Long-term running exercise improves cognitive function and promotes microglial glucose metabolism and morphological plasticity in the hippocampus of APP/PS1 mice.

BACKGROUND: The role of physical exercise in the prevention of Alzheimer's disease (AD) has been widely studied. Microglia play an important role in AD. Triggering receptor expressed in myeloid cells 2 (TREM2) is expressed on microglia and is known to mediate microglial metabolic activity and brain glucose metabolism. However, the relationship between brain glucose metabolism and microglial metabolic activity during running exercise in APP/PS1 mice remains unclear. METHODS: Ten-month-old male APP/PS1 mice and wild-type mice were randomly divided into sedentary groups or running groups (AD_Sed, WT_Sed, AD_Run and WT_Run, n = 20/group). Running mice had free access to a running wheel for 3 months. Behavioral tests, [18]F-FDG-PET and hippocampal RNA-Seq were performed. The expression levels of microglial glucose transporter (GLUT5), TREM2, soluble TREM2 (sTREM2), TYRO protein tyrosine kinase binding protein (TYROBP), secreted phosphoprotein 1 (SPP1), and phosphorylated spleen tyrosine kinase (p-SYK) were estimated by western blot or ELISA. Immunohistochemistry, stereological methods and immunofluorescence were used to investigate the morphology, proliferation and activity of microglia. RESULTS: Long-term voluntary running significantly improved cognitive function in APP/PS1 mice. Although there were few differentially expressed genes (DEGs), gene set enrichment analysis (GSEA) showed enriched glycometabolic pathways in APP/PS1 running mice. Running exercise increased FDG uptake in the hippocampus of APP/PS1 mice, as well as the protein expression of GLUT5, TREM2, SPP1 and p-SYK. The level of sTREM2 decreased in the plasma of APP/PS1 running mice. The number of microglia, the length and endpoints of microglial processes, and the ratio of GLUT5+/IBA1+ microglia were increased in the dentate gyrus (DG) of APP/PS1 running mice. Running exercise did not alter the number of 5-bromo-2'-deoxyuridine (BrdU)+/IBA1+ microglia but reduced the immunoactivity of CD68 in the hippocampus of APP/PS1 mice. CONCLUSIONS: Running exercise inhibited TREM2 shedding and maintained TREM2 protein levels, which were accompanied by the promotion of brain glucose metabolism, microglial glucose metabolism and morphological plasticity in the hippocampus of AD mice. Microglia might be a structural target responsible for the benefits of running exercise in AD. Promoting microglial glucose metabolism and morphological plasticity modulated by TREM2 might be a novel strategy for AD treatment.

Anti-LINGO-1 antibody ameliorates cognitive impairment, promotes adult hippocampal neurogenesis, and increases the abundance of CB1R-rich CCK-GABAergic interneurons in AD mice.

In view of the negative regulatory effect of leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 1 (LINGO-1) on neurons, an antibody against LINGO-1 (anti-LINGO-1 antibody) was herein administered to 10-month-old APP/PS1 transgenic Alzheimer's disease (AD) mice for 2 months as an experimental intervention. Behavioral, stereology, immunohistochemistry and immunofluorescence analyses revealed that the anti-LINGO-1 antibody significantly improved the cognitive abilities, promoted adult hippocampal neurogenesis (AHN), decreased the amyloid beta (Aß) deposition, enlarged the hippocampal volume, and increased the numbers of total neurons and GABAergic interneurons, including GABAergic and CCK-GABAergic interneurons rich in cannabinoid type 1 receptor (CB1R), in the hippocampus of AD mice. In contrast, this intervention significantly reduced the number of GABAergic interneurons expressing LINGO-1 and CB1R in the hippocampus of AD mice. More importantly, we also found a negative correlation between LINGO-1 and CB1R on GABAergic interneurons in the hippocampus of AD mice, while the anti-LINGO-1 antibody reversed this relationship. These results indicated that LINGO-1 plays an important role in the process of hippocampal neuron loss in AD mice and that antagonizing LINGO-1 can effectively prevent hippocampal neuron loss and promote AHN. The improvement in cognitive abilities may be attributed to the improvement in AHN, and in the numbers of GABAergic interneurons and CCK-GABAergic interneurons rich in CB1Rs in the hippocampus of AD mice induced by the anti-LINGO-1 antibody. Collectively, the double target effect (LINGO-1 and CB1R) initiated by the anti-LINGO-1 antibody may provide an important basis for the study of drugs for the prevention and treatment of AD in the future.

