
2.1. Genes related to neuroprotection/signal transduction/
protein folding and degradation
One of the interesting genes that affects the learning and
memory in SAMP8 mice is the amyloid precursor protein
(APP) (Kumar et al., 2000). The function of APP is not
entirely understood; however, the internalization and
endosomal processing of APP produces neurotoxic Ab
(Perez et al., 1999), and recent studies suggest that rodent
Ab is toxic (Boyd-Kimball et al., 2004). APP cDNA cloned
from the hippocampus of 8-month-old SAMP8 mouse
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D.A. Butterfield, H.F. Poon / Experimental Gerontology 40 (2005) 774–783
shows high similarity to that of other species (Kumar et al.,
2001). At the amino acid level, the homology was 99.2%
with other rodent APP sequences. A single amino acid
substitution of alanine instead of valine at position 300 of
APP was unique to SAMP8. However, familial AD
mutations were not observed in SAMP8 cDNA, suggesting
that the learning and memory deficits of SAMP8 maybe
different from that in familial AD (Kumar et al., 2001).
Moreover, the age-related increase of APP mRNA affects
the learning and memory in SAMP8 mice (Morley et al.,
2000). Such cognitive deficits are significantly improved
when the expression of APP is down-regulated by using an
antisense oligonucleotide specific to APP mRNA in aged
SAMP8 mice (Kumar et al., 2000; Kumar et al., 2001).
Based on significant modulation in oxidative stress
parameters in aged SAMP8 mice to which antisense
oligonucleotide against APP had been administrated, it
was proposed that the resulting cognitive improvement was
associated with the reduction of Ab-induced oxidative stress
(Poon et al., 2004). Therefore, these studies indicate that
the abnormal processing of APP may contribute to the
increased oxidative stress and cognitive deficits in aged
SAMP8 mice.
Further identification of genes that are specifically
expressed in the hippocampus of SAMP8 was performed
to understand the molecular basis of the pathological
changes and cognitive deficits of SAMP8 (Wei et al.,
1999a). The mRNAs of eukaryotic translation initiation
factor 2B subunit 1 (EIF-2B) like gene and phospholipase D
like gene are only expressed in SAMP8 mice but not in
SAMR1, suggesting these genes are relevant to the
dysfunction of the central nervous system (CNS) of
SAMP8 mice (Wei et al., 1999a).
Other analyses of neurotrophic genes revealed that the
expression of hippocampal glial cell line-derived neurotrophic factor (GDNF) mRNA in SAMP8 is less than that in
SAMR1 (Miyazaki et al., 2003), and neurotrophin-3 (NT-3)
and nerve growth factor (NGF) mRNA levels in the
midbrain, hippocampus and forebrain of SAMP8 mice are
also lower than those in SAMR1 at early stages (Kaisho
et al., 1994). These studies suggest that low neurotrophic
gene expression in young SAMP8 may contribute to their
hippocampal dysfunction.
Comparing the levels of Alzheimer’s disease (AD)related genes in the hippocampus and cerebral cortex of
SAMP8 mice to those of the SAMR1 by reverse
transcription polymerase chain reaction (RT-PCR) showed
that levels of apolipoprotein E (apoE) and mineralocorticoid
receptor (MR) mRNAs of SAMP8 were decreased, while
bcl-2 alpha and presenilin-2 (PS-2) mRNA levels were
significantly increased (Wei et al., 1999b). These studies
suggest that the abnormal expression of these AD-related
genes contribute to the age-related deterioration of learning
and memory in SAMP8. A microarray study of mRNA in
SAMP8 hippocampus also showed that genes associated
with the stress response and antioxidant systems are
strongly affected during age-related cognitive impairment
(Kumar et al., 2000). The genes identified in this study were
V(D)J recombination activating protein (RAG-1), ubiquitinlike protein, T-complex proteins a and b subunits,
T-complex protein 1 delta, episilon, gamma, eta, theta,
zeta subunit, heme oxygenase 1, endoplasmin precursor,
calnexin precursor, phospholipase C-alpha, JNK stressactivated protein kinase, mitogen-activated protein kinase
(MAPK) p38, MAPK kinase 4, JNK activating kinase,
RhoB, peroxisome proliferator activated receptor beta,
cytochrome P450 IIB9, cytochrome P450 IIIA, quinone
oxidoreductase, and microsomal UDP-glucuronosyltransferase 1–1 precursor (Kumar et al., 2000). Since the
translational products of these affected genes are involved
in signaling, chaperone function and antioxidant systems,
this study suggests that abnormalities of the signal
transduction, protein folding and antioxidant system may
contribute to the cognitive decline in aged SAMP8 mice.
