The SAMP8 MouseA Model to Develop Therapeutic Interventions for Alzheimer Disease

Current Pharmaceutical Design, 2012, 18, 1123-113011231873-4286/12 $58.00+.00© 2012 Bentham Science PublishersThe SAMP8 Mouse: A Model to Develop Therapeutic Interventions for Alzheimer’s DiseaseJohn E. Morley 1,2,*, Susan A. Farr 1,2, Vijaya B. Kumar 1,2 and Harvey J. Armbrecht 1,2,31Geriatric Research Education and Clinical Center (GRECC), St. Louis VA Medical Center; 2Division of Geriatric Medicine, Saint Louis University; 3Department of Biochemistry and Molecular Biology, Saint Louis University, St. Louis, Missouri, USAAbstract: The senescence accelerate mouse P8 (SAMP8) is an excellent model of early learning and memory problems. A number of studies have shown that it has cholinergic deficits, oxidative damage, alterations in membrane lipids and circadian rhythm disturbances. The brains of the SAMP8 overproduce amyloid precursor protein (APP), amyloid-beta protein and have an increased physphorylation of tau. An antisense to APP has been developed that reverses the cognitive deficits and oxidative damage. This antisense represents a poten-tial treatment for Alzheimer’s disease.Keywords: Antisense, amyloid-beta, SAMP8, oxidative damage, Alzheimer's, antisense, blood brain barrier, testosterone. INTRODUCTIONThe SAMP8 mouse was one of the strains developed in the 1970s in the laboratory of Professor Takeda at Kyoto University in Japan [1]. They were developed from breeding pairs of AKR/J mice, some of whom developed a variety of accelerated aging char-acteristics. Selective breeding of 5 litters of the senescence prone mice led to the development of the P series of mice. These mice were named “senescence accelerated mice (SAM).” Depending on the survival curves and phenotypic characteristics, the different members of the strain were characterized by being given a different number. Four of these strains have now been widely studied as potential models of age-associated pathologies. They all have vari-ous forms of amyloidosis which suggests that protein misfolding may be induced with aging. These are:[1]The SAMP1 which have obvious hair loss, lack of activityperiophthalmic lesions, senile amyloidosis (apo-A II type), hearing impairment, kidney disease and a very short life span. [2]The SAMP6 which develops osteoporosis and secondary amy-loidosis (Amyloid A type)[3]The SAMP8 which has predominantly memory and learningdisorders and[4]The SAMP10 with brain atrophy and a very short life span. The original breeding took place in a non-pathogen free area, perhaps accounting for some of these changes. While the SAMR mice were developed as long lived mice from AKR/J mice in Pro-fessor Takeda’s laboratory, there appears to have been significant outbreeding with other strains, such that the SAMR mice are no longer an appropriate control for the SAMP mice. This was con-firmed by recent studies in which microsatellite DNA markers were used to genetically profile the deficient strains [2]. For over 20 years SAMP mice have been reared under specific pathogen free conditions at Takeda Chemical Ind., Osaka; The Institute of labora-tory Animal Sciences, Faculty of Medicine, Kagoshima University and in our laboratory at the St. Louis Veterans Affairs Center in St. Louis, Missouri. Under these conditions, the different strains have maintained their phenotypic characteristics over numerous genera-tions.This review will focus on the SAMP8 mice which develop early learning and memory deficits associated with other characteristics*Address correspondence to this author at the Division of Geriatric Medi-cine, Saint Louis University School of Medicine, 1402 S. Grand Blvd., M238, St. Louis, MO 63104, USA; Tel: 314-977-8462, Fax: 314-771-8575; E-mail: morley@similar to Alzheimer’s disease [3,4,5]. These animals also have reduced anxiety-like behavior [6,7], altered circadian rhythm [8], and develop immune dysfunction late in their lifespan [9]. While SAMP8 female mice have a similar learning deficit to