Exercise decreases BACE and APP levels in the hippocampus of a rat model of Alzheimer's disease.

We investigated the effect of treadmill exercise training on the levels of Alzheimer's disease (AD)-related protein molecules in the DG and CA1 areas of a rat model of AD, i.c.v. infusion of Aß1-42 peptide, 2weeks (250pmol/day). Aß infusion markedly increased protein levels of amyloid precursor protein (APP), the secretase beta-site APP cleaving enzyme-1 (BACE-1) and Aß in the CA1 and DG areas. The results also revealed that 4weeks of treadmill exercise prevented the increase in the levels of APP, BACE-1 and Aß proteins in both hippocampal areas. Exercise, however, did not affect the levels of these proteins in normal rats. We suggest that exercise might be changing the equilibrium of APP processing pathway towards the nonpathogenic pathway most probably via increasing BDNF levels in the brain of AD model.

Cyclosporine restores hematopoietic function by compensating for decreased Tregs in patients with pure red cell aplasia and acquired aplastic anemia.

Most patients with acquired pure red cell aplasia (PRCA) and some with acquired aplastic anemia (AA) respond well to cyclosporine (CsA), but thereafter often show CsA dependency. The mechanism underlying this dependency remains unknown. We established a reliable method for measuring the regulatory T cell (Treg) count using FoxP3 and Helios expression as markers and determined the balance between Tregs and other helper T cell subsets in 16 PRCA and 29 AA patients. The ratios of interferon-γ-producing CD4(+) (Th1) T cells to Tregs in untreated patients and CsA-dependent patients were significantly higher (PRCA 5.77 ± 1.47 and 7.38 ± 2.58; AA 6.18 ± 2.35 and 8.94 ± 4.06) than in healthy volunteers (HVs; 3.33 ± 0.90) due to the profound decrease in the percentage of Tregs. In contrast, the ratios were comparable to HVs in convalescent CsA-treated AA patients (4.74 ± 2.10) and AA patients in remission after the cessation of CsA treatment (4.24 ± 1.67). Low-dose CsA (100 ng/ml) inhibited the proliferation of conventional T cells (Tconv) to a similar degree to the inhibition by Tregs in a co-culture with a 1:1 Treg/Tconv ratio. The data suggest that CsA may reverse the hematopoietic suppression in PRCA and AA patients by compensating for the inadequate immune regulatory function that occurs due to a profound decrease in the Treg count.

Regular exercise prevents non-cognitive disturbances in a rat model of Alzheimer's disease.

Previously, we reported that in a rat model of sporadic Alzheimer's disease (AD) generated by exogenous administration of Aß1₋42 (250 pmol/d for 2 wk) via mini-osmotic pump, the animals exhibited learning and memory impairment, which could be attributed to the deleterious alterations in the levels of cognition-related signalling molecules. We showed that 4 wk of treadmill exercise totally prevented these impairments. Here, we evaluated the effect of exercise on non-cognitive function and basal synaptic transmission in the Cornu Ammonis 1 (CA1) area using the same AD model. Our results indicated that the anxiety behaviour of Aß-treated rats was prevented by 4 wk of treadmill exercise. Exercised/Aß-infused rats spent a longer time in the centre area of the open field (OF), elevated plus maze (EPM) paradigms and the light area of the light-dark (LD) box, which were similar to those of control and exercise rats. Furthermore, under basal conditions the aberrant up-regulation of calcineurin (PP2B) and reduction of phosphorylated Ca²âº/calmodulin dependent protein kinase II (p-CaMKII) levels induced by AD-like pathology were normalised by the exercise regimen. We conclude that regular exercise may exert beneficial effects on both cognitive and non-cognitive functions in this AD model.

Risk factors for early fatal outcomes among children with hemophagocytic lymphohistiocytosis (HLH): a single-institution case-series in Vietnam.