2.2. Genes related to energy metabolism/immune
response/cytoskeleton and transport
In addition to genes that are involved in neuroprotection,
signal transduction, protein folding and degradation, other
altered gene expression in SAMP8 mice are related to or
involved in energy metabolism, immune response, the
cytoskeleton and transport. Decreased D 9-desaturase
mRNA with age in SAMP8 mice could contribute to altered
membrane fluidity and signaling pathways in synapses
(Kumar et al., 1999). The mRNAs of bullous pemphigoid
antigen like gene is only present in SAMR1, while the
mRNAs of glycogen debranching enzyme isoform like gene
is only expressed in SAMP8 mice, suggesting these genes
are relevant to the dysfunction of the CNS of SAMP8 mice
(Wei et al., 1999a). Comparing the levels of AD-related
genes in the hippocampus and cerebral cortex of SAMP8
mice to that of the SAMR1 by RT-PCR showed that levels
of apoE and glucocorticoid receptor-alpha (GR alpha)
mRNAs of SAMP8 were decreased, while tau mRNA levels
were significantly increased (Wei et al., 1999b). Moreover,
the ubiquitous kinesin heavy chain gene is altered in
SAMP8 mice brain. Since all of these genes are involved in
energy metabolism, immune response, cytoskeleton and
transport, the alteration of these genes may affect these
process and lead to neuronal damage in SAMP8 mice brain.
2.3. Summary
The alterations of gene expression described in the
studies cited above can be functionally classified into
neuroprotection, signal transduction, protein folding/degradation, the cytoskeleton, transport, and immune response
(Table 2). These changes in gene levels are consistent with
the pathological and neurochemical findings in SAMP8
mice that were recently reviewed (Nomura et al., 1996).
Therefore, one can speculate that the increased oxidative
D.A. Butterfield, H.F. Poon / Experimental Gerontology 40 (2005) 774–783
777
Table 2
Altered genes in SAMP8 mice brain
Expression
changesa
Function of gene productsb
Reference
Neuroprotection
APP
[
ApoE
Y
(Kumar et al.,
2000)
(Wei et al., 1999)
Heme oxygenase 1
Y
Cytochrome P450 IIB9
Y
Cytochrome P450 IIIA
[
Quinone oxidoreductase
[
Microsomal UDP-glucuronosyltransferase
1–1 precursor
Glial cell line-derived
neurotrophic factor
Neurotrophin-3
Y
Nerve growth factor
Y
A cell surface protease inhibitor that reduces copper; proteolytic peptides (Ab) are found
in amyloid deposits.
An lipoprotein that binds low density lipoprotein receptor (LDLR), involved in
clearance of circulating cholesterol, allele 4 linked to Alzheimer disease.
An enzyme that cleaves the heme ring at the alpha methylene bridge to form biliverdin
and carbon monoxide, involved in oxidative stress response; altered expression of
human version is associated with AD and Parkinson disease (PD).
A cytochrome P450 enzyme that is induced by phenobarbital and regulated by sex
hormones in a sex-dependent, organ-dependent fashion
A major drug metabolizing enzyme that oxidizes the Ca2C channel inhibior nifedipine,
involved in benzopyrene, steroid, retinoid, and toxin metabolism.