males, we could not demonstrate a retention deficit in the foot shock aversive T-maze [10]. For this reason all studies discussed in this review have been done in male SAMP8 mice.LEARNING AND MEMORY DEFICITSOriginal studies in the SAMP8 found that the mice had im-paired passive avoidance and one way active avoidance as early as 2 months of age compared to the R1 mice [11,12,13]. In our SAMP8 mice we have failed to find these changes in passive avoid-ance before 12 months, but found changes in complex appetitive tasks viz lever press and left-right sequence determination at 4 months of age and a T maze active avoidance task at 8 months of age [14,15]. A number of simple tasks are learned up until 12 months of age [16]. In our memory studies we examined the effect of backcrossing the SAMP8 sire to a CD-1 dame. The aversive T-maze memory deficits were present in 94% of backcross mice but were no longer present in 88% backcross mice [17]. These back-cross mice now provide an appropriate control to study when de-termining differences in SAMP8 mice from genetically similar mice without learning and memory deficits.In spatial learning behavior in an eight arm radial maze which was food motivated, SAMP8 mice showed mild deficits in refer-ence and working memory errors [7]. In appetitive tasks where the stimulus was not very strong, there were no learning deficits [7]. In the Morris water maze SAMP8 mice had a significant decrease in distance needed to swim to find the platform, but a prolongation in time to find the platform [18,19]. The Morris water maze results are often confounded by the fact that it is a potent anxiety test. These results could be interpreted that the SAMP8 mice show less anxiety than other mice. Further, reduced anxiety in SAMP8 mice is dem-onstrated by failure to show food neophobia and an increase in time spent drinking when receiving electric shocks compared to average mice [13,20]. Table I summarizes the results in different learning and mem-ory tests present in SAMP8 mice.CIRCADIAN RHYTHM DISRUPTIONChanges in circadian rhythm occur with aging. SAMP8 mice show accelerated circadian rhythm aging changes with a reduction in amplitude and an increase in fragmentation [6]. SAMP8 mice1124 Current Pharmaceutical Design, 2012, Vol. 18, No. 8 Morley et al.Table I. Learning and Memory Tests in the SAMP8 Mouse•Tests in which SAMP8 mice are impairedo Active avoidanceo Lever presso Left-right sequence determinationo Aversive T-mazeo Food motivated radial mazeo Object recognitiono Greek cross brightness discrimination•Tests in which variable results are reportedo Passive avoidanceo Morris Water Maze•Tests in which SAMP8 mice have normal memoryo Black-white discriminationalso show a higher level of activity during the light phase, resulting in a split rhythm [21,22]. This increase in activity at a time when the mice are usually dormant, could be considered to be the equiva-lent of the increased nocturnal activity associated with phase ad-vancement of the circadian rhythm seen in patients with Alz-heimer’s disease [23]. Melatonin improves this circadian rhythm disruption both in SAMP8 mice and humans with Alzheimer’s dis-ease [24,25]. A lengthening of the free running period has also been seen in some, but not all, studies of SAMP8 mice and appears to vary at different ages of the mice [26,27].With aging, SAMP8 mice have an increase in slow wave sleep with a shorter latency, leading to less periods of wakefulness [28]. Paradoxical sleep is more common in aged SAMP8 mice. There is a significant slowing in theta peak frequency in old SAMP8 mice. This decrease in theta oscillations is compatible with a decline in hippocampal function with aging. Reduction in theta rhythm has been implicated in the induction of long term potentiation. Theta oscillations are altered in Alzheimers’ Disease patients, even in early stages [29].SAMP8 mice have an unusual recovery pattern to sleep depri-vation [28]. They showed increased amounts of slow wave sleep and paradoxical