Impairments In Spatial Memory Retention Research Articles

Apolipoprotein E Isoform-Dependent Effects on Human Amyloid Precursor Protein/Aβ-Induced Behavioral Alterations and Cognitive Impairments and Insoluble Cortical Aβ42 Levels.

Mice expressing human amyloid precursor protein (APP) containing the dominant Swedish and Iberian mutations (AppNL–F) or also Arctic mutation (AppNL–G–F) show neuropathology and hippocampus-dependent cognitive impairments pertinent to Alzheimer’s disease (AD) in mouse models at 18 and 6 months of age, respectively. Apolipoprotein E, involved in cholesterol metabolism, plays an important role in maintaining the brain. There are three human apolipoprotein E isoforms: E2, E3, and E4. Compared to E3, E4 increases while E2 protects against AD risk. At 6 months of age, prior to the onset of plaque pathology, E3, but not E4, protected against hAPP/Aβ-induced impairments in spatial memory retention in the Morris water maze. However, these earlier studies were limited as hapoE was not expressed outside the brain and E3 or E4 was not expressed under control of an apoE promotor, E2 was often not included, hAPP was transgenically overexpressed and both mouse and hAPP were present. Therefore, to determine whether apoE has isoform-dependent effects on hAPP/Aβ-induced behavioral alterations and cognitive impairments in adult female and male mice at 6 and 18 months of age, we crossed AppNL–G–F and AppNL–F mice with E2, E3, and E4 mice. To distinguish whether genotype differences seen at either time point were due to main effects of hAPP, hapoE, or hAPP × hapoE genetic interactions, we also behavioral and cognitively tested E2, E3, and E4 female and male mice at 6 and 18 months of age. We also compared behavioral and cognitive performance of 18-month-old AppNL–G–F and AppNL–F female and male mice on a murine apoE background along with that of age—and sex-matched C57BL/6J wild-type mice. For many behavioral measures at both time points there were APP × APOE interactions, supporting that apoE has isoform-dependent effects on hAPP/Aβ-induced behavioral and cognitive performance. NL-G-F/E3, but not NL-G-F/E2, mice had lower cortical insoluble Aβ42 levels than NL-G-F/E4 mice. NL-F/E3 and NL-F/E2 mice had lower cortical insoluble Aβ42 levels than NL-F/E4 mice. These results demonstrate that there are apoE isoform-dependent effects on hAPP/Aβ-induced behavioral alterations and cognitive impairments and cortical insoluble Aβ42 levels in mouse models containing only human APP and apoE.

Chronic Alcohol Exposure-Induced Impairment in Spatial Memory Retention and Sex Specific Changes in BDNF–TrkB Signaling in the Hippocampus

Chronic Alcohol Exposure-Induced Impairment in Spatial Memory Retention and Sex Specific Changes in BDNF–TrkB Signaling in the Hippocampus

The Effects of 5-Fluorouracil/Leucovorin Chemotherapy on Cognitive Function in Male Mice.

5-Fluorouracil (5-Fu) and leucovorin (LV) are often given in combination to treat colorectal cancer. 5-Fu/LV prevents cell proliferation by inhibiting thymidylate synthase, which catalyzes the conversion of deoxyuridine monophosphate to deoxythymidine monophosphate. While 5-Fu has been shown to cause cognitive impairment, the synergistic effect of 5-Fu with LV has not been fully explored. The present investigation was designed to assess how the combination of 5-Fu and LV affect cognition in a murine model. Six-month-old male mice were used in this study; 15 mice received saline injections and 15 mice received 5-Fu/LV injections. One month after treatment, the elevated plus maze, Y-maze, and Morris water maze behavioral tasks were performed. Brains were then extracted, cryosectioned, and stained for CD68 to assay microglial activation and with tomato lectin to assay the vasculature. All animals were able to locate the visible and hidden platform locations in the water maze. However, a significant impairment in spatial memory retention was observed in the probe trial after the first day of hidden-platform training (first probe trial) in animals that received 5-Fu/LV, but these animals showed spatial memory retention by day 5. There were no significant increases in inflammation as measured by CD68, but 5-Fu/LV treatment did modulate blood vessel morphology. Tandem mass tag proteomics analysis identified 6,049 proteins, 7 of which were differentially expressed with a p-value of <0.05 and a fold change of >1.5. The present data demonstrate that 5-Fu/LV increases anxiety and significantly impairs spatial memory retention.