A cytosolic reductase that targets quinones, predicted to function in detoxification and
oxidative stress responses.
A enzyme that catalyzes glucuronidation of bilirubin IX alpha, biogenic amines and
quaternary amines, involved in metabolism of xenobiotics, amines, various drugs,
nicotine, and tobacco-derived lung carcinogens.
An antiapoptotic neurotrophic factor that is involved in neurogenesis, enhances survival
of midbrain dopaminergic neurons, putative therapeutic for neurodegenerative diseases.
A soluble growth factor ligand for TrkC tyrosine kinase receptors, important for
neuronal generation, differentiation, and survival; human NTF3 may play a role in nerve
regeneration.
A growth factor that plays roles in neuronal and mast cell differentiation, proliferation,
and survival, embryogenesis, neurogenesis, and sleep; increased expression is
associated with multiple sclerosis and AD.
Gene
Signal transduction
Eukaryotic translation
initiation factor 2B subunit 1 (EIF-2B)
Phospholipase D
Mineralocorticoid
receptor (MR)
JNK stress-activated protein kinase
Y
Y
[
[
Y
Y
Mitogen-activated protein kinase (MAPK) p38
MAPK Kinase 4
Y
RhoB
Y
[
Peroxisome proliferator
Y
activated receptor beta
Protein folding and degradation
Presenilin 2 PS-2
[
Ubiquitin-like protein
[
T-complex proteins a and
b subunits, T-complex
protein 1, eta, theta, subunit,
Endoplasmin precursor
[
Calnexin precursor,
Y
Phospholipase C-alpha
Y
[
A putative subunit of the heteropentameric EIF-2B complex that facilitates the exchange
of GDP bound to translation initiation factor eIF2 for GTP, interacts with adrenergic
receptors
A phospholipase that hydrolyzes phosphatidylcholine to phosphatidic acid, involved in
intracellular signaling, particularly from G protein receptors
A transcription factor that mediates salt homeostasis and blood pressure; may play a role
in stress adaptation.
A serine-threonine kinase that regulates c-Jun, acts in receptor signaling, cell growth and
differentiation, apoptosis, and response to stressors such as DNA damage, reactive
oxygen, hypoxia and rRNA damage.
A serine-threonine protein kinase, acts in signaling in response to cytokines and
physiological stimuli, and triggers.
A kinase that is involved in JNK and JAK-STAT cascades, mediates apoptosis and in
response to stress; MAPK kinase 4 is associated with AD and PD.
A Rho small monomeric GTPase that plays a role in the response to stress and apoptosis.
A transcriptional coactivator that binds and activates nuclear hormone receptors.
A protein that is involved in proteolysis of APP and Notch-1, induces apoptosis;
mutations in the human PS-2 gene are associated with familial, early onset AD.
An ubiquitin-like conjugating enzyme that catalyzes the attachment of NEDD8 to
cellular proteins, participates in the modification of Hs-cullin-4A, required for p27
ubiquitination and degradation.
A chaperone that contains T-complex polypeptide-1, plays a role in protein folding
(Kumar et al.,
2000)
(Kumar et
2000)
(Kumar et
2000)
(Kumar et
2000)
(Kumar et
2000)
al.,
al.,
al.,
al.,
(Miyazaki et al.,
2003)
(Kaisho et al.,
1994)
(Kaisho et al.,
1994)
(Wei et al., 1999)
(Wei et al., 1999)
(Wei et al., 1999)
(Kumar et al.,
2000)
(Kumar et
2000)
(Kumar et
2000)
(Kumar et
2000)
(Kumar et
2000)
al.,
al.,
al.,
al.,
(Wei et al., 1999)
(Kumar et al.,
2000)
(Kumar et al.,
2000)
A putative molecular chaperone that may play roles in protein folding, cytoprotection,
(Kumar et al.,
the immune response, and the heat shock and stress responses.