sleep following sleep deprivation. This suggests a failure to adequately compensate to sleep deprivation. Similar poor responses to sleep deprivation have been reported in humans [30].The reduction in rapid eye movement sleep that is present in SAMP8 mice can be partially reversed by a retinoic acid receptor agonist [31]. SAMP8 mice have a decrement in the retinoic acid receptor alpha and the transthyretin in the hippocampus. The reti-noic acid receptor agonist increased acetylcholine in the cortex of the SAMP8 mice.Overall, these studies suggest there may be a linkage between the disrupted circadian rhythm and the memory disturbances that occur in SAMP8 mice.PATHOLOGICAL CHANGES IN THE BRAINThere are numerous pathological changes in the brains of SAMP8 mice Table II. A number of these changes can be consid-ered to be classical age-related changes that occur earlier in the SAMP8 mice. For example, there is accelerated accumulation of Table II. Pathological Changes in SAMP8 MiceAnatomical:IncreasedlipofuscinPercodic acid Schiff positive granulesAstrogliosisVacuoles in magnocellular reticular formationDecreased dendritic spine densitySpongiformdegenerationAlzheimer-like changes:Increased amyloid precursor proteinIncreased amyloid-beta proteinAmyloid-like deposits (early; but plaques late)H yperphosphorylationoftauIncreased alpha synucleinIncreased oxidative damage: both protein and lipid Neurotransmitters:Increased hippocampal cholinergic neurostimulatory peptideDecreased choline acetyl transferase activityIncreased butyrl cholinesteraseIncreasedglutamateReduced ability of NMDA to release acetycholineReduced NMDA bindingDecreased protein kinase CIncreased leptin receptor activityIncreased neuronal nitric oxide synthaselipofusin which is greater in 100% SAMP8’s than in the back-crosses [17]. Periodic acid Schiff-positive granular structures of about 5 m in diameter that are associated with astrocytes occur in large numbers in the hippocampus and other brain structures of the SAMP8 mice [32]. Gliosis of astrocytes occurs early in SAMP8 mice [33,34]. This is associated with increased levels of glial fibril-lary acidic protein [35]. This is similar to the findings in brains of patients with Alzheimer’s disease. H owever, astrocyte derived 100 is not over-expressed in SAMP8 mice [28]. A marked de-crease in neuronal spine density occurs in the hippocampus of SAMP8 mice, similar to that seen in brains of Alzheimer’s patients [36,37]. Vacuoles occur in the magnocellular reticular formation [32]. These may be related to a murine leukemia virus present early in the development of the SAMP8 strain [38].It is now clear that SAMP8 mice overproduce a compound similar to amyloid-beta protein. Takemura et al [39] found a beta/A4 protein-like immunoreactive granular structure in multiple brain regions of the SAMP8 mice. This was confirmed by Fukunari et al [40] using a different antibody. Morley et al [41] found plaques which reacted to a amyloid-beta mouse antibody in the hippocampus of 21 month SAMP8 mice. They were not present in 12 month old mice. They used this to suggest that plaques are notThe SAMP8 Mouse Current Pharmaceutical Design, 2012, Vol. 18, No. 8 1125integral to the pathogenesis of amyloid induced memory distur-bances and brain damage.Our group has reported an increase in amyloid precursor protein and amyloid beta protein in the brains of old SAMP8 mice using a variety of mouse antibodies [41]. This is not found with all antibod-ies and the increases are small compared to transgenic mice. We failed to show an increase in either amyloid beta-1-40 or 1-42 (Holtzman SG and Morley JE: unpublished observations). The ex-act amyloid beta peptide form which is increased has not been char-acterized. Antibodies to amyloid-beta improve learning and mem-ory and increased acetylcholine in the hippocampus of the 12 month old SAMP8 mice [42,43].DelValleet al [44] found that SAMP8 mice have deposition of amyloid-beta protein from 6 months of age. These deposits in the hippocampus