Emotional behavior and expression patterns of tyrosine hydroxylase and tryptophan hydroxylase in senescence-accelerated mouse (SAM) P6 mice

Senescence-accelerated prone mouse 6 (SAMP6) is a model for senile osteoporosis. It was recently reported that SAMP6 has a memory deficit in the water maze test. Because emotion and cognition are thought to interact, in the present study to examine emotional behavior in SAMP6, we employed a battery of tasks (open field, elevated plus maze, light-dark exploration, marble-burying behavior, tail suspension), using three age groups (1, 4, and 8 months of age) of SAMP6 mice and age-matched control SAMR1 (senescence-accelerated resistant mouse 1) mice. All three age groups of SAMP6 showed higher activity than SAMR1 in the open field test and reduced anxiety as measured in terms of time spent on the open arms in the elevated plus maze, time spent in the light box in the light-dark exploration, and time spent in marble-burying behavior in the marble-burying test. All three age groups of SAMP6 showed reduced immobility time compared with SAMR1 in the tail suspension test. Western blot analyses showed increased expression levels of tyrosine hydroxylase phosphorylated at serine-40 in striatum and nucleus accumbens and of tryptophan hydroxylase phosphorylated at serine-58 in brain stem of 1-month-old SAMP6. These results suggest that one possible reason for the alterations of motor activity and emotional behavior of SAMP6, at least after 1 month of age, is increased dopamine and serotonin levels.     

Spatial memory performance and hippocampal neuron number in osteoporotic SAMP6 mice

The senescence-accelerated mouse strain P6 (SAMP6) is an inbred mouse that represents a clinically relevant model of senile osteoporosis. However, whether osteoporotic SAMP6 mice have cognitive deficits remains largely unexplored. Here, we used Morris water maze to assess reference memory and working memory performance in SAMP6 mice and SAMR1 controls, at 4 and 8 months of age. In addition, unbiased stereological techniques were used to estimate total neuron number in hippocampal CA1 subfield of the mice used in the behavioral study. Morris water maze test revealed impairments in working memory but not in reference memory of the 4- and 8-month-old SAMP6 mice compared with the SAMR1 mice at the same age. However, there were no significant differences in the total numbers of neurons in hippocampal CA1 subfield when comparing 4-month-old SAMR1 and 4-month-old SAMP6 and 8-month-old SAMR1 and 8-month-old SAMP6, which indicate that, in SAMP6 mice, the structural correlates of working memory deficits are to be found in parameters other than the number of neurons in hippocampal CA1 subfield. These findings suggest that SAMP6 mice exhibit selective cognitive deficits and highlight the importance of this mouse model for studying the brain alterations associated with osteoporosis.     

SAMP8 mice as a neuropathological model of accelerated brain aging and dementia: Toshio Takeda's legacy and future directions

Senescence accelerated mice P8 (SAMP8) show significant age‐related deteriorations in memory and learning ability in accordance with early onset and rapid advancement of senescence. Brains of SAMP8 mice reveal an age‐associated increase of PAS‐positive granular structures in the hippocampal formation and astrogliosis in the brain stem and hippocampus. A spongy degeneration in the brain stem appears at 1 month of age and reaches a maximum at 4‐8 months. In addition, clusters of activated microglia also appear around the vacuoles in the brain stem. β/A4(Aβ) protein‐like immunoreactive granular structures are observed in various regions and increase in number markedly with age. Other age‐associated histological changes include cortical atrophy, neuronal cell loss in locus coeruleus and lateral tegmental nuclei, intraneuronal accumulation of lipopigments in Purkinje cells and eosinophilic inclusion bodies in thalamic neurons. A blood–brain barrier dysfunction and astrogliosis are also prominent with advancing age in the hippocampus. These changes are generally similar to the pathomorphology of aging human brains and characterized by their association with some specific glioneuronal reactions. As for the hallmarks of Alzheimer brains, tau morphology has not yet been confirmed regardless of the age‐related increase in phosphorylated tau in SAMP8 mice brains, but early age‐related Aβ deposition in the hippocampus has recently been published. SAMP8 mice are, therefore, not only a senescence‐accelerated model but also a promising model for Alzheimer's disease and other cognitive disorders.     