2000)
A protein that binds calcium, functions as a chaperone in the endoplasmic reticulum
(Kumar et al.,
(ER), mediates retention of misfolded proteins in the ER; mouse calnexin may
2000)
contribute to neuropathies associated with Charcot-Marie-Tooth syndrome
A glucose regulated 58kDa protein that acts as a protein disulfide isomerase and possibly
(Kumar et al.,
a protease, involved in folding and maturation of N-linked glycoproteins
2000)
processing.
(continued on next page)
778
D.A. Butterfield, H.F. Poon / Experimental Gerontology 40 (2005) 774–783
Table 2 (continued)
Gene
Expression
changesa
Function of gene productsb
Reference
(continued on next page)
Energy metabolism
D 9-desaturase
Glycogen debranching
enzyme isoform
Immune response
Glucocorticoid receptoralpha (GR alpha)
Cytoskeleton and transport
Bullous pemphigoid antigen
Tau
Ubiquitous kinesin heavy
chain
A desaturase that converts linoleic acid to arachidonic acid, contains a fatty acid
desaturase domain and a cytochrome b5-like heme or steroid binding domain.
A glucanotransferase and glucosidase that is required for glycogen degradation.
(Kumar et al.,
1999)
(Wei et al., 1999)
Y
A hormone-dependent transcription factor that inhibits inflammation, regulates
apoptosis an immune response
(Wei et al., 1999)
Y
A cytoskeletal protein that binds actin and microtubules, connects cytoskeleton to
hemidesmosomes, acts as autoantigen in bullous pemphigoid.
A microtubule-associated protein that stabilizes microtubules, functions in neurite
outgrowth; abnormal human Tau phosphorylation, folding, expression, and gene
mutations are associated with many neurodegenerative diseases.
A secretory granule protein that may function in intracellular organelle transport.
(Wei et al., 1999)
Y
[
[
Y
(Wei et al., 1999)
(Kumar et al.,
2000)
a
Aged SAMP8 compared to young SAMP8 and/or age-mated SAMR1.
Functions of the end products of these genes are stated according to BIOBASE’s Proteome BioKnowledge w Library from Incytec Corp (Hodges et al.,
2002; Csank et al., 2002; Costanzo et al., 2000).
b
stress in SAMP8 mice could be contributed by impaired
neuroprotection and abnormal immune response. Abnormal
signal transduction may result in neurochemical abnormalities. Impaired protein folding may contribute to the protein
aggregation in SAMP8 mice brain. A recent comprehensive
microarry study was preformed on the olfactory system of
SAMP8 mice (Getchell et al., 2003), demonstrating that the
expressions of numerous genes are altered more than threefold in SAMP8 mice. These genes were categorized into
immune factors, stress response, cellular proteins, enzymatic metabolism, cell cycle regulator and extracellular
matrix-adhesion (Getchell et al., 2003). Similar studies on
hippocampus and other brain regions will be beneficial to
understand the learning and memory deficits in SAMP8 at
the gene level.
3. Protein abnormalities in SAMP8 mice
3.1. Neuroprotection/ROS production
One of the direct results of increased APP gene
expression in the SAMP8 mice brain is the increased
level of Ab level (Poon et al., 2004). As noted above,
using antisense or antibody to reduce the level of Ab in
SAMP8 improved cognitive function and reduced
oxidative stress in SAMP8 mice brain, suggesting that
the increased Ab level in brain contributes to the CNS
dysfunction in SAMP8 mice (Kumar et al., 2000; Poon
et al., 2004d; Poon et al., 2005a). Moreover, a peripheral
antibody prevents the entry of Ab into the CNS and
inhibits Ab from associating with the brain vasculature
of SAMP8 mice (Banks et al., 2005). These studies of
Ab in SAMP8 mice suggest that increased Ab is
involved in the learning and memory deficits in these
mice as it is involved in AD. Consistent with this
suggestion, antisense oligonucleotide directed at the
MRNA of APP led to significant reduction of oxidative
modification of specific proteins in aged SAMP8 mice
brain as assessed by proteomics (Poon et al., 2005a).