Hemophagocytic lymphohistiocytosis (HLH) is a rare and fatal hematological syndrome that causes a disturbance of the immune system. Overall mortality of HLH is greater than 50% and the majority of patients who die do so within the first 8 weeks of chemotherapy treatment. To find clinical parameters relating to high-risk HLH patients, this study examined associations between an early fatal outcome and potential prognostic clinical factors and laboratory findings on admission. Eighty-nine pediatric HLH patients were prospectively recruited in Children's Hospital No. 1, Ho-Chi-Minh City, Vietnam, during the period from January 2010 to August 2012. Associations between early fatal outcome and clinical and laboratory findings, including a cerebrospinal fluid examination and virological test on admission, were examined. During the 8-week therapy, 25 (28%) HLH patients died. Persistent fever (>2 weeks), severe thrombocytopenia (<75 × 10(9)/L), hyperbilirubinemia, and prolonged activated partial thromboplastin time (APTT) (>33 sec) were significant risk factors of early fatal outcome. Multivariate logistic regression analysis revealed that thrombocytopenia and prolonged APTT (P for trend was 0.054 and 0.013, respectively) were independently associated with the early fatal outcome. Persistent fever, severe thrombocytopenia, hyperbilirubinemia, and prolonged APTT on admission will be useful and practical predictors to determine high-risk HLH patients.

A high-salt diet further impairs age-associated declines in cognitive, behavioral, and cardiovascular functions in male Fischer brown Norway rats.

Aging-associated declines in cognitive, emotional, and cardiovascular function are well known. Environmental stress triggers critical changes in the brain, further compromising cardiovascular and behavioral health during aging. Excessive dietary salt intake is one such stressor. Here, we tested the effect of high salt (HS) on anxiety, learning-memory function, and blood pressure (BP) in male Fischer brown Norway (FBN) rats. Adult (A; 2 mo) and old (O; 20 mo) male rats were fed normal-salt (NS; 0.4% NaCl) or HS (8% NaCl) diets for 4 wk after being implanted with telemeter probes for conscious BP measurement. Thereafter, tests to assess anxiety-like behavior and learning-memory were conducted. The rats were then killed, and samples of plasma, urine, and brain tissue were collected. We found that systolic BP was higher in O-NS (117 ± 1.2 mm Hg) than in A-NS (105 ± 0.8 mm Hg) rats (P < 0.05). Furthermore, BP was higher in O-HS (124 ± 1.4 mm Hg) than in O-NS (117 ± 1.2 mm Hg) rats (P < 0.05). Moreover, anxiety-like behavior (light-dark and open-field tests) was not different between A-NS and O-NS rats but was greater in O-HS rats than in A-NS, O-NS, or A-HS rats (P < 0.05). Short-term memory (radial arm water maze test) was similar in A-NS and O-NS rats but was significantly impaired in O-HS rats compared with A-NS, O-NS, or A-HS rats (P < 0.05). Furthermore, oxidative stress variables (in plasma, urine, and brain) as well as corticosterone (plasma) were greater in O-HS rats when compared with A-NS, O-NS, or A-HS rats (P < 0.05). The antioxidant enzyme glyoxalase-1 expression was selectively reduced in the hippocampus and amygdala of O-HS rats compared with A-NS, O-NS, or A-HS rats (P < 0.05), whereas other antioxidant enzymes, glutathione reductase 1, manganese superoxide dismutase (SOD), and Cu/Zn SOD remained unchanged. We suggest that salt-sensitive hypertension and behavioral derangement are associated with a redox imbalance in the brain of aged FBN rats.

Grape powder supplementation prevents oxidative stress-induced anxiety-like behavior, memory impairment, and high blood pressure in rats.

We examined whether or not grape powder treatment ameliorates oxidative stress-induced anxiety-like behavior, memory impairment, and hypertension in rats. Oxidative stress in Sprague-Dawley rats was produced by using L-buthionine-(S,R)-sulfoximine (BSO). Four groups of rats were used: 1) control (C; injected with vehicle and provided with tap water), 2) grape powder-treated (GP; injected with vehicle and provided for 3 wk with 15 g/L grape powder dissolved in tap water), 3) BSO-treated [injected with BSO (300 mg/kg body weight), i.p. for 7 d and provided with tap water], and 4) BSO plus grape powder-treated (GP+BSO; injected with BSO and provided with grape powder-treated tap water). Anxiety-like behavior was significantly greater in BSO rats compared with C or GP rats (P < 0.05). Grape powder attenuated BSO-induced anxiety-like behavior in GP+BSO rats. BSO rats made significantly more errors in both short- and long-term memory tests compared with C or GP rats (P < 0.05), which was prevented in GP+BSO rats. Systolic and diastolic blood pressure was significantly greater in BSO rats compared with C or GP rats (P < 0.05), whereas grape powder prevented high blood pressure in GP+BSO rats. Furthermore, brain extracellular signal-regulated kinase-1/2 (ERK-1/2) was activated (P < 0.05), whereas levels of glyoxalase-1 (GLO-1), glutathione reductase-1 (GSR-1), calcium/calmodulin-dependent protein kinase type IV (CAMK-IV), cAMP response element-binding protein (CREB), and brain-derived neurotrophic factor (BDNF) were significantly less (P < 0.05) in BSO but not in GP+BSO rats compared with C or GP rats. We suggest that by regulating brain ERK-1/2, GLO-1, GSR-1, CAMK-IV, CREB, and BDNF levels, grape powder prevents oxidative stress-induced anxiety, memory impairment, and hypertension in rats.