Cognitive impairment resulting from treatment with docetaxel, doxorubicin, and cyclophosphamide

Breast cancer is the most commonly diagnosed cancer among women and it is estimated that about 30% of newly diagnosed cancers in women will be breast cancers. While advancements in treating breast cancer have led to an average 5-year survival rate of 90%, many survivors experience cognitive impairments as a result of chemotherapy treatment. Doxorubicin, cyclophosphamide, and docetaxel (TAC) are commonly administered as breast cancer treatments; however, there are few studies that have tested the cognitive effects of TAC. In the current study, 12-week-old female C57BL/6 mice received 4 weekly intraperitoneal injections of either saline or a combination therapy of doxorubicin and cyclophosphamide followed by 4 weekly docetaxel injections. Four weeks after the last injection, mice were tested for hippocampus-dependent cognitive performance in the Y-maze and the Morris water maze. During Y-maze testing, mice exposed to TAC exhibited impairment. During the water maze assessment, all animals were able to locate the visible and hidden platform locations. However, mice that received the TAC presented with a significant impairment in spatial memory retention on the probe trial days. TAC treatment significantly decreases the dendritic complexity of arborization in the dentate gyrus region of the hippocampus. In addition, comparative proteomic analysis revealed downregulation of proteins within key metabolic and signaling pathways associated with cognitive dysfunction, such as oxidative phosphorylation, ephrin signaling, and calcium signaling.

Protective Effects of Aminoguanidine against Sodium Metavanadate-Induced Spatial Memory Retention Impairment in Morris Water Maze

Background: Vanadium is a potential neurotoxic agent widely distributed in the environment. Understanding the neurotoxic mechanisms of vanadium on learning and memory seems necessary. Methods: We investigated the time-dependent (1-week, 2- week and 4-week) effects of sodium metavanadate (SMV) (25 mg/kg/day; pre-training oral administration) and 4-day intraperitoneal injections of aminoguanidine (AG) as a selective inducible nitric oxide synthase inhibitor (10, 50, and 100 mg/kg) on spatial memory retention in Morris water maze. Animals were trained for 4 days and tested 48 h after the last training trial. Results: The data showed that 4-week oral pre-treatment with SMV (25 mg/kg/day) induced spatial memory retention deficits and decreased the time spent in the target quadrant. We found that 4-day administration of different doses of AG during training trials significantly decreased the time and distance of finding the hidden platforms. Additionally, SMV-induced spatial memory retention impairments were prevented in animals received combined SMV (25 mg/kg/day, 4 weeks) and AG (10 mg/kg/day, 4 days). Conclusion: Our findings showed the protective role of AG on SMV-induced spatial memory retention deficits.

Behavioral and molecular effects of intrahippocampal infusion of auraptene, resveratrol, and curcumin on H-89-induced deficits on spatial memory acquisition and retention in Morris water maze.

Our aim was to investigate the effects of resveratrol, auraptene, and curcumin on the spatial learning and spatial memory retention in the Morris water maze (MWM). The effects of 4-day bilateral intrahippocampal (i.h.) infusions of dimethyl sulfoxide (DMSO), H-89 as a protein kinase AII inhibitor, auraptene/H-89, resveratrol/H-89, and curcumin/H-89 were investigated on spatial memory acquisition in MWM. The rats were trained for 4 days; each day included one block of four trials. Post-training probe tests were performed on day 5 in acquisition test. For retention assessments, different animals were trained for 4 days and then infused (i.h.) with either DMSO, H-89, auraptene/H-89, resveratrol/H-89, or curcumin/H-89. The retention test was performed 48 h after the last training trial. The bilateral infusion of H-89 led to a significant impairment in spatial memory in acquisition and retention tests accompanied with a significant decrease in expressions of cAMP response-element binding (CREB) and pCREB proteins in hippocampus. Resveratrol and curcumin reversed the H-89-induced spatial memory acquisition and retention impairments with significant increases in both CREB and pCREB proteins expressions compared to H-89-treated animals. Auraptene showed significant effects in reversing H-89-induced impairments in spatial memory retention but not spatial memory acquisition.