Characterization of a 3xTg‐AD mouse model of Alzheimer's disease with the senescence accelerated mouse prone 8 (SAMP8) background

No model fully recapitulates the neuropathology of Alzheimer's disease (AD). Although the triple‐transgenic mouse model of AD (3xTg‐AD) expresses Aβ plaques and tau‐laden neurofibrillary tangles, as well as synaptic and behavioral deficits, it does not display frank neuronal loss. Because old age is the most important risk factor in AD, senescence‐related interactions might be lacking to truly establish an AD‐like environment. To investigate this hypothesis, we bred the 3xTg‐AD mouse with the senescence‐accelerated mouse prone 8 (SAMP8), a model of accelerated aging. We generated four groups of heterozygous mice with either the SAMP8 or SAMR1 (senescence‐resistant‐1) genotype, along with either the 3xTg‐AD or non‐transgenic (NonTg) genotype. Despite no differences among groups in total latency to escape the Barnes maze, a greater number of errors were noticed before entering the target hole in 19‐month‐old P8/3xTg‐AD mice at day 5, compared to other groups. Postmortem analyses revealed increased cortical levels of phospho‐tau (Thr231) in female P8/3xTg‐AD mice (+277% vs. R1/3xTg‐AD mice), without other tau‐related changes. Female P8/3xTg‐AD mice exhibited higher cortical soluble Aβ40 and Aβ42 concentrations (Aβ40, +85%; Aβ42, +35% vs. R1/3xTg‐AD), whereas insoluble forms remained unchanged. Higher Aβ42 load coincided with increased astroglial activation in female P8/3xTg‐AD mice, as measured with glial fibrillary acidic protein (GFAP) (+57% vs. R1/3xTg‐AD mice). To probe neuronal degeneration, concentrations of neuronal nuclei (NeuN) were measured, but no differences were detected between groups. Altogether, the SAMP8 genotype had deleterious effects on spatial memory and exerted female‐specific aggravation of AD neuropathology without overt neurodegeneration in 3xTg‐AD mice.     

Pigment Epithelium-Derived Factor Plays a Role in Alzheimer’s Disease by Negatively Regulating Aβ42

Alzheimer’s disease (AD) is the most common cause of dementia. Pigment epithelium-derived factor (PEDF), a unique neurotrophic protein, decreases with aging. Previous reports have conflicted regarding whether the PEDF concentration is altered in AD patients. In addition, the effect of PEDF on AD has not been documented. Here, we tested serum samples of 31 AD patients and 271 normal controls. We found that compared to PEDF levels in young and middle-aged control subjects, PEDF levels were reduced in old-aged controls and even more so in AD patients. Furthermore, we verified that PEDF expression was much lower and amyloid β-protein (Aβ)42 expression was much higher in senescence-accelerated mouse prone 8 (SAMP8) strain mice than in senescence-accelerated mouse resistant 1 (SAMR1) control strain mice. Accordingly, high levels of Aβ42 were also observed in PEDF knockout (KO) mice. PEDF notably reduced cognitive impairment in the Morris water maze (MWM) and significantly downregulated Aβ42 in SAMP8 mice. Mechanistically, PEDF downregulated presenilin-1 (PS1) expression by inhibiting the c-Jun N-terminal kinase (JNK) pathway. Taken together, our findings demonstrate for the first time that PEDF negatively regulates Aβ42 and that PEDF deficiency with aging might play a crucial role in the development of AD.     