Compared to SAMR1 mice, manganese superoxide
dismutase (Mn-SOD) activity in the cerebral cortex of aged
SAMP8 is decreased, suggesting that Mn-SOD inhibition may
be involved in the increased oxidative stress in the SAMP8
mice brain (Kurokawa et al., 2001). Moreover, the activity of
glutamine synthase (GS), an oxidatively sensitive enzyme
(Butterfield et al., 1997), in aged SAMP8 mice brain is also
decreased when compared to young SAMP8 mice or agematched SAMR1 mice (Butterfield et al., 1997; Sato et al.,
1996). Glutathione peroxidase (GPx) is another enzyme
whose activity is significantly decreased in aged SAMP8
mice brain (Okatani et al., 2002), while the activity of nitric
oxidate synthase (NOS) is increased in aged SAMP8 mice
when compared to those of young-adult SAMP8 (Inada et al.,
1996). Moreover, the catalase activity in the cerebral cortex of
SAMP8 is also decreased as a function of age, while the
activity of acyl-CoA oxidase, a microperoxisomal H2O2producing enzyme, is increased compared to young SAMP8
mice (Sato et al., 1996). The alterations of catalase and
acyl-CoA oxidase activities are also observed when SAMP8
mice are compared to age-matched SAMR1 (Sato et al., 1996),
suggesting that the abnormality of activities in these
microperoxisomal enzymes may contribute to the early
increase in oxidative stress observed in the cerebral cortex
of SAMP8 mice. All of these enzymes mentioned are
associated with oxidative stress, indicating that oxidative
stress plays a significant role in the learning and memory
deficits in SAMP8 mice (Butterfield et al., 1997).
D.A. Butterfield, H.F. Poon / Experimental Gerontology 40 (2005) 774–783
3.2. Energy metabolism/cytoskeleton and transport
One of the major effects of increased oxidative stress in
brains is protein oxidation. Oxidized proteins may cause
aggregation and/or inactivation (Butterfield and Stadtman,
1997; Butterfield and Lauderback, 2002; Poon et al., 2004a;
Poon et al., 2004b). Our laboratory used proteomics to identify
the proteins that are oxidatively modified and/or differentially
expressed in aged SAMP8 when compared to that in young
SAMP8 mice. We found that the expression of neurofilament
triplet L protein (NFL), lactate dehydrogenase 2 (LDH-2),
heat shock protein 86, and alpha-spectrin are significantly
decreased; the expression of triosephosphate isomerase (TPI)
is increased; and the oxidative modification of LDH-2,
dihydropyrimidinase-like protein 2, alpha-spectrin, creatine
kinase, aldoase 3 (Aldo3), coronin 1a (Coro1a) and
peroxiredoxin 2 (Prdx2) are increased in the aged SAMP8
mice (Poon et al., 2004; Poon et al., 2005a,b,c). Oxidized
proteins generally have lower activity (Butterfield and
Lauderback, 2002). Consequently, these oxidized proteins in
aged SAMP8 mouse brain that are involved in energy
metabolism, neuroprotection, and synaptic maintenance may
impair these cellular functions. Indeed, decreased energy
metabolism, impaired neuroprotection and synaptic dysfunction are all observed in aged SAMP8 mice brain (Miyamoto,
1997; Morley et al., 2001; Miyazaki et al., 2003; Nomura et al.,
1996; Sato et al., 1996; Kurokawa et al., 1996). Furthermore,
decreased D 9-desaturase mRNA and activity with age in
SAMP8 mice were reported, which could be responsible for
the low levels of unsaturated fatty acids, and altered membrane
fluidity and signaling pathways in synapses (Kumar et al.,
1999). Also, decreased hexokinase activity could be involved
in the decreased brain glucose metabolism in female SAMP8
mice (Kurokawa et al., 1996). These studies are consistent
with our proteomics results that the impaired energy
metabolism and synaptic functions are sequelae of the
alterations of brain proteins in SAMP8 mice. This concept
was strengthened by our observation that lipoic acid treatment
of aged SAMP8 mice, a procedure that led to cognitive
improvement and decreased oxidative stress (Farr et al., 2003),
resulted in significant reduction in oxidative modification of
specific proteins (Poon et al., 2005b). These results implicate
alterations in metabolic, cytoskeletal, and transport proteins in
loss of cognitive abilities upon aging in SAMP8 mice.