Propensity score matching in estimating the effect of managerial education on academic planning behavior. Study design: a cross-sectional study.

BACKGROUND: In many academic settings teaching a particular topic is applied to every student enrolled in the same academic year, it is a difficult task for researchers to design a randomized control group study. This research aimed to estimate the effect of teaching management and planning on increasing academic planning behavior (APB), using propensity score matching (PSM). METHODS: In a cross-sectional survey utilizing a self-reported structured questionnaire on a systematic random sample of 421 students in Hanoi Medical University, one of the eight medical schools in Vietnam, this evaluation study adopted regression procedures to assess model fit, then PSM to create a matched control group in order to allow for evaluating the effect of management education. RESULTS: The study showed both direct and indirect effects of the education on behavior. After PSM to adjust for the possible confounders to balance statistically two groups--with and without management education, there is statistically a significant difference in APB between these two groups, making a net difference of 18.60% (p<.05). The estimated 18.6 percentage point increase can be translated into the practice of APB by 670 students in the population. This number of academic planners can be attributed to a high recall of important management and planning education. CONCLUSIONS: The study provided theoretical as well as practical implications to guide the design of the education and evaluation of teaching.

Cardiac dysregulation following intrahippocampal kainate-induced status epilepticus.

Status epilepticus (SE) is a prevalent disorder associated with significant morbidity, including the development of epilepsy and mortality. Cardiac arrhythmias (i.e. inappropriate sinus tachycardia and bradycardia, asystole, and atrioventricular blocks) are observed in patients following SE. We characterized ictal (during a seizure) and interictal (between seizure) cardiac arrhythmogenesis following SE using continuous electrocardiography and video electroencephalography (vEEG) recordings throughout a 14-day monitoring period in an intrahippocampal chemoconvulsant mouse model that develops epilepsy. We quantified heart rhythm abnormalities and examined whether the frequency of cardiac events correlated with epileptiform activity, circadian (light/dark) cycle, the presence of seizures, and survival during this period of early epileptogenesis (the development of epilepsy) following SE. Shortly following SE, mice developed an increased interictal heart rate and heart rhythm abnormalities (i.e. sinus pause and sinus arrhythmias) when compared to control mice. Heart rhythm abnormalities were more frequent during the light cycle and were not correlated with increased epileptiform activity or seizure frequency. Finally, SE animals had early mortality, and a death event captured during vEEG recording demonstrated severe bradycardia prior to death. These cardiac changes occurred within 14 days after SE and may represent an early risk factor for sudden death following SE.

Comparing a standard and tailored approach to scaling up an evidence-based intervention for antiretroviral therapy for people who inject drugs in Vietnam: study protocol for a cluster randomized hybrid type III trial.