Four-month treadmill exercise prevents the decline in spatial learning and memory abilities and the loss of spinophilin-immunoreactive puncta in the hippocampus of APP/PS1 transgenic mice.

BACKGROUND: Previous studies have reported that exercise could improve the plasticity of hippocampal synapses. However, the effects of exercise on synapses in the hippocampus in Alzheimer's disease (AD) are not completely known. METHODS: In this study, thirty 12-month-old male APP/PS1 double transgenic mice were randomly divided into a sedentary group (n = 15) and a running group (n = 15). Fifteen 12-month-old male wild-type littermates were assigned to the control group (n = 15). While running mice were assigned to treadmill running for four months, the control mice and sedentary mice did not run during the study period. After Morris water maze testing, five mice in each group were randomly selected for a stereological assessment of spinophilin-immunoreactive puncta in the CA1, CA2-3 and dentate gyrus (DG) of the hippocampus. RESULTS: Morris water maze testing revealed that while the learning and memory abilities in sedentary APP/PS1 mice were significantly worse than those in wild-type control mice, the learning and memory abilities in running APP/PS1 mice were significantly better than those in sedentary APP/PS1 mice. The stereological results showed that the spinophilin-immunoreactive puncta numbers of the CA1, CA2-3 and DG in the hippocampus of sedentary APP/PS1 mice were significantly lower than those of wild-type control mice and that the numbers of these spines in the CA1, CA2-3 and DG in the hippocampus of running APP/PS1 mice were significantly higher than those of sedentary APP/PS1 mice. Moreover, a running-induced improvement in spatial learning and memory abilities was significantly correlated with running-induced increases in the spinophilin-immunoreactive puncta numbers in the CA1 and DG of the hippocampus. CONCLUSIONS: Four-month treadmill exercise induced a significant improvement in spatial learning and memory abilities and a significant increase in the number of spinophilin-immunoreactive puncta of the CA1, CA2-3 and DG in the hippocampus of APP/PS1 mice. Running-induced improvements in spatial learning and memory abilities were significantly correlated with running-induced increases in the spinophilin-immunoreactive puncta numbers in the CA1 and DG of the hippocampus.

Synthesis of Terminal Vinylindoles via RhIII -Catalyzed Direct C-H Alkenylation with Potassium Vinyltrifluoroborate.

An efficient RhIII -catalyzed direct C2-alkenylation of indoles using readily available potassium vinyltrifluoroborate under mild conditions has been developed. This protocol features wide substrate scope and excellent functional group compatibility, enabling a facile access to diverse terminal vinylindoles in moderate to good yields. Furthermore, the C2-alkenylated indole can be easily transformed into 9H-carbazole through a ring-closing metathesis/aromatization cascade.

Antagonizing LINGO-1 reduces activated microglia and alleviates dendritic spine loss in the hippocampus of APP/PS1 transgenic mice.

In Alzheimer's disease (AD), microglia are involved in synaptic pruning and mediate synapse loss. LINGO-1 is a negative regulator of nerve growth, and whether antagonizing LINGO-1 can attenuate synaptic pruning by microglia and rescue dendritic spines in the hippocampus in AD is still unclear. On this basis, the anti-LINGO-1 antibody, which binds to LINGO-1 protein and antagonizes the effects of LINGO-1, was administered to 10-month-old APP/PS1 transgenic mice for 2 months. The Morris water maze test, immunohistochemical and stereological methods, immunofluorescence and 3D reconstruction were used. Compared to wild-type mice, APP/PS1 transgenic mice had worse performance on behavioral tests, fewer dendritic spines but more microglia in the hippocampus. Meanwhile, the microglia in APP/PS1 transgenic mice had more branches of medium length (4-6 µm) and a cell body area with greater variability. Moreover, APP/PS1 transgenic mice had more postsynaptic termini colocalized with microglia in the hippocampus than wild-type mice. The anti-LINGO-1 antibody significantly reversed these changes in AD, indicating that the anti-LINGO-1 antibody can improve hippocampus-dependent learning and memory abilities and effectively rescue dendritic spines in the hippocampus of AD mice and that microglia might participate in this progression in AD. These results provide a scientific basis for further studying the mechanism of the anti-LINGO-1 antibody in AD and help to elucidate the role of LINGO-1 in the treatment of AD.

Anti-LINGO-1 antibody protects neurons and synapses in the medial prefrontal cortex of APP/PS1 transgenic mice.