779
brains, and thus to cognitive impairment. Moreover, two
intracellular aspartic proteinases, cathepsin E (CE) and
D (CD) in the brain stem of SAMP8 are markedly accumulated
as a function of age (Amano et al., 1995). Together with the
oxidized hsp86 protein in aged SAMP8 mice (Poon et al.,
2004c), these studies indicate that aberrant protein degradation
may also occur in the CNS dysfunction of SAMP8 mice. These
studies suggest that calcium dysregulation, altered signal
transduction and abnormal protein degradation may also
contribute to the learning and memory deficits in aged SAMP8
mice.
3.4. Summary
It is interesting that the protein abnormalities described
above also belong to similar functional categories as those
of altered gene expression mentioned in the previous section,
e.g. neuroprotection, signal transduction, protein folding/degradation, cytoskeleton and transport, and immune response
(Table 3). Therefore, the protein alterations likely also
contribute to the pathological and neurochemical abnormalities observed in aged SAMP8 mice (Nomura et al., 1996).
Moreover, some of the proteins described above are also
involved in reactive oxygen species (ROS) production,
indicating that oxidative stress plays a significant role in the
pathological and neurochemical changes, and thereby in
learning and memory deficits in aged SAMP8 mice. It should
be noted that the permeability of the blood brain barrier
(BBB) of aged SAMP8 mice is also reportedly altered
(Vorbrodt et al., 1995). Such an alteration in the BBB could
cause abnormal protein accumulation in the brains of
SAMP8 mice. For instance, significant amounts of albumin
enter the parenchyma of the hippocampus in aged SAMP8
mice due to impaired BBB integrity (Vorbrodt et al., 1995).
Moreover, impaired BBB function could contribute to the
decline in energy metabolism in aged SAMP8 brain, since the
glucose transporter (GLUT-1) in brain microvascular
endothelia, representing the anatomic site of the BBB, was
decreased in SAMP8 (Vorbrodt et al., 1999). However, the
transport alteration of the BBB varies among different brain
regions; therefore, it is difficult to correlate the alterations in
BBB integrity to the learning and memory deficits observed
in aged SAMP8 mice (Banks et al., 2000).
3.3. Signal transduction/protein folding and degradation
4. Conclusion
In addition to alterations in the levels of oxidative stress
related proteins, the levels of two calcium dependent proteins
(calbindin and protein kinase C (PKC)-g) also are decreased
with age in aged SAMP8 mouse brain (Armbrecht et al.,
1999). PKC-g is involved in the acquisition and retention
process, and calbindin regulates intracellular calcium concentration and is involved in the mitochondrial permeability
transition pore. Therefore, abnormal levels of these proteins
may contribute to calcium dysregulation and apoptosis in
This mini-review summarizes current findings of altered
gene expression and abnormal proteins in SAMP8 mice
brain. The genes and proteins described in this review are
functionally categorized into neuroprotection, signal transduction, protein folding/degradation, cytoskeleton and
transport, immune response and ROS production. All of
these processes are reportedly involved in age-related
cognitive decline (Butterfield and Stadtman, 1997; Poon et al.,
2004a; Poon et al., 2004b; Lal and Forster, 1988; Wilson
780
D.A. Butterfield, H.F. Poon / Experimental Gerontology 40 (2005) 774–783
Table 3
Altered proteins in SAMP8 mice brain
Proteins
Neuroprotection
Manganese superoxide
dismutase (Mn-SOD)
Glutamine synthase
(GS),
Alterationa
Function of proteinsb
Reference
Activity Y
A mitochondrial enzyme that converts superoxide to hydrogen peroxide,
acts in oxidative stress responses, alterations may contribute to AD.