Age-related alteration in cerebral blood flow and energy failure is correlated with cognitive impairment in the senescence-accelerated prone mouse strain 8 (SAMP8)

Cerebrovascular dysfunction is an early pathogenic event in Alzheimer’s disease (AD) and plays a key role in the disease process. Cerebral hypoperfusion, brain glucose hypometabolism and disrupted blood–brain barrier (BBB) integrity contributed to the onset and progression of AD. However, the relationships between the age-related cognitive impairment and cerebral blood flow (CBF), energy metabolism and BBB have not been clearly explained. In this study, we investigated the cognitive function, CBF, BBB damage and expression level of glucose transporter (GLUT) 1 and 3 of senescence-accelerated mouse prone 8 (SAMP8), and the correlations between each of them were analyzed. When compared with SAMR1 (senescence-accelerated mouse resistant 1), the cognitive abilities of SAMP8 were damaged apparently even at 4 months of age, showing up a slower and more capricious acquisition in Morris water maze tasks. In both SAMP8 and SAMR1, reduced CBF and increased BBB leakage were observed with increasing age, but an earlier and more severe impairment was detected in SAMP8. In addition, alterations of GLUT1 and GLUT3 protein expression in cortex and hippocampus were more prominent in SAMP8. Correlation analysis demonstrated that the increased escape latency was correlated negatively with CBF and expression of glucose transporters; and positively with BBB permeability in the hippocampus. These results suggested that CBF, BBB integrity, the expression of GLUT1 and GLUT3 were significantly affected by age and strain, which were also closely associated with cognitive ability. The alteration in CBF and energy failure induced by aging and vascular insults resulted in cognitive decline in SAMP8.     

Hippocampal neuron loss is correlated with cognitive deficits in SAMP8 mice

The objective of this study is to examine whether neuron loss occurs in SAMP8 and whether neuron loss is correlated with cognitive deficits of these mice. Neuronal loss is considered as one of the most important pathological hallmarks of Alzheimer disease (AD). In addition to the early-onset, irreversible, severe deficits of learning and memory, SAMP8 mice show spontaneous age-related neurodegenerative changes and other characteristics seen in AD patients, such as amyloid plaques and neurofibrillary tangles. However, it is still unknown whether neuron loss occurs in SAMP8 and whether neuron loss is correlated with cognitive deficits of these mice. We employed 8-month-old SAMP8 and SAMR1 mice to investigate the cognitive function and neuron numbers. The behaviors were examined by the grading score of senescence and Morris water maze (MWM) test, the neuron number in hippocampus was estimated by the optical fractionator technique. The grading score of senescence and MWM test demonstrated that SAMP8 exhibited notable age-related changes in appearance and cognitive function. Moreover, severe hippocampal neuron loss was found in SAMP8 as determined by the optical fractionator stereological method. Compared to SAMR1, the neuron number of CA1, CA3 and DG in SAMP8 was reduced by 15.6, 19.8 and 20.2 %, respectively, and the neuron loss in hippocampus was associated with cognitive deficits. Collectively, these results suggest that hippocampal neuronal loss is well correlated with learning and memory deficits in SAMP8 and SAMP8 represents an important mouse model for AD.     

经颅电刺激对阿尔兹海默病大鼠学习记忆能力和海马CA_1区磷酸化tau蛋白表达情况的影响

目的探讨经颅电刺激对阿尔兹海默病(Alzeheimer’s disease,AD)大鼠学习记忆能力和海马CA_1区磷酸化tau蛋白表达的影响。方法健康SD大鼠,随机分为:正常组、假手术组、模型组及经颅电刺激2 w、4 w、6 w组。采用大鼠侧脑室注射Aβ25-35凝聚态β-淀粉样肽,同时腹腔注射D-半乳糖的方法,建立AD动物模型。Morris水迷宫实验检测各组大鼠学习、记忆能力,HE染色,观察海马CA_1区形态学结构,免疫组化测定海马CA_1区磷酸化tau蛋白表达情况。结果 (1)Morris水迷宫实验大鼠测试学习和记忆能力,经颅电刺激2 w组与模型组比较差异无统计学意义(P0.05),经颅电刺激4 w组、6 w组与模型组比较,逃避潜伏期成绩均好于模型组,差异有统计学意义(P0.05);(2)随电刺激时间延长,经颅电刺激各组磷酸化tau蛋白量逐渐降低,与模型组比较差异有统计学意义(P0.05)。结论经颅电刺激能够改善阿尔兹海默病大鼠的学习记忆能力,机制可能与下调海马CA_1区磷酸化tau蛋白表达有关,对细胞的重塑有积极影响,远期效果有待进一步研究。     

