Biochimica et Biophysica Acta 1822 (2012) 650–656

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Biochimica et Biophysica Acta

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The senescence accelerated mouse (SAMP8) as a model for oxidative stress and
Alzheimer's disease ☆
John E. Morley a,⁎, Harvey James Armbrecht a, c, Susan A. Farr a, b, Vijaya B. Kumar a, c
a
Division of Geriatric Medicine, Saint Louis University School of Medicine, St. Louis, MO, USA
b
John Cochrane VA Medical Center, St. Louis, MO, USA
c
GRECC (Geriatric Research, Education and Clinical Center), VA Medical Center, St. Louis, MO, USA

a r t i c l e i n f o a b s t r a c t

Article history: The senescence accelerated mouse (SAMP8) is a spontaneous animal model of overproduction of amyloid
Received 2 September 2011 precursor protein (APP) and oxidative damage. It develops early memory disturbances and changes in the
Received in revised form 11 November 2011 blood–brain barrier resulting in decreased efflux of amyloid-β protein from the brain. It has a marked in-
Accepted 12 November 2011
crease in oxidative stress in the brain. Pharmacological treatments that reduce oxidative stress improve
Available online 26 November 2011
memory. Treatments that reduce amyloid-β (antisense to APP and antibodies to amyloid-β) not only im-
Keywords:
prove memory but reduce oxidative stress. Early changes in lipid peroxidative damage favor mitochondrial
Senescence accelerated mouse (SAMP8) dysfunction as being a trigger for amyloid-β overproduction in this genetically susceptible mouse strain.
Oxidative damage This sets in motion a cycle where the increased amyloid-beta further damages mitochondria. We suggest
Alzheimer's disease that this should be termed the Inflammatory-Amyloid Cycle and may well be similar to the mechanisms re-
Blood–brain barrier sponsible for the pathophysiology of Alzheimer's disease. This article is part of a Special Issue entitled: Anti-
Amyloid-beta oxidants and Antioxidant Treatment in Disease.
© 2011 Elsevier B.V. All rights reserved.

1. Introduction An alternative hypothesis, called the mitochondrial cascade hy-

There are approximately 35.6 million people world-wide with de-
mentia and this number is expected to increase to over 115 million by
2050. Alzheimer's disease is the most common neurodegenerative
disorder that produces dementia. Alzheimer's disease results in irre-
versible loss of cortical neurons, especially in the associative cortex
and the hippocampus. The molecular findings in Alzheimer's disease
consist of amyloid-beta protein (Aβ) deposits in senile plaques, intra-
cellular neurofibrillary tangles, cholinergic deficits and loss of synap-
tic processes and dendritic spines. The classical belief is that the
pathology of Alzheimer's disease is due to overproduction of Aβ.
This “amyloid hypothesis” suggests that Aβ activates phosphorylation
of tau through glycogen synthase kinase (GSK) leading to neurofibril-
lary tangles, directly causes memory deficits through effects of solu-
ble amyloid causing synaptic damage and memory impairment,
results in the amyloid plaques, damages the blood brain barrier trap-
ping Aβ within the brain and produces cell death through apoptosis,
excitotoxicity, inflammation and oxidative stress [1].
☆ This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treat-
ment in Disease.
⁎ Corresponding author at. Division of Geriatric Medicine, Saint Louis University
School of Medicine, 1402 S. Grand Blvd., M238, St. Louis, MO 63104, USA. Tel.: + 1
314 977 8462; fax: + 1 314 771 8575.
E-mail address: morley@slu.edu (J.E. Morley).
pothesis, was proposed by Swerdlow and Kahn in 2004 [2]. This
hypothesis suggested that damage to mitochondrial DNA results in
mitochondrial dysfunction in Alzheimer's disease. The increase in
oxidative stress is in turn responsible for activation of the Aβ. This
has now been termed the modified Aβ cascade hypothesis [3,4].
Alzheimer's patients have an increase in mitochondrial DNA muta-
tions [5]. In addition, their hippocampal neurons have a deficiency
in cytochrome oxidase, the enzymatically active component of com-
plex IV [6]. This leads to a decrease in ATP production and an increase
in oxidative stress resulting in synaptic dysfunction, apoptosis, and
tau hyperphosphorylation. These two hypotheses are contrasted in
Fig. 1.
Two basic types of rodent models for Alzheimer's disease exist.
These consist of the transgenic (over-producing human Amyloid
Precursor Protein and associated secretases, tau and ApoE) mice
and the spontaneous senescence accelerated mouse P8 (SAMP8).
There is evidence for increased oxidative damage in the transgenic
mice which can be reversed to some extent by antioxidants [7–10].
In these models antioxidants also reduced Aβ and plaque burden
but not APP [11]. However, these models overexpress genes with
mutations seen in early onset Alzheimer's disease, which account
for less than 5% of all Alzheimer's disease. A spontaneous mouse
model where the processes are not dominated by overproduction
of Aβ would appear to be a better model to investigate the two hy-
potheses of causation of Alzheimer's disease. This review will de-
scribe such a model, the SAMP8, and also explore in depth the role