include both amyloid beta 1-40 and 1-42 as well as other fragments.Hyperphosphorylation of tau is present in 5 month old SAMP8 mice [45]. It is associated with an increase in Cdk5/p25 but not GSK3 activity. Alpha-synuclein, which induces tau phosphoryla-tion [46,47], is found in higher levels in SAMP8 mice [48]. NEUROCHEMICAL CHANGESOne of the earliest hypotheses of the cause of Alzheimer’s dis-ease was the presence of a cholinergic defect [49]. This has led to the development of multiple drugs with marginal functionality for the treatment of persons with Alzheimer’s disease. In the SAMP8 mice there is a decrease in cholinesterase acetyl transferase activity [50]. Acetylcholine esterase activity is not altered in SAMP8 mice but butylcholinesterase activity (BuChE) is increased [51,52]. This increase in BuChE most probably is due to the increased microglial activity. An increase in BuChE is seen in the CSF of patients with Alzheimer’s disease [53]. Binding activity for muscarinic acetyl-choline receptors is reduced in SAMP8 mice [54].There is an increase in glutamate and glutamine concentrations in the brains of SAMP8 mice [55]. Increased release of excitory neurotransmitters in response to depolarization occurs in the 10 month SAMP8 brain [55]. N-methyl-D-aspartic acid (NMDA) abil-ity to reduce acetylcholine release is reduced in SAMP8 mice by 6 months of age [56]. There is decreased binding of NMDA in the hippocampus of older SAMP8 mice. NMDA produces calcium influx into the brain. This results in an increase in cyclic AMP re-sponse element binding protein (CREB) phosphorylation by protein kinase C and calmodulin kinases. Protein kinase C is reduced in SAMP8 mice as is CREB [57-59]. CREB plays an essential role in long term potentiation.There is some evidence that somatostatin mRNA expression is decreased in the SAMP8 [60]. Somatostatin analogs improve mem-ory in the SAMP8 [61]. Somatostatin levels are decreased during aging in the corpus stratum [62], and in the transgenic (TG2576) AD mouse model [62,63]. This decrease in somatostatin has been also found in Alzheimer’s patients brains [64,65].Fig.(1) provides a schema for the neurotransmitter changes that occur in SAMP8 mice. The biochemical findings are in concert with our pharmacological findings [66,67]. The pharmacological and biochemical findings were combined to produce the pathway. Anatomically changes occur both in the septum and the hippocam-pus.The role of the increase in hippocampal cholinergic neurostimu-lating peptide, which is released by NMDA and enhances choliner-gic phenotype in young animals, in producing the cholinergic defi-cit in older SAMP8 animals is unclear [68,69].OXIDATIVE STRESSIncreased oxidative stress in SAMP8 mice has been universally observed [70]. In 1989, Nomura et al. [71] found a higher amount of malondealdehyde and lower levels of super oxidase dismutase in SAMP8 compared to SAMPR1 mice. SAMP8 mice also had an increase in thiobarbituric acid reactivity and a decrease in glu-tathione [72]. Glutamine synthase is also reduced, while the mi-croperoxisomal H2O2-producing enzyme, acylCoA oxidase is in-creased compared to young mice [73]. Nitric oxide synthase is in-creased in old SAMP8 compared to young animals [74]. The in-crease is in neuronal nitric oxide [75]. This increase appears to lead to increased astrogliosis [76].Farret al. [77] compared 12 month to 6 month SAMP8 mice. They found an increase in older SAMP8’s of protein carbonyls (an index of protein oxidation), increased thiobarbituric acid reactive substance (lipid peroxidation) and a decline in the weakly immobi-lized/strongly immobilized ratio of the protein-specific spin label Mal-6. Chronic administration of either alpha-lipoic acid or n-acetylcysteine improved memory and reversed the measures of oxidative stress.In our proteomic studies we found that a number of proteins that are oxidatively modified (viz lactate dehydrogenase-2, dihy-dropyrimindase-like protein 2, alpha-spectrin, creatine kinase, aldo-lase 