Hypoxia Increases Aβ-Induced Tau Phosphorylation by Calpain and Promotes Behavioral Consequences in AD Transgenic Mice

Chronic hypoxia has been reported to contribute to the development of Alzheimer’s disease (AD). However, the mechanism of hypoxia in the pathogenesis of AD remains unclear. The purpose of this study was to investigate the effects of chronic hypoxia treatment on β-amyloid, tau pathologies, and the behavioral consequences in the double transgenic (APP/PS1) mice. Double transgenic mice (APP/PS1 mice) were treated with hypoxia, and spatial learning and memory abilities of mice were assessed in the Morris water maze. β-amyloid level and plaque level in APP/PS1 double transgenic mice were detected by immunohistochemistry. Protein tau, p35/p25, cyclin-dependent kinase 5 (CDK5), and calpain were detected by western blotting analysis. Chronic hypoxia treatment decreased memory and cognitive function in AD mice. In addition, chronic hypoxia treatment resulted in increased senile plaques, accompanying with increased tau phosphorylation. The hypoxia-induced increase in the tau phosphorylation was associated with a significant increase in the production of p35 and p25 and upregulation of calpain, suggesting that hypoxia induced aberrant CDK5/p25 activation via upregulation of calpain. Our results showed that chronic hypoxia exposure accelerates not only amyloid pathology but also tau pathology via calpain-mediated tau hyperphosphorylation in an AD mouse model. These pathological changes possibly contribute to the hypoxia-induced behavioral change in AD mice.     

Genistein protects hippocampal neurons against injury by regulating calcium/calmodulin dependent protein kinase IV protein levels in Alzheimer's disease model rats

Genistein has a neuroprotective effect in Alzheimer's disease, but its mechanism of action needs further clarification. Accumulating evidence suggests that excessive phosphorylation of tau protein causes production of neurofibrillary tangles, which is one of the main pathological characteristics of Alzheimer's disease, and tau protein can be phosphorylated by calcium/calmodulin dependent protein kinase IV (CAMK4). After 7 days of pre-administration of genistein (90 mg/kg), an Alzheimer's disease rat model was established using an intraperitoneal injection of D-galactose combined with an intracerebral injection of amyloid-β peptide (25–35). The rat was then continu-ously administered genistein (90 mg/kg) for 42 days. The Morris water maze test, western blotting and hematoxylin-eosin staining results showed that genistein significantly decreased the escape latency and increased the number of times crossing the platform, reduced p-tau, CALM, CAMKK1 and p-CAMK4 protein levels in the hippocampus, and alleviated hippocampal neuron damage. These findings indicate that genistein may play a neuroprotective role in Alzheimer's disease through regulating CAMK4 to modulate tau hyperphosphorylation.     

Lithium treatment decreases activities of tau kinases in a murine model of senescence

Lithium modulates glycogen synthase kinase 3beta (GSK-3beta), a kinase involved in Alzheimer disease-related tau pathology. To investigate mechanisms of aging and the potential therapy of lithium in neurodegenerative disease, we treated senescence-accelerated mouse (SAM)P8 mice, a murine model of senescence, and mice of the control SAMR1 strain with lithium. The treatment reduced hippocampal caspase 3 and calpain activation, indicating that it provides neuroprotection. Lithium also reduced both the levels and activity of GSK-3beta and the activity of cyclin-dependent kinase 5 and reduced hyperphosphorylation of 3 different phosphoepitopes of tau: Ser199, Ser212, and Ser396. In lithium-treated primary cultures of SAMP8 and SAMR1 cerebellar neurons, there was a marked reduction in protease activity mediated by calpain and caspase 3. Both lithium and SB415286, a specific inhibitor of GSK-3beta, reduced apoptosis in vitro. Taken together, these in vivo and in vitro findings of lithium-mediated reductions in GSK-3beta and cyclin-dependent kinase 5 activities, tau phosphorylation, apoptotic activity, and cell death provide a strong rationale for the use of lithium as a potential treatment in neurodegenerative diseases.     