0925-4439/$ – see front matter © 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.bbadis.2011.11.015
 J.E. Morley et al. / Biochimica et Biophysica Acta 1822 (2012) 650–656 651

Fig. 1. A. The amyloid-beta peptide cascade hypothesis. In this version all changes in Alzheimer's disease are driven by overproduction of amyloid precursor protein. B. The modified
amyloid hypothesis where alternations in mitochondrial function drive the pathogenesis of Alzheimer's disease.

of oxidative damage in memory function. The SAMP8 mouse is a spe-
cific model of memory dysfunction, other SAM mice strains are
models of senescence.
2. The SAMP8 mouse
The SAMP8 mouse was one of the accelerated senescence strains
that spontaneously developed from breeding pairs of the AKR/J
series [12]. The fact that the breeding was not pathogen free and
that significant outbreeding occurred, together appear to have
been responsible for the development of this unique lineage. The
SAMP8 mouse develops early learning and memory deficits (be-
tween 8 and 10 months) together with other characteristics sim-
ilar to those seen in Alzheimer's disease. Other characteristics of
these mice include an altered circadian rhythm [13], reduced anxi-
ety behavior [14], immune dysfunction late in their lifespan [15]
and reduced lifespan [16]. Female mice have less robust memory
changes than male SAMP8, and for this reason most studies have
been carried out in male SAMP8 mice [17]. Microsatellite DNA
markers have shown that the AKR strain classically used as a control
animal are inappropriate for this purpose [18]. For this reason, we
developed a backcross of SAMP8 to CD-1 and found that memory
deficits were no longer present in the 88% backcross mice. These
mice appear to be more appropriate controls for comparison with
the SAMP8.
Studies using a variety of learning techniques (passive avoidance,
one way active avoidance, aversive T-maze, object recognition, lever
press appetitive task, Greek cross and Morris Water maze) have
demonstrated both learning and retention deficits in the SAMP8
mice [19–26]. These memory deficits can be reversed by multiple
pharmacological agents that modulate the neurotransmitters that
appear to play a role in Alzheimer's disease, albeit with a shift in
the dose response curve [27–29].
Pathologically, the SAMP8 mice have a reduction in neuronal
spine density [30], an increase in astrocyte gliosis, an accumulation
of periodic acid Schiff-positive granules and vacuoles in the magno-
cellular reticular formation [31–34]. There is also an early increase
in lipofusion [35].
SAMP8 mice overproduce a compound similar to amyloid-beta
protein [36–38]. Amyloid plaques occur late in life (~20 months) in
652 J.E. Morley et al. / Biochimica et Biophysica Acta 1822 (2012) 650–656