The medial prefrontal cortex (mPFC), one of the most vulnerable brain regions in Alzheimer's disease (AD), plays a critical role in cognition. Leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein-1 (LINGO-1) negatively affects nerve growth in the central nervous system; however, its role in the pathological damage to the mPFC remains to be studied in AD. In this study, an anti-LINGO-1 antibody was administered to 10-month-old APP/PS1 mice, and behavioral tests, stereological methods, immunohistochemistry and immunofluorescence were used to answer this question. Our results revealed that LINGO-1 was highly expressed in the neurons of the mPFC of AD mice, and the anti-LINGO-1 antibody improved prefrontal cortex-related function and reduced the protein level of LINGO-1, atrophy of the volume, Aß deposition and massive losses of synapses and neurons in the mPFC of AD mice. Antagonizing LINGO-1 could effectively alleviate the pathological damage in the mPFC of AD mice, which might be an important structural basis for improving prefrontal cortex-related function. Abnormal expression of LINGO-1 in the mPFC may be one of the key targets of AD, and the effect initiated by the anti-LINGO-1 antibody may provide an important basis in the search for drugs for the prevention and treatment of AD.

Exercise more efficiently regulates the maturation of newborn neurons and synaptic plasticity than fluoxetine in a CUS-induced depression mouse model.

Depression, a common and important cause of morbidity and mortality worldwide, is commonly treated with antidepressants, electric shock and psychotherapy. Recently, increasing evidence has shown that exercise can effectively alleviate depression. To determine the difference in efficacy between exercise and the classic antidepressant fluoxetine in treating depression, we established four groups: the Control, chronic unpredictable stress (CUS/STD), running (CUS/RUN) and fluoxetine (CUS/FLX) groups. The sucrose preference test (SPT), the forced swimming test (FST), the tail suspension test (TST), immunohistochemistry, immunofluorescence and stereological analyses were used to clarify the difference in therapeutic efficacy and mechanism between exercise and fluoxetine in the treatment of depression. In the seventh week, the sucrose preference of the CUS/RUN group was significantly higher than that of the CUS/STD group, while the sucrose preference of the CUS/FLX group did not differ from that of the CUS/STD group until the eighth week. Exercise reduced the immobility time in the FST and TST, while fluoxetine only reduced immobility time in the TST. Hippocampal structure analysis showed that the CUS/STD group exhibited an increase in immature neurons and a decrease in mature neurons. Exercise reduced the number of immature neurons and increased the number of mature neurons, but no increase in the number of mature neurons was observed after fluoxetine treatment. In addition, both running and fluoxetine reversed the decrease in the number of MAP2+ dendrites in depressed mice. Exercise increased the number of spinophilin-positive (Sp+) dendritic spines in the hippocampal CA1, CA3, and dentate gyrus (DG) regions, whereas fluoxetine only increased the number of SP+ spines in the DG. In summary, exercise promoted newborn neuron maturation in the DG and regulated neuronal plasticity in three hippocampal subregions, which might explain why running exerts earlier and more comprehensive antidepressant effects than fluoxetine.

Running exercise protects spinophilin-immunoreactive puncta and neurons in the medial prefrontal cortex of APP/PS1 transgenic mice.

The medial prefrontal cortex (mPFC) is thought to be closely associated with emotional processes, decision making, and memory. Previous studies have identified the prefrontal cortex as one of the most vulnerable brain regions in Alzheimer's disease (AD). Running exercise has widely been recognized as a simple and effective method of physical activity that enhances brain function and slows the progression of AD. However, the effect of exercise on the mPFC of AD is unclear. To address these issues, we investigated the effects of 4 months of exercise on the numbers of spinophilin-immunoreactive puncta and neurons in the mPFC of 12-month-old APPswe/PSEN1dE9 (APP/PS1) transgenic AD model mice using stereological methods. The spatial learning and memory abilities of mice were tested using the Morris water maze. Four months of running exercise delayed declines in spatial learning and memory abilities. The stereological results showed significantly lower numbers of spinophilin-immunoreactive puncta and neurons in the mPFC of APP/PS1 mice than in the wild-type control group. The numbers of spinophilin-immunoreactive puncta and neurons in the mPFC of running APP/PS1 mice were significantly greater than those in the APP/PS1 control mice. In addition, running-induced improvements in spatial learning and memory were significantly associated with running-induced increases in spinophilin-immunoreactive puncta and neurons numbers in the mPFC. Running exercise could delay the loss of spinophilin-immunoreactive puncta and neurons in the mPFC of APP/PS1 mice. This finding might provide an important structural basis for exercise-induced improvements in the spatial learning and memory abilities of individuals with AD.

Anti-LINGO-1 antibody treatment alleviates cognitive deficits and promotes maturation of oligodendrocytes in the hippocampus of APP/PS1 mice.

Leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 1 (LINGO-1), a negative regulator of oligodendrocyte differentiation and myelination, is associated with cognitive function, and its expression is highly upregulated in Alzheimer's disease (AD) patients. Anti-LINGO-1 antibody treatment can effectively antagonize the negative regulatory effect of LINGO-1. In this study, we aim to assess the effect of anti-LINGO-1 antibody treatment on cognition and hippocampal oligodendrocytes in an AD transgenic animal model. First, 10-month-old male amyloid-ß (Aß) protein precursor (APP)/presenilin 1 (PS1) mice were administered anti-LINGO-1 antibody for 8 weeks. Then, learning and memory abilities were assessed with the Morris water maze (MWM) and Y-maze tests, and Aß deposition and hippocampal oligodendrocytes were investigated by immunohistochemistry, immunofluorescence, and stereology. We found that anti-LINGO-1 antibody alleviated the deficits in spatial learning and memory abilities and working and reference memory abilities, decreased the density of LINGO-1 positive cells, decreased Aß deposition, significantly increased the number of mature oligodendrocytes and the density of myelin, reversed the abnormal increases in the number of oligodendrocyte lineage cells and the densities of oligodendrocytes precursor cells in APP/PS1 mice. Our results provide evidence that LINGO-1 might be involved in the process of oligodendrocyte dysmaturity in the hippocampus of AD mice, and that antagonizing LINGO-1 can alleviate cognitive deficits in APP/PS1 mice and decrease Aß deposition and promote oligodendrocyte differentiation and maturation in the hippocampus of these mice. Our findings suggest that changes in LINGO-1 and oligodendrocytes in the hippocampus play important roles in the pathogenesis of AD and that antagonizing LINGO-1 might be a potential therapeutic strategy for AD.

Atrophy of lacunosum moleculare layer is important for learning and memory in APP/PS1 transgenic mice.

Changes in the hippocampus are closely associated with learning and memory in Alzheimer's disease; however, it is not clear which morphological and cellular and subcellular changes are essential for learning and memory. Here, we accurately quantitatively studied the hippocampal microstructure changes in Alzheimer's disease model mice and analyzed the relationship between the hippocampal microstructure changes and learning and memory. Ten-month-old male APP/PS1 transgenic mice and age-matched nontransgenic littermate mice were randomly selected. The spatial learning and memory abilities were assessed using the Morris water maze. The volumes of each layer and numbers of neurons, dendritic spines and oligodendrocytes in the hippocampal subregions were investigated using unbiased stereological techniques. The APP/PS1 transgenic mice showed a decline in hippocampus-dependent spatial learning and memory abilities, smaller volumes of each layer (other than stratum radiatum) and fewer numbers of neurons, dendritic spine synapses and mature oligodendrocytes in the hippocampal subregions than nontransgenic mice. In particular, the decline of spatial learning ability was significantly correlated with the atrophy of lacunosum moleculare layer (LMol) and the decrease of hippocampal neurons and mature oligodendrocytes rather than dendritic spines. The CA1-3 fields (including LMol) atrophy was significantly correlated with the decrease both of neurons, dendritic spines and mature oligodendrocytes. However, the dentate gyrus atrophy was significantly correlated with the decrease of neurons and mature oligodendrocytes rather than dendritic spines. The loss of neurons, dendritic spines synapses and mature oligodendrocytes together caused the LMol atrophy and then led to a decline in hippocampus-dependent spatial learning ability in mice with Alzheimer's disease.

Anti-Lingo-1 antibody ameliorates spatial memory and synapse loss induced by chronic stress.

Chronic stress can induce cognitive impairment, and synapse number was significantly decreased in the hippocampus of rats suffering from chronic stress. Lingo-1 is a potent negative regulator of axonal outgrowth and synaptic plasticity. In the current study, the effects of anti-Lingo-1 antibody on the spatial learning and memory abilities and hippocampal synapses of stressed rats were investigated. After 4 weeks of stress exposure, the model group was randomly divided into a chronic stress group and an anti-Lingo-1 group. Then, the anti-Lingo-1 group rats were treated with anti-Lingo-1 antibody (8 mg/kg) for 3 weeks. The effects of anti-Lingo-1 antibody on the spatial learning and memory abilities were investigated with the Morris water maze test. Immunohistological staining and an unbiased stereological method were used to estimate the total number of dendritic spine synapses in the hippocampus. At the behavioral level, after 3 weeks of treatment, the anti-Lingo-1 group rats displayed significantly more platform location crossings in the Morris water maze test than the chronic stress group rats. Anti-Lingo-1 significantly prevented the declines in dendritic spine synapses and postsynaptic density protein-95 (PSD-95) expression in the dentate gyrus and the CA1 and CA3 regions of the hippocampus. The present results indicated that anti-Lingo-1 antibody may be a safe and effective drug for alleviating memory impairment in rats after chronic stress and protecting synapses in the hippocampus of stressed rats.