Genistein suppresses the mitochondrial apoptotic pathway in hippocampal neurons in rats with Alzheimer’s disease

Genistein is effective against amyloid-β toxicity,but the underlying mechanisms are unclear.We hypothesized that genistein may protect neurons by inhibiting the mitochondrial apoptotic pathway,and thereby play a role in the prevention of Alzheimer's disease.A rat model of Alzheimer's disease was established by intraperitoneal injection of D-galactose and intracerebral injection of amyloid-β peptide(25–35).In the genistein treatment groups,a 7-day pretreatment with genistein(10,30,90 mg/kg) was given prior to establishing Alzheimer's disease model,for 49 consecutive days.Terminal deoxyribonucleotidyl transferase-mediated d UTP nick end labeling assay demonstrated a reduction in apoptosis in the hippocampus of rats treated with genistein.Western blot analysis showed that expression levels of capase-3,Bax and cytochrome c were decreased compared with the model group.Furthermore,immunohistochemical staining revealed reductions in cytochrome c and Bax immunoreactivity in these rats.Morris water maze revealed a substantial shortening of escape latency by genistein in Alzheimer's disease rats.These findings suggest that genistein decreases neuronal loss in the hippocampus,and improves learning and memory ability.The neuroprotective effects of genistein are associated with the inhibition of the mitochondrial apoptotic pathway,as shown by its ability to reduce levels of caspase-3,Bax and cytochrome c.     

快速老化痴呆模型小鼠SAMP8学习记忆能力的增龄性变化

目的对快速老化痴呆模型小鼠SAMP8学习记忆能力的增龄性变化进行较系统的研究,为利用该模型进行其他研究提供实验依据。方法此实验选用1、4、8、12月龄的快速老化痴呆模型小鼠SAMP8,与同龄的正常老化小鼠SAMR1作对照,从老化度评分、避暗实验、Morris水迷宫实验和自主活动实验等方面观察了SAMP8小鼠学习记忆能力的增龄性变化。结果与对照组SAMR1相比,SAMP8小鼠随月龄增加老化度评分呈增高趋势,在8、12月龄的老化度评分值显著高于同龄对照组(P<0.05);避暗实验中,8、12月龄的SAMP8小鼠在电击24h后进入暗箱的潜伏期比同龄SAMR1小鼠显著缩短(P<0.05);Morris水迷宫实验中,1、4月龄SAMP8小鼠找到暗台的潜伏时间与同龄SAMR1小鼠相比差异无显著性,而8、12月龄SAMP8小鼠与同龄对照组相比,潜伏时间显著延长(P<0.05);从自主活动实验看,1、4、8月龄SAMP8小鼠单位时间内自主活动次数与同龄SAMR1小鼠相比无显著变化,而12月龄SAMP8小鼠与同龄对照组相比单位时间内自主活动次数显著减少(P<0.05)。结论SAMP8小鼠随月龄增长学习记忆能力逐渐减退;与同龄对照组相比,8、12月龄SAMP8小鼠出现明显衰老特征,表现出学习记忆能力明显低下,故可作为老化痴呆的动物模型用于痴呆有关研究。     

Acupuncture improves dendritic structure and spatial learning and memory ability of Alzheimer's disease mice