Table 1 cytosolic reductase that is thought to detoxify oxidative stress. RhoB

Comparison of Alzheimer's disease, SAMP8 mouse and transgenic mice models. was also decreased and is a GTPase involved in the response to stress
Alzheimer's SAMP8 Transgenic and apoptosis. JNK stress-activated protein kinase is a serine-
disease models threonine kinase which regulates c-JUN. It is involved in responses
Overproduction of amyloid-β Yes Yes Yes to stressors such as DNA damage and reactive oxygen species. Its
Amyloid plaques Yes Latea Yes levels were decreased with aging.
Phosphorylated tau Increased Increased In some models In the SAMP8 mice there is an increase with aging in neuronal
Cerebral amyloid angiopathy Yes Yes Yes
nitric oxide synthase [47,70]. This is believed to be responsible for in-
Neuron loss Yes Yes ?
Synaptic dysfunction Yes Yes Yes creased astrogliosis [70]. These changes in the astrocytes are associat-
Dendritic spine loss Yes Marked ? ed with an increase in glial fibrillary acidic protein (FGAP) [71]. In
Gliosis Yes Yes Yes Alzheimer's disease brains there are also high levels of GFAP and as-
Cholinergic deficit Yes Yes Yes trocyte hypertrophy [72].
Learning and memory impaired Yes Yes Yes
When SAMP8 mice age from 6 to 12 months, there is a marked in-
Circadian rhythm disturbances Yes Yes ?
Oxidative damage Yes 4 months 8 months crease in oxidative stress [73]. Both protein carbonyls (an index of
protein oxidation) and thiobarbituric acid reactive substance (a
? = uncertain.
a
Occur at 16 to 18 months. marker of lipid peroxidation) increase. This is accompanied by a de-
cline in the weakly immobilized to strongly immobilized ratio of the
protein-specific spin label Mal-6. Administration of either alpha-
these mice, suggesting that the plaques per se are not involved in the lipoic acid or n-acetyl cysteine for 4 weeks not only improved mem-
pathogenesis of the memory defect [38]. There is an overproduction ory but also reversed the measures of oxidative stress. These findings
of amyloid precursor protein and Aβ as shown with a number of an- support the concept that oxidative stress plays a role in the memory
tibodies [38]. The increase may not be in either Aβ1–40 or 1–42 dysfunction of SAMP8 mice.
though Manich et al. [39] found both these species in hippocampal
granules. Other characteristics of Alzheimer's disease shared by 4. Reversal of oxidative stress in SAMP8 mice
SAMP8 mice are hyperphosphorylation of tau [40], increased alpha
synuclein [41], an increase in presinilin [42], increased oxidative Proteomics has demonstrated increased oxidization and/or ni-
damage [43], decreased choline acetyl transferase activity [44], in- tration of certain proteins in Alzheimer's disease brains [74]. In
creased glutamate [45], altered NMDA function [46] and increased the SAMP8 mouse, proteomics demonstrated increased protein
neuronal nitric oxide synthase [47]. Low testosterone is associated carborylation of α-enolase, LDH-2, α-spectrin and DRP-2 [75].
with Alzheimer's disease and rapid progression of mild cognition im- The oxidative changes in α-enolase and DRP-2 have previously
pairment in males [48,49]. SAMP8 mice have low testosterone and been observed in Alzheimer's brains [76,77]. It is postulated that
testosterone replacement reduces APP [50]. these oxidative changes lead to abnormal brain metabolism and
Further evidence for an increase in APP in the SAMP8 comes from neurochemical changes. When SAMP8 mice were treated with
studies with antibodies and antisense developed to Aβ. These have alpha-lipoic acid we found a decrease in the specific carbonyl con-
been shown to cross the blood brain barrier and improve memory tent of lactate dehydrogenase B, dihydropyimidase-like protein 2
in the SAMP8 [51–53]. Antisense to APP has been shown to enter and α-enolase [78]. In addition, brain levels of neurofilament trip-
into cells, reduce Aβ and enhance memory [54,55]. It also increases let L protein, α-enolase and ubiquitous mitochondrial creatine ki-
egress of Aβ from the brain [56]. nase increased. Restoration of these proteins to their normal
Overall, the available studies in the SAMP8 suggest it might be an condition by alpha-lipoic acid may play a role in the improvement
ideal model to examine the interaction of oxidative damage and APP of memory observed in the SAMP8.
production. Table 1 compares the changes in the SAMP8, transgenic Lipid peroxidation is increased in SAMP8 mice as early as 2 months
mice and Alzheimer's. of age [79]. Lipid composition of the brain membranes appears to play