The Effects of 5‐Fluorouracil/Leucovorin Chemotherapy on Cognitive Function in Mice

5‐fluorouracil (5‐Fu) and leucovorin (LV) are often given in combination to treat colorectal cancer. 5‐Fu/LV prevents cell proliferation by inhibiting thymidylate synthase (TS), which is an enzyme that catalyzes the conversion of deoxyuridine monophosphate to deoxythymidine monophosphate. While 5‐Fu has been shown to cause cognitive impairments, the synergistic effect of 5‐Fu with LV has not been fully explored. The present investigation was designed to assess how the combination of 5‐Fu and LV affect cognition in a murine model. A total of 30 nine‐month‐old male mice were used in this study; 8 mice received 0.9 % saline injections, 6 mice received LV (90 mg/kg) injections, 8 mice received 5‐Fu (50 mg/kg) injections, and 8 mice received 5‐Fu and LV (50 mg/kg and 90 mg/kg) injections. One‐month post‐treatment, Y‐maze and Morris water maze (MWM) behavioral tasks were performed. Brains were then extracted, cryosectioned, and stained with CD68 and tomato lectin. All animals in the MWM task were able to locate the visible and hidden platform locations in the water maze; however, treatment effects were seen when spatial memory retention was assessed in the probe trials (no platform). A significant impairment in spatial memory retention was observed in the probe trial after the first day of hidden platform training (first probe trial) in animals that received LV, 5‐Fu, and 5‐Fu/LV. However, by day 5, animals that received 5‐Fu only and 5‐Fu/LV showed spatial memory retention in the probe trials, whereas the LV only mice were impaired. We are currently performing microscopy to quantify changes in the activated microglia and brain vasculature. In studies conducted by Mustafa et. al and El Betagy et. al, Lister‐hooded rats were given 5‐Fu and LV and performed the novel location recognition task. For both studies, rats that received 5‐Fu/LV failed to discriminate between the two object locations, suggesting a spatial memory deficit. While these studies are promising, there is still a need to determine how this drug combination affects other aspects of memory and brain function. The present data suggests that LV may exacerbate the cognitive deficits seen with 5‐Fu treatment, as mice that received LV treatment only remained impaired by day 5 of the MWM. Mice that received 5‐Fu and 5‐Fu/LV were also impaired but showed spatial memory retention by day 5.Support or Funding InformationThis work was supported by Pilot Grant under NIH P20 GM109005 (ARA).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Behavioral Effects of Focal Irradiation in a Juvenile Murine Model.

Chemotherapy has been successfully used to reduce radiation dose and volume for most pediatric patients. However, because of the failure of chemotherapeutic agents to cross the blood-brain barrier and the lack of response of some brain tumors to these agents, radiation therapy is still used to treat many childhood cancers with CNS involvement. In this study, we investigated the radiation effects on cognition and dendritic structure in the hippocampus in juvenile male mice. Twenty-one-day-old male C57BL/6 mice were irradiated using the small animal radiation research platform (SARRP). Animals were exposed to either a 10 Gy single dose or 10 Gy × 2 fractionated doses of X-ray cranial radiation. Five weeks after irradiation, animals were tested for hippocampus-dependent cognitive performance in the Morris water maze. Significant impairment in spatial memory retention was observed in the probe trial after the first day of hidden-platform training (first probe trial) in animals that received either 10 Gy single-dose or 10 Gy × 2 fractionated doses. However, by day 5, mice that received a 10 Gy single dose showed spatial memory retention in the probe trials, whereas mice that received the 20 Gy fractionated doses remained impaired. During Y-maze testing, animals exposed to radiation were impaired; the irradiated mice were not able to distinguish among the three Y-maze arms and spent approximately the same amount of time in all three arms during the retention trial. Radiation significantly compromised the dendritic architecture and reduced spine density throughout the hippocampal trisynaptic network.