An enzyme that catalyzes the condensation of glutamate and ammonia to
form glutamine, altered expression is associated with AD.
(Kurokawa et al., 2001)
Activity Y
Glutathione peroxidase
(GPx)
Catalase
Activity Y
Activity Y
Peroxiredoxin 2 (Prdx2)
Oxidation [
ROS production
Ab
Protein level [
Nitric oxide synthase
(NOS)
Activity [
Acyl-CoA oxidase
Activity [
Cytoskeleton and transport
DihydropyrimidinaseOxidation [
like protein 2
Neurofilamenttriplet L
protein (NEFL),
Protein level Y
Alpha-spectrin
Protein level Y
Coronin 1a (Coro1a)
Oxidation [
Signal transduction
Calbindin
Protein level Y
Protein kinase C
(PKC) -g,
Protein level Y
Protein folding and degradation
Cathepsin D
Level [
Cathepsin E
Level [
Heat shock protein 86
Protein level Y
Oxidation [
Energy metabolism
Lactate dehydrogenase
2 (LDH-2),
Triosephosphate isomerase
Protein level Y
Oxidation [
Protein level [
An antioxidant enzyme that detoxifies peroxide in an oxidative stress
response.
A tetrameric hemoprotein that detoxifies hydrogen peroxide, part of the
oxidative stress response.
An antioxidant enzyme that acts in the response to lipid hydroperoxide
and may play a role in protection of cells from ROS, expression is altered
in neurodegenerative diseases.
A proteolytic product of APP, found in amyloid deposits in AD brains
and is thought to be central to the pathogenesis of AD.
A enzyme that produces nitric oxide from L-arginine and oxygen,
regulates cell proliferation, vasodilatation, and is mis-expressed in CNS
diseases.
An oxidase that catalyzes the first step in very long chain fatty acid betaoxidation by converting acyl-CoA to enoyl-CoA and generates hydrogen
peroxide.
A brain protein that binds tubulin heterodimers and regulates
microtubule formation, involved in neuronal growth cone collapse and
axonal growth, phosphorylated form is found in neurofibrillary tangles in
Alzheimer’s patients. Oxidized in AD brain.
A neurofilament protein that is required for maintaining cell shape,
axonal diameter, and function of motor neurons; human NEFL is
associated with the axonal form of Charcot-Marie-Tooth and other
neurodegenerative diseases
A member of a family of actin crosslinking proteins for the membraneassociated cytoskeleton. It binds calcium, and is cleaved during
apoptosis and maybe cleaved during memory recall.
A putative cytoskeletal-associated protein and a putative phagosome
coat protein that may act in endosome to lysosome transport, acts in
mycobacterial survival in phagosome
(Farr et al., 2003; Sato
et al., 1996; Howard et
al., 1996)
(Okatani et al., 2002)
(Sato et al., 1996)
(Poon et al., 2005)
(Poon et al., 2004)
(Inada et al., 1996)
(Sato et al., 1996)
(Poon et al., 2005)
(Poon et al., 2005; Poon
et al., 2005)
(Poon et al., 2005; Poon
et al., 2005)
(Poon et al., 2005)
A protease that functions in vitamin D-dependent calcium-binding, may
modulate intracellular calcium signaling in neurons, associated with the
mitochondrial permeability transition pore, decreased expression
correlates with decreased neuron survival in AD.
A protein kinase that has a potential calcium-binding domain and is
important for cellular signaling; increased proteolysis may be associated
with AD.