3, coronin 1a and peroxiredom 2) are increased in old SAMP8 mice [78]. We further showed that alpha-lipoic acid treatment re-duced the oxidative modification of some of these proteins [79].The available studies strongly support the concept that oxida-tive damage plays a central role in the alterations that occur in the brain of SAMP8 mice.BLOOD BRAIN BARRIERTwo studies by Ueno et al [80,81] suggested that the blood brain barrier for albumin transport was disrupted in SAMP8 mice. Our group failed to find a disruption of the blood brain barrier for albumin in the SAMP8 mice [82]. Other studies have found a mild disruption of the blood brain barrier in the SAMP8’s [83-85].We found that transport of the cytokine, tumor necrosis-factor alpha was higher into certain areas [86]. This is compatible with our finding that transport of cytokines into the brain can lead to mem-ory impairment [87].Pituitary adenylate cyclase-activating peptide (PACAP) en-hances memory when its transport across the blood brain barrier is increased [88]. Aged SAMP8 mice show decreased transport rates into the whole brain and hippocampus [89].Efflux of amyloid-beta protein is considered a component of the mechanisms for the increase in amyloid-beta protein in Alzheimer’s disease [90]. We showed that efflux of mouse beta proteins 1-40 and 1-42 was impaired in the old SAMP8 mice [91]. An antibody to amyloid-beta 1-42 failed to improve amyloid-beta 1-42 clearance from the brain [92].Transport of amyloid precursor protein into the brain is depend-ent on the receptor for advanced glycation endproducts (RAGE) and the efflux transporter is low-density lipoprotein receptor (LDLR)[93]. LDLR levels were elevated in SAMP8 compared to SAMR1 mice, while another amyloid-Beta protein transporter, LDL-related protein 1, showed no differences. RAGE levels were increased in SAMP8 mice. These findings may be partly responsi-ble for the altered transport of amyloid-beta protein and also con-tribute to the elevated oxidative stress in SAMP8 mice. MEMBRANE LIPIDSAlterations of fat content in brain membranes has been associ-ated with modulation of memory [94]. Supplementation with phos-phatidylcholine in animals enhances the brain acetylcholine concen-tration and leads to memory improvement [95]. When phosphati-dylcholine was supplemented to SAMP8 mice they had an increase in docasahexanoic and palmitic acid in the brain membranes [96].Petursdottiret al [97] found that, with aging, SAMP8 mice had lower percentages of docosahexaenoic acid in phosphatatidylserine1126 Current Pharmaceutical Design, 2012, Vol. 18, No. 8 Morley et al.and phosphatidylinositol and higher arachidonic acid in phosphati-dylserine in the hippocampus. Alpha-tocopherol levels incr4eased with aging. In a subsequent study we showed that a diet rich in docasohexanoic acid improved learning and retention in SAMP8 mice and increased docosahexanoic acid in phospholipids in the hippocampus and the amygdala [98].Kumaret al [99] found a decrease in delta-9-desaturase activity in older SAMP8 mice. This was associated with declines in unsatu-rated fatty acid levels and would lead to a decrease in membrane fluidity.GENE EXPRESSIONPresenilin-1 is a component of the complex that forms gamma-secretase. The other components are nicastrin, APH-1 and Pen-2. Gamma-secretase is the enzyme that cleaves Amyloid Precursor Protein. Gamma-secretase activity results in the production of the small peptides, Abeta [1-40] and Abeta [1-42]. We cloned presini-lin-1 from the SAMP8 mouse [100]. Presenilin levels are increased in the hippocampus of the SAMP8 mouse compared to CD-1 mice.In 2000, Kumar et al. [101] examined gene expression in the hippocampus. We found that there were alterations in the chaperone regulator family and in xenobiotic metabolizing enzymes. The xenobiotic metabolizing enzymes play a role in defense against oxidants. Chaperone signaling complexes appear to play a role in tau and amyloid accumulation in Alzheimer’s disease [102].Carteret al. [103] found