Acupuncture can improve the cognitive state of Alzheimer's disease, but its mechanism is not clear. Dendritic atrophy and synaptic loss in Alzheimer's disease brain are positively correlated with cognitive damage. Therefore, we speculated that the effect of acupuncture on improving cognitive function may be associated with reduced dendritic damage in the brain. Acupuncture at Qihai(CV6), Zhongwan(CV12), Danzhong(CV17), bilateral Zusanli(ST36), and bilateral Xuehai(SP10) acupoints was performed once a day(1-day rest after 6-day treatment) for 14 consecutive days. Senescence-accelerated mouse prone 8(SAMP8) mice without acupuncture and senescence-accelerated mouse resistant 1(SAMR1) mice were used as normal controls. After 14 days of treatment, spatial learning and memory ability of mice was assessed in each group using the Morris water maze. Dendritic changes of pyramidal cells in the hippocampal CA1 region were analyzed by quantitative Golgi staining. Our results showed that acupuncture shortened escape latency and lengthened retention time of the former platform quadrant in SAMP8 mice. Further, SAMP8 mice exhibited a significant increase in the number of apical and basal dendritic branches and total length of apical and basal dendrites after acupuncture. These results suggest that acupuncture improves spatial learning and memory ability of middle-aged SAMP8 mice by ameliorating dendritic structure.     

Icariin upregulates phosphorylated cyclic adenosine monophosphate response element binding protein levels in the hippocampus of the senescence- accelerated mouse

At 8 weeks after intragastric administration of icariin to senescence-accelerated mice (P8 strain), Morris water maze results showed that escape latency was shortened, and the number of platform crossings was increased. Immunohistochemical staining and western blot assay detected significantly increased levels of cyclic adenosine monophosphate response element binding protein. These results suggest that icariin upregulates phosphorylated cyclic adenosine monophosphate response element binding protein levels and improves learning and memory functions in hippocampus of the senescence-accelerated mouse.     

Telmisartan Protects Against Aluminum-Induced Alzheimer-like Pathological Changes in Rats

Currently, there is no effective mean for treatment or prevention of Alzheimer’s disease (AD). Commonly used AD drugs have a moderate effect and treat only the associated symptoms, therefore there is a strong need to search for more effective agents. Our goal is to examine telmisartan neuroprotective effect in aluminum-induced cognitive impairment in rats. Aluminum chloride (10 mg/kg, i.p) was administered for 2 months then behavioral tests (Y-maze and Morris water maze) were done. Hippocampal biochemical and histological analysis were then carried out. AD-like histological, biochemical, and behavioral alterations appeared in aluminum-treated rats. Telmisartan improved rats’ condition on behavioral and histological levels. It reversed the increase in hippocampal amyloid beta protein, phosphorylated tau protein contents together with augmentation of neprilysin level, it also diminished levels of nuclear factor kappa-B, FAS ligand, tumor necrosis factor-alpha, malondialdehyde, and acetylcholinesterase content.

These findings show the protective action of telmisartan against AD-like pathological alterations.

     

Effects of triptolide on hippocampal microglial cells and astrocytes in the APP/PS1 double transgenic mouse model of Alzheimer’s disease

The principal pathology of Alzheimer's disease includes neuronal extracellular deposition of amyloid-beta peptides and formation of senile pl aques,which in turn induce neuroinflammation in the brain.Triptolide,a natural extract from the vine-like herb Tripterygium wilfordii Hook F,has potent anti-inflammatory and immunosuppressive efficacy.Therefore,we determined if triptolide can inhibit activation and proliferation of microglial cells and astrocytes in the APP/PS1 double transgenic mouse model of Alzheimer's disease.We used 1 or 5 μg/kg/d triptolide to treat APP/PS1 double transgenic mice(aged 4–4.5 months) for 45 days.Unbiased stereology analysis found that triptolide dose-dependently reduced the total number of microglial cells,and transformed microglial cells into the resting state.Further,triptolide(5 μg/kg/d) also reduced the total number of hippocampal astrocytes.Our in vivo test results indicate that triptolide suppresses activation and proliferation of microglial cells and astrocytes in the hippocampus of APP/PS1 double transgenic mice with Alzheimer's disease.     