an important role in memory in the SAMP8 mice [80–82]. The levels
3. Oxidative damage and the SAMP8 of the antioxidant, alpha-tocopheral increase with aging in the
SAMP8 mouse [83]. Butterfield et al. [84] found that oxidation of
Mitochondria are the major generator of cellular energy and also lipids in the SAMP8 could be reversed by the antioxidants, N-Test-
the major source of potentially harmful reactive oxygen species. butyl-alpha-phenylnitrone and vitamin E.
Thus, as mitochondrial dysfunction occurs with aging, it plays a A number of other approaches to reducing oxidative stress in
major role in both the physiological aging process and neurode- SAMP8 mice have had success in improving function in these
generation [57,58]. This concept has been termed the free radical mice. Dietary restriction by 40% decreased superoxide radicals
theory of aging. Multiple studies have shown that oxidative damage and metabolic rate while extending the lifespan [85]. Both an
is a hallmark of Alzheimer's disease [59–63]. Thus, a valid model of onion extract and di-n-propyl-triscelfide decreased lipid hydroper-
Alzheimer's disease needs to demonstrate the presence of oxidative oxide in the hippocampus of SAMP8 mice and improved memory
stress. [86]. Similarly, the antioxidant oolong and green teas reversed
Oxidative damage has been universally observed in the SAMP8 memory deficits, decreased brain lipofusion and increased serum
[16,64]. Nomura et al. [65] were the first to find higher amounts of Trolox equivalent antioxidant activity [87]. Lotus seedpod
malondealdehyde and lower levels of superoxidase dismutase in proanthocyanidins (LSPC) improved memory in the Y-maze test
SAMP8 compared to SAMR1 mice. Other early findings included an [88]. LSPC decreased the elevated levels of malondialdehyde, nitric
increase in thiobarbituric acid reactivity and a decrease in glutathione oxide and nitric oxide synthase and increased the levels
catalyze, and glutamine synthase [66–68]. There was also an increase glutathione, glutathione peroxidase and superoxidase dismutase in
in the H2O2-producing enzyme, acylCoA oxidase as the SAMP8 ages. the brain and serum of SAMP8 mice. Mulberry extracts are rich in
In a microarray study Kumar et al. [69] found 4 genes involved in phenolics and anthocyanins. Feeding mulberry extracts to SAMP8s
the stress response and antioxidant metabolism are altered with for 12 weeks improved memory in avoidance testing, decreased
aging in the SAMP8 mouse. There was a decrease in heme oxygenase1 amyloid-beta protein, increased antioxidant enzyme activity and de-
which forms biliverdin from the heme ring and is associated with creased lipid oxidation [89]. Similarly, the phenolic rich extra virgin
Alzheimer's disease. Quinone oxireductase was increased. It is a olive oil improved memory and decreased oxidative damage in the
 J.E. Morley et al. / Biochimica et Biophysica Acta 1822 (2012) 650–656
brains of SAMP8 mice [90]. Icariin, another antioxidant, improved
memory in the water maze and the step-down passive avoidance
tests [91].
5. Effects of melatonin in SAMP8 mice
Melatonin is a well recognized powerful antioxidant and anti-
inflammatory agent [92]. It has beneficial effects by ameliorating
both oxidative and nitrosative stress state. Melatonin has both pro-
and anti-inflammatory effects, promoting early inflammatory re-
sponses and attenuating later responses to protect against the chronic
effects of inflammation. The effects of melatonin in the SAMP8 mouse
have been studied in detail. There is a marked aging-associated in-
crease in oxidative stress and inflammation in the livers of the
SAMP8 mice [93]. Melatonin decreased mRNA expression of TNFα,
IL-1β, iNOS and NKkB 1 and 2 in the liver. The protein levels of TNFα
and IL-1 β were also reduced. Thus, melatonin reduces inflammation
in SAMP8 mice.
With aging in the brain of the SAMP8 there is a reduction in ATP
production associated with diminished activity of the respiratory
chain complexes [94]. Melatonin administration prevented mito-
chondrial impairment and maintained ATP production in the SAMP8
mice [95]. There is a decrease in the melatonin-1 receptor with
aging in the SAMP8 mouse [96]. Melatonin reduced thiobarbituric
acid reactive substances and protein carbonyl levels in the brains of
SAMP8 mice, while increasing glutathione peroxidase levels [97].
Melatonin decreased cell loss in cerebral cortex in parallel with the
reduction in lipid and protein oxidative damage [98]. The tau hyper-