Changes in cognition and dendritic complexity following intrathecal methotrexate and cytarabine treatment in a juvenile murine model

Acute lymphoblastic leukemia (ALL) is the most prevalent childhood cancer and accounts for 26.8% of cancer diagnoses among children, worldwide—approximately 3000 children each year. While advancements in treating ALL have led to a remission rate of more than 90%, many survivors experience adverse neurocognitive and/or neurobehavioral effects as a result of intrathecal chemotherapy. Methotrexate (MTX) is commonly administered with cytosine arabinoside (AraC, cytarabine) during intrathecal chemotherapy for ALL. To date, few studies exist that test the cognitive effects of intrathecal injections of MTX/AraC on juvenile populations. The purpose of our study was to investigate the combined effects of MTX/AraC on cognition and dendritic structure in the hippocampus in juvenile male mice. Twenty, 21-day-old male C57BL/6 mice were used in this study; 10 mice received intrathecal MTX/AraC treatment, and 10 were given intrathecal saline injections. Five weeks after injections, we tested the animals’ hippocampus-dependent cognitive performance in the Morris water maze. After the first day of hidden-platform training, we observed that the mice that received MTX/AraC treatment showed signs of significant impairment in spatial memory retention. MTX/AraC treatment significantly compromised the dendritic architecture and reduced mushroom spine density in the dorsal ganglion (DG), CA1, and CA3 areas of the hippocampus. The present data provided evidence that MTX/AraC compromised the dendritic architecture and impaired hippocampal dependent cognition. This could provide insight into chemotherapy-induced cognitive decline in juvenile patients treated for ALL.

Implications of p75NTR for dentate gyrus morphology and hippocampus-related behavior revisited

The pan-neurotrophin receptor p75NTR is expressed in the adult brain in a discrete pattern. Although numerous studies have addressed its implications for hippocampal functions, the generated sets of data are surprisingly conflicting. We have therefore set out to re-investigate the impact of a deletion of the full-length p75NTR receptor on several parameters of the dentate gyrus (DG), including neurogenesis and hippocampus-related behavior by using p75NTR(ExIII) knockout mice. Moreover, we investigated further parameters of the DG (cholinergic innervation, dendritic spines). In addition, we analyzed on the morphological level the impact of aging by comparing adult and aged p75NTR(ExIII) mice and their age-matched littermates. Adult (4-6 months old), but not aged (20 months old), p75NTR(ExIII) knockout mice display an enhanced volume of the DG. However, adult neurogenesis within the adult DG was unaffected in both adult and aged p75NTR(ExIII) knockout mice. We could further demonstrate that the change in the volume of the DG was accompanied by an increased cholinergic innervation and increased spine densities of granule cells in adult, but not aged p75NTR deficient mice. These morphological changes in the adult p75NTR deficient mice were accompanied by specific alterations in their behavior, including altered behavior in the Morris water maze test, indicating impairments in spatial memory retention.

Effects of Radiation Combined Injury on Hippocampal Function are Modulated in Mice Deficient in Chemokine Receptor 2 (CCR2)