Enhanced accumulation of tau in doubly transgenic mice expressing mutant betaAPP and presenilin-1

Abeta amyloidosis and tauopathy are characteristic changes in the brain of Alzheimer's disease. Although much evidence suggests that Abeta deposit is a critical initiation factor, the pathological pathway between Abeta amyloidosis and tau accumulation remains unclear. Tau accumulation was examined in the doubly transgenic mouse (APP-PS) expressing betaAPP(KM670/671NL) (Tg2576) and presenilin-1 L286V (PS-1 L286Vtg). Accelerated and enhanced Abeta amyloid deposits were detected from 8 weeks. Tau accumulation appeared at 4.5 months and markedly increased in dystrophic neurites around Abeta amyloid. Accumulated tau was phosphorylated, conformationally altered, and argyrophilic. Expression of tau and accumulation of sarkosyl-insoluble phosphorylated tau were increased in APP-PS brains compared with those of Tg2576 mice. Straight or twisted tubules mimicking paired helical filament were revealed at electron microscopic level in 16-month-old APP-PS. These findings suggest that mutant presenilin-1 accelerated Abeta-induced tauopathy and further promoted fibril formation of tau.     

What is the new target inhibiting the progression of Alzheimer’s disease？

To stop the progression of Alzheimer＇s disease in the early stage, it is necessary to identify new therapeutic targets. We examined striatal-enriched phosphatase 61 expression in the brain tissues of 12-month-old APPswe/PSEN1dE9 transgenic mice. Immunohistochemistry showed that striatal-enriched phosphatase 61 protein expression was significantly increased but phosphorylated N-methyl-D-aspartate receptor 2B levels were significantly decreased in the cortex and hippocampus of APPswe/PSEN1dE9 transgenic mice. Western blotting of a cell model of Alzheimer＇s disease consisting of amyloid-beta peptide （1-42）-treated C57BL/6 mouse cortical neurons in vitro showed that valeric acid （AP5）, an N-methyl-D-aspartate receptor antagonist, significantly inhibited amyloidbeta 1-42-induced increased activity of striatal-enriched phosphatase 61. In addition, the phosphorylation of N-methyl-D-aspartate receptor 2B at Tyr1472 was impaired in amyloid-beta 1-42-treated cortical neurons, but knockdown of striatal-enriched phosphatase 61 enhanced the phosphorylation of N-methyl-D-aspartate receptor 2B. Collectively, these findings indicate that striatal-enriched phosphatase 61 can disturb N-methyl-D-aspartate receptor transport and inhibit the progression of learning and study disturbances induced by Alzheimer＇s disease. Thus, striatal-enriched phosphatase 61 may represent a new target for inhibiting the progression of Alzheimer＇s disease.     

3R tau expression modifies behavior in transgenic mice

Tauopathy is a group of disorders characterized by the accumulation of hyperphosphorylated tau protein in the brain, resulting in dementia. Here, tau‐related behavior was evaluated in a mouse model with brain overexpression of the shortest human tau isoform (0N3R). Two groups of animals [tau‐transgenic (tau‐tg) and control littermates] were tested for learning and memory at 1 and 7 months. In the Morris water maze, all mice learned the task at 1 month of age and did not learn at 7 months. In contrast, at 7 months, the tau‐tg animals demonstrated better retention of the passive avoidance response compared with their control littermates, which did not learn. In the open field test, no differences were measured between transgenic and nontransgenic young mice, but significantly higher locomotion was observed in the 7‐month‐old tau‐tg mice compared with controls. Behavior during the elevated plus maze test was the same at 1 month, but at 7 months increased entrance to the different arms was observed in the tau‐tg group. Tau expression and phosphorylation levels were analyzed at 8 months. In the subcortical brain region associated with passive avoidance behavior, the tau‐tg mice demonstrated increased brain tau expression coupled with reduced relative phosphorylation. In contrast, increased tau expression and phosphorylation were measured in the cerebral cortex of the tau‐tg mice. In conclusion, 7‐8‐month‐old tau‐tg mice overexpressing nonmutated 0N3R human tau isoform demonstrated enhanced behavior in the passive avoidance test, paralleled by relative tau hypophosphorylation in the subcortical brain region. © 2010 Wiley‐Liss, Inc.