BACKGROUND: People who inject drugs (PWID) bear a disproportionate burden of HIV infection and experience poor outcomes. A randomized trial demonstrated the efficacy of an integrated System Navigation and Psychosocial Counseling (SNaP) intervention in improving HIV outcomes, including antiretroviral therapy (ART) and medications for opioid use disorder (MOUD) uptake, viral suppression, and mortality. There is limited evidence about how to effectively scale such intervention. This protocol presents a hybrid type III effectiveness-implementation trial comparing two approaches for scaling-up SNaP. We will evaluate the effectiveness of SNaP implementation approaches as well as cost and the characteristics of HIV testing sites achieving successful or unsuccessful implementation of SNaP in Vietnam. METHODS: Design: In this cluster randomized controlled trial, two approaches to scaling-up SNaP for PWID in Vietnam will be compared. HIV testing sites (n = 42) were randomized 1:1 to the standard approach or the tailored approach. Intervention mapping was used to develop implementation strategies for both arms. The standard arm will receive a uniform package of these strategies, while implementation strategies for the tailored arm will be designed to address site-specific needs. PARTICIPANTS: HIV-positive PWID participants (n = 6200) will be recruited for medical record assessment at baseline; of those, 1500 will be enrolled for detailed assessments at baseline, 12, and 24 months. Site directors and staff at each of the 42 HIV testing sites will complete surveys at baseline, 12, and 24 months. OUTCOMES: Implementation outcomes (fidelity, penetration, acceptability) and effectiveness outcomes (ART, MOUD uptake, viral suppression) will be compared between the arms. To measure incremental costs, we will conduct an empirical costing study of each arm and the actual process of implementation from a societal perspective. Qualitative and quantitative site-level data will be used to explore key characteristics of HIV testing sites that successfully or unsuccessfully implement the intervention for each arm. DISCUSSION: Scaling up evidence-based interventions poses substantial challenges. The proposed trial contributes to the field of implementation science by applying a systematic approach to designing and tailoring implementation strategies, conducting a rigorous comparison of two promising implementation approaches, and assessing their incremental costs. Our study will provide critical guidance to Ministries of Health worldwide regarding the most effective, cost-efficient approach to SNaP implementation. TRIAL REGISTRATION: NCT03952520 on Clinialtrials.gov. Registered 16 May 2019.

Effect of Exercise and Aß Protein Infusion on Long-Term Memory-Related Signaling Molecules in Hippocampal Areas.

Alzheimer's disease (AD) results from over-production and aggregation of ß-amyloid (Aß) oligopeptides in the brain. The benefits of regular physical exercise are now recognized in a variety of disorders including AD. In order to understand the effect of exercise at the molecular level, we studied the impact of exercise on long-term memory-related signaling molecules in an AD rat model. The rat model of AD (AD rat) was produced by 14-day osmotic pump infusion of i.c.v. 250 pmol/day Aß1-42. The effects of 4 weeks of regular rodent treadmill exercise on the protein levels of CREB, CaMKVI, and MAPK-ERK1/2 in this model were determined by immunoblot analysis in the CA1 and dentate gyrus (DG) areas of the hippocampus, which is among the first brain structures impacted by AD. Aß infusion caused marked reductions in the basal protein levels of CaMKVI and phosphorylated CREB without significantly affecting total CREB levels in both CA1 and DG areas. As predicted, our exercise regimen totally prevented these effects in the brains of exercised AD rats. Surprisingly, however, neither Aß infusion nor exercise had any significant effect on the levels of phosphorylated or total ERK in the CA1 and DG areas. Additionally, exercise did not increase any of these molecules in healthy normal rats, which indicated a protective effect of exercise. These findings suggest that CaMKIV is likely a major kinase for phosphorylation of CREB. Therefore, regular exercise is highly effective in preventing the effects of AD even at the molecular level in both areas of the hippocampus. Considering the well-known resistance of the DG area to insults relative to area CA1, the present findings revealed similar molecular vulnerability of the two areas to AD pathology.

Correction to: Moderate Treadmill Exercise Protects Synaptic Plasticity of the Dentate Gyrus and Related Signaling Cascade in a Rat Model of Alzheimer's Disease.

The original version of this article unfortunately does not include the second affiliating institution of Dr. Munder A. Zagaar. "Department of Pharmacy Pracce and Clinical Health Sciences, Texas Southern University, Houston, TX 77004" should have been included on the paper.

Correction to: Comparison of the Effect of Exercise on Late-Phase LTP of the Dentate Gyrus and CA1 of Alzheimer's Disease Model.

The original version of this article unfortunately does not include the second affiliating institution of Dr. Munder A. Zagaar. "Department of Pharmacy Pracce and Clinical Health Sciences, Texas Southern University, Houston, TX 77004" should have been included on the paper.

Correction to: Prevention by Regular Exercise of Acute Sleep Deprivation-Induced Impairment of Late Phase LTP and Related Signaling Molecules in the Dentate Gyrus.

The original version of this article unfortunately does not include the second affiliating institution of Dr. Munder A. Zagaar. "Department of Pharmacy Pracce and Clinical Health Sciences, Texas Southern University, Houston, TX 77004" should have been included on the paper.