that chemokine CCL19 was ectopi-cally expressed in the hippocampus of older SAMP8 mice. This suggested a role for inflammation in the development of memory defects in SAMP8 mice.Chenget al. [104] compared 12 month SAMP8 to SAMR1 mice using gene expression. They found an upregulation of mito-chondrial genes (e.g., cytochrome C oxidase subunit 1) and cy-toskeletal genes (e.g., dynein cytoplasnice heavy chain I) in the hippocampus of SAMP8. Dynein and other cytoskeletal proteins are altered in Alzheimer’s disease [105]. Genes involved in long term potentiation and dendritic spine growth were down regulated.As none of the gene expression profiling studies were done against an appropriate control, we recently compared 4 and 12 month SAMP8 mice against the 50% backcross. Comparing the 12 month old 50% backcross and SAMP8 mice, there were significant differences in expression of 536 hippocampal genes. Pathway analysis demonstrated significant differences in the phosphatidyli-nositol signaling and long term potentiation pathways. There were no significant differences in these pathways at 4 months. This sug-gests that the differences in these pathways arise as the SAMP8 ages from 4 to 12 months, the same time period during which learn-ing and memory deficits arise. Given the importance of these path-ways in learning and memory Fig. (1), these differences could con-tribute to the deficits seen in the SAMP8 mice at 12 months. TESTOSTERONETestosterone levels decline with aging in older males [106-109]. Low testosterone levels are more common in males with Alz-heimer’s disease [109,110]. We showed that low bioavailable tes-tosterone levels independently predicted rapid progression from mild cognitive impairment to Alzheimer’s disease [111].SAMP8 mice at 12 months of age have low testosterone levels [112]. Testosterone replacement enhances learning and retention in older SAMP8 mice. Testosterone decreases amyloid precursor pro-tein levels in the hippocampus of SAMP8 mice (Kumar and Mor-ley: Unpublished observations).LEPTIN AND MEMORYAbnormalities in leptin have been found in persons with Alz-heimer’s disease [113]. H osoi et al [114] found that there was an increase in leptin-induced STAT3 phosphorylation in the hypo-thalamus of SAMP8 mice compared to SAMR1. In addition, the leptin receptor (Ob-Rb) expression was upregulated in SAMP8 mice.Previously we had shown that obese mice which have a leptin deficiency have impaired learning [115]. We then showed that leptin improved learning and retention in two tasks in CD-1 mice. Older SAMP8 mice required lower doses of leptin to improve memory, a finding compatible with the increase in the Ob-Rb re-ceptor in SAMP8 mice.Ghrelin is an orexigenic peptide which is produced from the fundus of the stomach [116]. Ghrelin enhances memory and in-creases hippocampal spine density [117]. H igher doses of ghrelin are required to enhance memory in 12 month old SAMP8 mice than in younger mice.Our group developed a number of small antisenses to amyloid precursor protein (APP)[118]. We found that 2 phosphothiolated oligonucleotide antisenses against the midportion of APP improved acquisition and retention in the T-maze footshock avoidance para-digm. A random antisense was ineffective as some of the internal ODNs which served as controls. The two effective antisenses are from the internal sequence of APP mRNA and had no effect on mRNA of APP, but decreased APP protein levels by as much as 48% to 68% in the P8 hippocampus, amygdala and septum. These ODNs may be blocking the translation rather than causing extensive degradation of message by ds-nuculeases. Such a reduction was accompanied by a decrease in Amyloid-beta protein levels.SAMP8 APP was cloned by us [119] and its sequence was 99.7% homologous with rat and mice, and 89.2% homologous with human APP. The ODNs designed from P8 sequence were first tested for APP expression in H eLa cells and the two that showed the reduction in expression in a time and concentration dependent manner