(Armbrecht et al., 1999)
A lysosomal aspartyl protease that degrades intracellular and
endocytosed proteins; increased expression is associated with AD.
An intracellular nonlysosomal aspartic proteinase involved in the
degradation of intra- and extracellular proteins and in antigen processing,
up-regulation in hippocampal blood vessels and microglia correlates
with AD
A putative heat shock protein that serves as a tumor-specific
transplantation antigen, interacts with the proto-oncogene Pim1 and is
involved in Pim1 stabilization and function, human HSP86 mediates
protein folding, involved in activation of the caspase cascade.
(Amano et al., 1995)
A glycolytic enzyme that catalyzes the reversible NAD-dependent
interconversion of pyruvate to L-lactate
A glycolytic enzyme that catalyzes the reversible interconversion of
glyceraldehyde 3-phosphate and dihydroxyacetone phosphate in glycolysis, forms a complex with Na, K-ATPase and cofilin, human TPI1
variant forms result in neurodegeneration. Oxidized in AD brain.
(Poon et al., 2005; Poon
et al., 2005)
(Poon et al., 2005; Poon
et al., 2005)
(Armbrecht et al., 1999)
(Amano et al., 1995)
(Poon et al., 2005; Poon
et al., 2005)
(contined on next page)
D.A. Butterfield, H.F. Poon / Experimental Gerontology 40 (2005) 774–783
781
Table 3 (continued)
Proteins
Alterationa
Function of proteinsb
Reference
Creatine kinase,
Oxidation [
(Poon et al., 2005)
Aldolase 3 (Aldo3),
Oxidation [
D 9-desturase
Activity Y
Hexokinase
Activity Y
A brain creatine kinase that is important for energy homeostasis,
expression of human CKB is elevated in some cancers, and CK is
oxidized in AD brain.
A brain-specific glycolytic enzyme that converts fructose-1,6-bisphosphate into dihydroxyacetonephosphate and glyceraldehyde-3-phosphate.
A desaturase that converts linoleic acid to arachidonic acid and contains
a fatty acid desaturase domain and a cytochrome b5-like heme or steroid
binding domain
A glycolytic enzyme that catalyzes ATP-dependent conversion of
glucose to glucose 6 phosphate.
(Poon et al., 2005)
(Poon et al., 2005)
(Kurokawa et al., 1996)
a
Alteration in aged SAMP8 mice brain when compared to young SAMP8 and/or age-mated SAMR1.
Functions of these proteins are stated according to BIOBASE’s Proteome BioKnowledge w Library from Incytec Corp (Hodges et al., 2002; Csank et al.,
2002; Costanzo et al., 2000).
b
et al., 2002). Moreover, the abnormal APP and Ab
metabolism in SAMP8 mice brain suggest that the learning
and memory deficits in SAMP8 could have some similarities
to those in AD. These findings support the view that SAMP8
mouse is useful for the investigation of the mechanism of
age-related learning and memory deficits (Nomura et al.,
1996). However, the genes and proteins described in this
review likely are only part of the mechanisms that contribute
to the cognitive dysfunction in aged SAMP8 mice. In order to
more completely understand the learning and memory
deficits in aged SAMP8 mice, higher throughput techniques
of proteomics and genomics are necessary to study the
alteration of genes and proteins in SAMP8 mice brain.
Moreover, it is necessary to determine what types of
cognitive dysfunction occurs in SAMP8 mice and how the
learning and memory deficits are generated. This review
indicates that oxidative stress is critically important in these
processes, and Ab may play a significant role in age-related
cognitive decline in SAMP8. As such, we opine that the
SAMP8 mouse is a useful animal model to investigate the
fundamental mechanisms involved in age-related learning
and memory deficits at both gene and protein levels that may
have relevance to age-associated AD.
Acknowledgements
This work was supported in part by grants from the
National Institutes of Health to D. A. Butterfield (AG10836; AG-05119).
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