Chemokines and their receptors play a crucial role in normal brain function as well as in pathological conditions such as injury and disease-associated neuroinflammation. Chemokine receptor-2 (CCR2), which mediates the recruitment of infiltrating and resident microglia to sites of central nervous system (CNS) inflammation, is upregulated by ionizing irradiation and traumatic brain injury. Our objective was to determine if a deficiency in CCR2 and subsequent effects on brain microglia affect neurogenesis and cognitive function after radiation combined injury (RCI). CCR2 knock-out ⁻/⁻ and wild-type (WT) mice received 4 Gy of whole body ¹³⁷Cs irradiation. Immediately after irradiation, unilateral traumatic brain injury was induced using a controlled cortical impact system. Forty-four days postirradiation, animals were tested for hippocampus-dependent cognitive performance in the Morris water-maze. After cognitive testing, animals were euthanized and their brains snap frozen for immunohistochemical assessment of neuroinflammation (activated microglia) and neurogenesis in the hippocampal dentate gyrus. All animals were able to locate the visible and hidden platform locations in the water maze; however, treatment effects were seen when spatial memory retention was assessed in the probe trials (no platform). In WT animals that received combined injury, a significant impairment in spatial memory retention was observed in the probe trial after the first day of hidden platform training (first probe trial). This impairment was associated with increased neurogenesis in the ipsilateral hemisphere of the dentate gyrus. In contrast, CCR2⁻/⁻ mice, independent of insult showed significant memory retention in the first probe trial and there were no differences in the numbers of newly born neurons in the animals receiving irradiation, trauma or combined injury. Although the mechanisms involved are not clear, our data suggests that CCR2 deficiency can exert a protective effect preventing the impairment of cognitive function after combined injury.

Effects of alpha-lipoic acid on associative and spatial memory of sham-irradiated and 56Fe-irradiated C57BL/6J male mice

Cranial irradiation with 56Fe, a form of space radiation, causes hippocampus-dependent cognitive changes. 56Fe irradiation also increases reactive oxygen species (ROS) levels, which may contribute to these changes. Therefore, we investigated the effects of the antioxidant alpha lipoic acid (ALA) on cognition following sham-irradiation and irradiation. Male mice were irradiated (brain only) with 56Fe (3Gy) or sham-irradiated at 6–9months of age. Half of the mice remained fed a regular chow and the other half of the mice were fed a caloric-matched diet containing ALA starting two-weeks prior to irradiation and throughout cognitive testing. Following cognitive testing, levels of 3-nitrotyrosine (3NT), a marker of oxidative protein stress, and levels of microtubule-associated protein (MAP-2), a dendritic protein important for cognition, were assessed using immunohistochemistry and confocal microscopy. ALA prevented radiation-induced impairments in spatial memory retention in the hippocampal and cortical dependent water maze probe trials following reversal learning. However, in sham-irradiated mice, ALA treatment impaired cortical-dependent novel object recognition and amygdala-dependent cued fear conditioning. There was a trend towards lower 3NT levels in irradiated mice receiving a diet containing ALA than irradiated mice receiving a regular diet. In the hippocampal dentate gyrus of mice on regular diet, irradiated mice had higher levels of MAP-2 immunoreactivity than sham-irradiated mice. Thus, ALA might have differential effects on the brain under normal physiological conditions and those involving environmental challenges such as cranial irradiation.

ApoE isoform modulates effects of cranial 56Fe irradiation on spatial learning and memory in the water maze

Apolipoprotein E, which plays an important role in lipid transport and metabolism and neuronal repair, might modulate the CNS risk following 56Fe irradiation exposure during space missions. In this study, we investigated this risk by behavioral and cognitive testing male E2, E3, and E4 mice 3 months following cranial 56Fe irradiation. In the open field, mice irradiated with 2Gy showed higher activity levels than sham-irradiated mice or mice irradiated with 1Gy. In addition, E2 mice showed higher activity and lower measures of anxiety than E3 and E4 mice in the open field and elevated zero maze. During hidden platform training, sham-irradiated mice showed most robust learning, 1Gy irradiated mice reduced learning, and 2Gy irradiated mice no improvement over the four sessions. In the water maze probe trials, sham-irradiated E2, E3, and E4 mice and E2 and E4 mice irradiated with 1Gy showed spatial memory retention, but E3 mice irradiated with 1Gy, and E2, E3, and E4 mice irradiated with 2Gy did not. Thus, cranial 56Fe irradiation increases activity levels in the open field and impairs spatial learning and memory in the water maze. E3 mice are more susceptible than E2 or E4 mice to impairments in spatial memory retention in the water maze, indicating that apoE isoform modulates the CNS risk following space missions.