were selected to study in SAMP8 mice.LeBlancet al [120] found that cells transfected with an an-tisense APP mRNA reduced APP and amyloid-beta by 80 to 90%. An antisense to the C-terminus of APP reduced the level of APP in PC12 cells [121-123]. The antisense oligonucleotide decreased nerve growth factor induction of increased cellular size and neurite length. Allinquant et al [124] showed that an antisense oligonucleo-tide decreased axon and dendrite outgrowth by embryonic cortical neurons. These findings are generally opposite to what would be expected if reducing APP improved cell function. H owever, we have recently shown that low levels of amyloid-beta peptide have a physiological role as enhancers of learning and memory [125].McMahonet al [126] found that peptide nucleic acid antisense to APP lowers amyloid-beta [1-40] by 37% and [1-42] by 47% in normal mice brains.Neuronal cell lines derived from trisomy (Ts16) mice overpro-duce APP. Antisense to APP reduces APP in these mice [127]. The antisense resulted in reversed impairment of 3H-choline uptake in this cell line, suggesting that the APP has been impairing choliner-gic function. The APP antisense also decreased basal levels of cal-cium cones and enhanced the calcium responses to glutamergic and nicotinic agonist in these cells [128].Our further studies in old SAMP8 mice have demonstrated that our antisense to APP improves learning and memory when adminis-tered peripherally [129]. We showed that the APP antisense crosses the blood brain barrier and that it enters into brain cells [130]. We have also shown that the antisense to APP can be given intranasally (unpublished).Our antisense also reduces brain oxidative markers in the SAMP8 mouse [130]. Antisense to APP also reduced carbonyl levels of aldolase 3, coronin 1a and perioxiredoxin 2 compared to the effects seen with a random antisense [131]. Expression of alpha-ATP synthase was increased.The SAMP8 Mouse Current Pharmaceutical Design, 2012, Vol. 18, No. 8 1127We have found that the slowed efflux of amyloid-beta [1-42] from the brains of the SAMP8 mice can be reversed by our an-tisense [132].Recently we have found that our antisense improves memory in the H siao transgenic mice that overproduce amyloid-beta (unpub-lished observations).CONCLUSIONThe SAMP8 mouse is an excellent mouse model for Alz-heimer’s like pathology. It has early cognitive deficits, oxidative damage in the brain, loss of dendritic and spines in the central nerv-ous system.There is overproduction of amyloid precursor protein and amy-loid-beta protein and increased phosphorylation of tau in the hippo-campus of the SAMP8 mouse. Antibodies to amyloid-beta protein reverse the memory deficits and increase acetylcholine release in SAMP8 mice. An antisense to APP has been shown to improve memory, enhance removal of amyloid-beta from the brain and de-crease oxidative damage. It can be administered peripherally. This antisense to APP has promise as a therapeutic agent for the treat-ment of Alzheimer’s disease.Overall, the SAMP8 mouse is an excellent model to study both aging changes and early Alzheimer Disease changes in comparison to the transgenic mice.CONFLICTS OF INTERESTDrs. Morley, Farr and Kumar are shareholders in Edunn Bio-tech Co. There are no other conflicts to declare.REFERENCES[1]Takeda T, Josokawa M, Takeshita S, et al. A new murine modelaccelerated senescence. Mech Ageing Dev 1981; 17: 183-94.[2]Hosokawa M, Kasai R, Higuchi K, et al. Grading score system: amethod for evaluation of the degree of senescence in senescenceaccelerated mouse (SAM). Mech Ageing Dev 1994; 26: 91-102. [3]Woodruff-Pak DS. Animal models of Alzheimer’s disease: thera-peutic implications. J Alz Dis 2008; 15: 507-21.[4]Pallas M, Camins A, Smith MA, et al. From aging to Alzheimer’sdisease: unveiling “the switch” with the senescence-acceleratedmouse model (SAMP8). J Alz Dis 2008; 15: 615-24.Fig. (1). Putative Alterations in Neurotransmitter Activity in SAMP8 Mice Leading to Alterations in Learning and Memory。