Factors Associated with Depression among the Elderly Living in Urban Vietnam.

The proportion of elderly people in big cities of developing countries, including Vietnam, is rapidly increasing during the age of rampant urbanization. This is being followed by a sustained rise of illnesses, especially mental health issues. The objective of this study was to analyze the association between depression and the factors associated with depression among the elderly. In a cross-sectional study, 299 elderly living in Hanoi, Vietnam, were approached for data collection. Self-reported depression among the elderly was 66.9% (32.8% mild, 30.4% moderate, and 3.7% severe cases). In multivariate analysis, there were significant associations between age, number of physical activities, number of medicine intake, and 3 domains of quality of life (physical health, psychological health, and environmental health) and depression. Age and the number of medicine intake are positively correlated with depression, accounting for 57.94% and 58.93%, respectively. On the contrary, the number of physical activities and the 3 domains of quality life mentioned above are negatively correlated with depression. In the urban setting of a developing country like Vietnam, the elderly have experienced common depression. Recognizing depression among the elderly-which is individual and social-helps us design public health programs. Screening for early depression, joining social programming, and participating in physical activities may improve the mental life of the elderly.

Wortmannin Attenuates Seizure-Induced Hyperactive PI3K/Akt/mTOR Signaling, Impaired Memory, and Spine Dysmorphology in Rats.

Numerous studies have shown epilepsy-associated cognitive deficits, but less is known about the effects of one single generalized seizure. Recent studies demonstrate that a single, self-limited seizure can result in memory deficits and induces hyperactive phosphoinositide 3-kinase/Akt (protein kinase B)/mechanistic target of rapamycin (PI3K/Akt/mTOR) signaling. However, the effect of a single seizure on subcellular structures such as dendritic spines and the role of aberrant PI3K/Akt/mTOR signaling in these seizure-induced changes are unclear. Using the pentylenetetrazole (PTZ) model, we induced a single generalized seizure in rats and: (1) further characterized short- and long-term hippocampal and amygdala-dependent memory deficits, (2) evaluated whether there are changes in dendritic spines, and (3) determined whether inhibiting hyperactive PI3K/Akt/mTOR signaling rescued these alterations. Using the PI3K inhibitor wortmannin (Wort), we partially rescued short- and long-term memory deficits and altered spine morphology. These studies provide evidence that pathological PI3K/Akt/mTOR signaling plays a role in seizure-induced memory deficits as well as aberrant spine morphology.

Strain-dependence of the Angelman Syndrome phenotypes in Ube3a maternal deficiency mice.

Angelman syndrome (AS) is a genetic neurodevelopmental disorder, most commonly caused by deletion or mutation of the maternal allele of the UBE3A gene, with behavioral phenotypes and seizures as key features. Currently no treatment is available, and therapeutics are often ineffective in controlling AS-associated seizures. Previous publications using the Ube3a maternal deletion model have shown behavioral and seizure susceptibility phenotypes, however findings have been variable and merit characterization of electroencephalographic (EEG) activity. In this study, we extend previous studies comparing the effect of genetic background on the AS phenotype by investigating the behavioral profile, EEG activity, and seizure threshold. AS C57BL/6J mice displayed robust behavioral impairments, spontaneous EEG polyspikes, and increased cortical and hippocampal power primarily driven by delta and theta frequencies. AS 129 mice performed poorly on wire hang and contextual fear conditioning and exhibited a lower seizure threshold and altered spectral power. AS F1 hybrid mice (C57BL/6J × 129) showed milder behavioral impairments, infrequent EEG polyspikes, and fewer spectral power alterations. These findings indicate the effect of common genetic backgrounds on the Ube3a maternal deletion behavioral, EEG, and seizure threshold phenotypes. Our results will inform future studies on the optimal strain for evaluating therapeutics with different AS-like phenotypes.

Prevention by Regular Exercise of Acute Sleep Deprivation-Induced Impairment of Late Phase LTP and Related Signaling Molecules in the Dentate Gyrus.