Alcohol preference, behavioural reactivity and cognitive functioning in female rats exposed to a three-bottle choice paradigm

Alcohol abuse is a substantial and growing health problem in Western societies. In the last years in vivo and in vitro studies have suggested that males and females display a different alcohol drinking behaviour, with swingeing differences not only in the propensity for alcohol use but also in the metabolic and behavioural consequences. In this study we investigated, in adult female rats, ethanol self-administration and preference pattern using a 3-bottle paradigm with water, 10% ethanol solution, and white wine (10%, v/v), along a four-week period. The influence of alcohol free-access on explorative behaviour in the open field (OF), and on spatial learning and reference memory in the Morris water maze (MWM) were also evaluated. Our results indicate that: (i) female rats show a higher preference for alcohol, in the first two weeks of the paradigm, displaying a higher consumption of 10% ethanol solution than white wine; in the last two weeks, they reduce their alcoholic preference, drinking the same moderate amounts of the two alcoholic beverages; (ii) at the fourth week of the free-access paradigm rats show a lower explorative behaviour in the open field and a worsening in spatial memory retention in the Morris water maze. In conclusion our data suggest that, despite the ability to self-regulate alcohol intake, female rats suffer from relevant impairments in spatial memory retention and cognitive flexibility, displaying a sexually dimorphic modification in the adaptive strategies.

Acetyl‐L‐Carnitine ameliorates spatial memory deficits induced by inhibition of phosphoinositol‐3 kinase and protein kinase C

Glycogen synthase kinase-3β (GSK-3β) plays a crucial role in memory deficits and tau hyperphosphorylation as seen in Alzheimer's disease, the most common dementia in the aged population. We reported that ventricular co-injection of wortmannin and GF-109203X (WT/GFX) can induce tau hyperphosophorylation and memory impairment of rats through activation of GSK-3 [Liu S. J., Zhang A. H., Li H. L., Wang Q., Deng H. M., Netzer W. J., Xu H. X. and Wang J. Z. (2003) J. Neurochem. 87, 1333]. In the present study, we found that feeding the rats with Acetyl-L-Carnitine (ALCAR, 50 mg/day·rat, per os) for 2 weeks rescued the WT/GFX-induced spatial memory retention impairment of the rats by antagonizing GSK-3β activation independent of Akt, PKCζ and Erk1/2. We also found that ALCAR arrested microtubule-associated protein tau hyperphosphorylation at multiple Alzheimer's disease sites in vivo and in vitro. Moreover, ALCAR enhanced the expression of several memory-associated proteins including c-Fos, synapsin I in rat hippocampus. These results suggest that ALCAR could ameliorate WT/GFX-induced spatial memory deficits through inhibition tau hyperphosphorylation and modulation of memory-associated proteins.

Melatonin ameliorates Alzheimer-like pathological changes and spatial memory retention impairment induced by calyculin A

Melatonin ameliorates Alzheimer-like pathological changes and spatial memory retention impairment induced by calyculin A

Melatonin ameliorates Alzheimer-like pathological changes and spatial memory retention impairment induced by calyculin A

We have reported recently that inhibition of protein phosphatase (PP)-2A and PP-1 by calyculin A, a specific inhibitor of PP-2A and PP-1, induced Alzheimer-like hyperphosphorylation of tau and spatial memory retention impairment. In this study, we tested the in vivo effects of melatonin on these Alzheimer-like changes. We found that administration of melatonin intraperitoneally for 9 consecutive days before injection of calyculin A could prevent calyculin A-induced synaptophysin loss, memory retention deficits, as well as hyperphosphorylation of tau and neurofilaments. Furthermore, melatonin partially reversed the phosphorylation of the catalytic subunit of PP-2A at Tyrosine 307 (Y307), a crucial site negatively regulating the activity of PP-2A, and reduced the levels of malondialdehyde, a marker of oxidative stress, induced by calyculin A. These results suggest that melatonin could serve as a potential therapeutic agent for preventing Alzheimer-like pathological changes and behavioral abnormality via modulating the activity of PP-2A and oxidative stress.