phosphorylation seen in SAMP8 mice was also reduced by melatonin.
Melatonin elevated hippocampal pyramidal volume and increased
the numerical density and surface volume of mitochondria [99]. Mel-
atonin improved cognitive performance in the Y-maze and in the
eight arm radial maze [99].
6. Oxidative stress and amyloid-beta protein
A 42mer phosphorothiolated antisense oligonucleotide directed
against the Aβ region of amyloid precursor protein improves memory
Fig. 2. The neurotransmitter sequence of the effects of increased amyloid-beta is based on previous work by our group [1,16].
653
in the SAMP8 mice [54]. This antisense also decreased lipid peroxida-
tion and protein oxidation in the brain of the SAMP8 mouse [100].
The antisense also decreased carbonyl levels of aldolase 3, coronin
1a and peroxiredoxin 2 [101]. These findings suggest that reducing
Aβ can lead to reversal of the oxidative damage in SAMP8 mice.
It is believed that impairment of efflux of Aβ from the brain across
the blood–brain barrier is a mechanism by which Aβ accumulates in
the brains of persons with Alzheimer's disease [102]. Lipoprotein re-
ceptor protein-1 (LRP-1) is the pump that produces efflux of the Aβ
from the brain. In Alzheimer's brains there are elevated levels of the
lipid peroxidation product, 4-hydroxy-2-nonenal which are aggregat-
ed with LRP-1 [103]. The fact that SAMP8 mice also has a deficit in the
efflux of Aβ from the brain, suggests that this may be due to oxidative
damage of the blood brain barrier.
7. Hormesis and amyloid-beta
The law of hormesis suggests that low doses of a substance (toxin
or physiological modulator) may have different effects on a biochem-
ical process or, more specifically, that low doses stimulate and high
doses inhibit the same process. Recently, our group [104] and Puzzo
et al. [105,106] have found that low doses (picomolar) of Aβ actually
enhance long term potentiation, increase hippocampal acetylcholine
production and enhance memory, while higher doses inhibit these
processes. Blocking the production of Aβ in young mice or cells has
the opposite effect. This suggests that the physiological role of Aβ
may be memory enhancement with overproduction leading to cogni-
tive dysfunction and Alzheimer's disease.
Aβ is a potent antioxidant in free oxidative systems [107]. This is
related to the ability of Aβ to bind to zinc, copper and iron [108].
This led Atwood et al. [109] to suggest that the formation of amyloid
plaques could act to remove reactive oxygen species. They believed
that excessive Aβ accumulation may prevent metal ion chelation
and result in increasing oxidative stress. Alternatively increased Aβ
may decrease oxidative stress by quenching hydroxyl radicals [110].
No studies examining the effects of picomolar concentrations of Aβ
on free radical generation have been undertaken.
654 J.E. Morley et al. / Biochimica et Biophysica Acta 1822 (2012) 650–656
8. Conclusion
Oxidative damage to neuronal cells is believed to play a central
role in the pathogenesis of Alzheimer's disease. There is no ideal ani-
mal model to study Alzheimer's disease. However, the SAMP8 mouse
appears to be an excellent model to study the interactions between
Aβ overproduction and oxidative damage to brain tissue.
Fig. 2 provides a schematic of the alterations in the SAMP8 brain
that lead to memory failure and tissue damage. At present, there is in-
adequate information to answer the chicken or egg question of
whether Aβ drives increased mitochondrial dysfunction and oxida-
tive damage or whether mitochondrial dysfunction leads to inflam-
mation resulting in excess Aβ production. The fact that blocking Aβ
production with an antisense improves memory and decreases oxida-
tive damage would suggest that Aβ is the primary culprit. However,
decreasing oxidative damage with a variety of agents improves mem-
ory and decreases brain damage suggesting the opposite conclusion.
Thus, we suggest that either overproduction of Aβ or alternatively
mitochondrial dysfunction or brain injury resulting in inflammation
can trigger what then becomes a vicious cycle. The early lipid perox-
idative damage seen in SAMP8 mice would favor mitochondrial
dysfunction as being the trigger for the amyloid-beta overproduction
in a genetically susceptible mouse strain. We suggest this should be
termed the Inflammatory-Amyloid Cycle. Finally, we believe that low
dose Aβ is physiologically important in maintaining memory and may,
in fact, actually protect against oxidative damage to neurons.
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