The dentate gyrus (DG) and CA1 regions of the hippocampus are intimately related physically and functionally, yet they react differently to insults. The purpose of this study was to determine the protective effects of regular treadmill exercise on late phase long-term potentiation (L-LTP) and its signaling cascade in the DG region of the hippocampus of rapid eye movement (REM) sleep-deprived rats. Adult Wistar rats ran on treadmills for 4 weeks then were acutely sleep deprived for 24 h using the modified multiple platform method. After sleep deprivation, the rats were anesthetized and L-LTP was induced in the DG region. Extracellular field potentials from the DG were recorded in vivo, and levels of L-LTP-related signaling proteins were assessed both before and after L-LTP expression using immunoblot analysis. Sleep deprivation reduced the basal levels of phosphorylated cAMP response element-binding protein (P-CREB) as well as other upstream modulators including calcium/calmodulin kinase IV (CaMKIV) and brain-derived neurotrophic factor (BDNF) in the DG of the hippocampus. Regular exercise prevented impairment of the basal levels of P-CREB and total CREB as well as those of CaMKIV in sleep-deprived animals. Furthermore, regular exercise prevented sleep deprivation-induced inhibition of L-LTP and post-L-LTP downregulation of P-CREB and BDNF levels in the DG. The current findings show that our exercise regimen prevents sleep deprivation-induced deficits in L-LTP as well as the basal and poststimulation levels of key signaling molecules.

Comparison of the Effect of Exercise on Late-Phase LTP of the Dentate Gyrus and CA1 of Alzheimer's Disease Model.

We investigated the neuroprotective effect of regular treadmill exercise training on long-term memory and its correlate: the late-phase long-term potentiation (L-LTP) and plasticity- and memory-related signaling molecules in the DG and CA1 areas of a rat model of Alzheimer's disease (AD) (i.c.v. infusion of Aß1-42 peptides, 2 weeks, 250 pmol/day). Testing in the radial arm water maze revealed severe impairment of spatial long-term memory in Aß-infused sedentary rats but not in exercised Aß-infused rats. The L-LTP, measured as changes in the field (f)EPSP and in the amplitude of population spike (pspike), was induced by multiple high-frequency stimulation in the CA1 and DG areas of anesthetized rats. The L-LTP of fEPSP in both areas was severely impaired in the sedentary Aß rats but not in exercised Aß rats. However, L-LTP of the pspike was severely suppressed in the CA1 area but not in the DG of sedentary Aß rats. Immunoblot analysis revealed no increase in the levels of phosphorylated (p)-CREB, CaMKIV, and brain-derived neurotrophic factor (BDNF) in both CA1 and DG areas of sedentary Aß rats during L-LTP, whereas the levels of these molecules were robustly increased in exercised Aß rats. Impairment of synaptic function may be due to deleterious changes in the molecular signaling cascades that mediate synaptic structural and functional changes. The protective effect of regular exercise can be a promising therapeutic measure for countering or delaying the AD-like pathology.

Moderate Treadmill Exercise Protects Synaptic Plasticity of the Dentate Gyrus and Related Signaling Cascade in a Rat Model of Alzheimer's Disease.

The dentate gyrus (DG) of the hippocampus is known to be more resistant to the effects of various external factors than other hippocampal areas. This study investigated the neuroprotective effects of moderate treadmill exercise on early-phase long-term potentiation (E-LTP) and its molecular signaling pathways in the DG of amyloid ß rat model of sporadic Alzheimer's disease (AD). Animals were preconditioned to run on treadmill for 4 weeks and concurrently received ICV infusion of Aß1₋42 peptides (250 pmol/day) during the third and fourth weeks of exercise training. We utilized in vivo electrophysiological recordings to assess the effect of exercise and/or AD pathology on basal synaptic transmission and E-LTP magnitude of the perforant pathway synapses in urethane-anesthetized rats. Immunoblotting analysis was used to quantify changes in the levels of learning and memory-related key signaling molecules. The AD-impaired basal synaptic transmission and suppression of E-LTP in the DG were prevented by prior moderate treadmill exercise. In addition, exercise normalized the basal levels of memory and E-LTP-related signaling molecules including Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), calcineurin (PP2B), and brain-derived neurotrophic factor (BDNF). Exercise also prevented the reduction of phosphorylated CaMKII and aberrant increase of PP2B seen after E-LTP induction in amyloid-infused rats. Our data suggests that by restoring the balance of kinase-phosphatase, 4 weeks of moderate treadmill exercise prevents DG synaptic deficits and deleterious alterations in signaling pathways associated with AD.