Sex-dependent cognitive phenotype of mice lacking mGluR8

Metabotropic glutamate receptors (mGluRs) modulate glutamatergic and GABAergic neurotransmission. mGluR8 is generally located presynaptically where it regulates neurotransmitter release. Previously we reported that 6-month-old mGluR8 −/− male mice show higher measures of anxiety in anxiety tests involving avoidable anxiety-provoking stimuli than age-matched wild-type male mice. In wild-type mice, middle-aged females and males show higher measures of anxiety in such tests and reduced spatial learning than young adults. In this study we evaluated in middle-aged mice the effects of mGluR8 deficiency on measures of anxiety involving avoidable and unavoidable anxiety-provoking stimuli and on cognitive performance and whether these effects are sex-dependent. Female and male mGluR8 −/− mice showed increased measures of anxiety in the open field. In contrast, male mGluR8 −/− mice showed increased but female mGluR8 −/− mice decreased measures of anxiety in the elevated plus maze and the acoustic startle response. mGluR8 deficiency impaired novel location recognition and spatial memory retention in the water maze. The impairment in spatial memory retention in the water maze, but not in novel location recognition, was more pronounced in female than male mice. Thus, potential sex differences in the therapeutic effects of mGluR8 modulation to reduce measures of anxiety and improve cognitive performance should be carefully considered.

Acetyl-L-Carnitine Attenuates Okadaic Acid Induced Tau Hyperphosphorylation and Spatial Memory Impairment in Rats

Tau hyperphosphorylation and memory deficit are characteristic alterations of Alzheimer's disease (AD). Protein phosphatases (PP) 2A plays a crucial role in AD-like lesions. Inhibition of PP2A through hippocampal injection of okadaic acid (OA) induces tau hyperphosphorylation and memory impairment of rats. By using this model, we explored in the present study the effects of acetyl-L-carnitine (ALCAR), a constituent of the inner mitochondrial membrane, on the memory retention, tau phosphorylation, and oxidative stress in rats. We found that pre-treatment of ALCAR (50 mg/d . rat, per os) for two weeks efficiently improved the OA-induced spatial memory retention impairment of the rats. ALCAR antagonized tau hyperphosphorylation at multiple AD sites and it abated the OA-induced PP2A inhibition and oxidative stress. Our study provides the first in vivo evidence that ALCAR can attenuate AD-like PP2A inhibition, tau hyperphosphorylation, and spatial memory deficit of the rats. It suggests that ALCAR may hold potential in AD treatment.

Effects of137Cs γ Irradiation on Cognitive Performance and Measures of Anxiety inApoe−/−and Wild-Type Female Mice

Mice deficient in apoE (Apoe-/-) can be used to assess the potential role of apoE in the effects of cranial irradiation on hippocampal function. Radiation-induced impairments in hippocampal function may be more pronounced in female Apoe-/- mice and more pronounced in mice irradiated and tested cognitively later in life. To assess this possibility, female wild-type and Apoe-/- mice were irradiated at 6 months of age with 10 Gy 137Cs gamma rays and tested cognitively 3 months later. Sham-irradiated wild-type female mice showed enhanced hippocampal-dependent novel location recognition compared to sham-irradiated Apoe-/- female mice. However, cranial irradiation impaired novel location recognition similarly in both genotypes. Cranial irradiation also impaired hippocampal-dependent spatial memory retention similarly in wild-type and Apoe-/- female mice in the water maze. Because novel location recognition was not affected after 137Cs gamma irradiation in younger mice, these data support the possibility that older mice are more susceptible to the effects of gamma radiation on novel location recognition. Together with the impairments in spatial memory retention in the water maze after irradiation, these data support the existence of detrimental effects of cranial irradiation on hippocampal function. In addition, compared to wild-type female mice, Apoe-/- female mice showed enhanced levels of anxiety, and in Apoe-/-, but not in wild-type, female mice, radiation decreased levels of anxiety. Because levels of anxiety during the hidden session of the water maze were associated with ability to locate the hidden platform, assessments of anxiety need to be considered in evaluating the effects of cranial irradiation on cognitive performance after cranial irradiation.