Fluoxetine Promotes Hippocampal Oligodendrocyte Maturation and Delays Learning and Memory Decline in APP/PS1 Mice.

Oligodendrogenesis dysfunction impairs memory consolidation in adult mice, and an oligodendrocyte abnormality is an important change occurring in Alzheimer's disease (AD). While fluoxetine (FLX) is known to delay memory decline in AD models, its effects on hippocampal oligodendrogenesis are unclear. Here, we subjected 8-month-old male amyloid precursor protein (APP)/presenilin 1 (PS1) mice to the FLX intervention for 2 months. Their exploratory behaviors and general activities in a novel environment, spatial learning and memory and working and reference memory were assessed using the open-field test, Morris water maze, and Y maze. Furthermore, changes in hippocampal oligodendrogenesis were investigated using stereology, immunohistochemistry, immunofluorescence staining, and Western blotting techniques. FLX delayed declines in the spatial learning and memory, as well as the working and reference memory of APP/PS1 mice. In addition, APP/PS1 mice exhibited immature hippocampal oligodendrogenesis, and FLX increased the numbers of 2'3'cyclic nucleotide 3'-phosphodiesterase (CNPase)+ and newborn CNPase+ oligodendrocytes in the hippocampi of APP/PS1 mice. Moreover, FLX increased the density of SRY-related HMG-box 10 protein (SOX10)+ cells and reduced the percentage of oligodendrocyte lineage cells displaying the senescence phenotype (CDKN2A/p16INK4a) in the hippocampus of APP/PS1 mice. Moreover, FLX had no effect on the serotonin (5-HT) 1A receptor (5-HT1AR) content or number of 5-HT1AR+ oligodendrocytes, but it reduced the content and activity of glycogen synthase kinase 3ß (GSK3ß) in the hippocampus of APP/PS1 transgenic mice. Taken together, FLX delays the senescence of oligodendrocyte lineage cells and promotes oligodendrocyte maturation in the hippocampus of APP/PS1 mice. FLX may regulate GSK3ß through a mechanism other than 5-HT1AR and then inhibit the negative effect of GSK3ß on oligodendrocyte maturation in the hippocampus of an AD mouse model.

Quantitative study of the capillaries within the white matter of the Tg2576 mouse model of Alzheimer's disease.

INTRODUCTION: To quantitatively investigate the capillaries within the white matter of Tg2576 Alzheimer's disease (AD) transgenic mice during the early stage. METHODS: In the current study, 10-month-old male Tg2576 AD mice were used as the early-stage AD group and age-matched nontransgenic littermate mice were used as the wild-type group. Then, the Morris water maze was used to examine the spatial learning and memory abilities of the mice in both groups, and unbiased stereological methods were used to accurately quantify the volume of white matter and the parameters of the capillaries within the white matter, such as the total length, total volume, and total surface area of capillaries. RESULTS: The Morris water maze performance of the Tg2576 group was worse than that of the wild-type group, while the white matter volume did not significantly differ between the wild-type group and the Tg2576 group. The total length, total volume, and total surface area of the capillaries within the white matter of the Tg2576 group were significantly decreased compared to those of the wild-type group. CONCLUSIONS: The current study provide structural basis for understanding the pathological changes of the early stage of AD and cognitive decline in AD might be associated with changes in the white matter capillaries. Capillaries within the white matter might, thus, serve as a valid target for the prevention and treatment of early-stage AD.

Fluoxetine delays the cognitive function decline and synaptic changes in a transgenic mouse model of early Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with cognitive decline. Previous studies have reported that the syndrome of AD begins with subtle alterations in hippocampal synapses prior to frank neuronal degeneration. It has recently been reported that fluoxetine (FLX) shows positive effects on AD patients who have depression and anxiety. However, it is unclear whether FLX can affect the pathogenesis of AD mice in the early stage of AD. To address this question, 8-month-old male APP/PS1 double-transgenic AD mice were administered a 10-week course of FLX (10 mg/kg/day) injections. Then, spatial learning and memory were evaluated using a Morris water maze test. Immunohistological staining and an unbiased stereological method were used to estimate the total number of dendritic spine synapses in the hippocampus. We found that FLX significantly shortened the mean escape latencies of the 10-month-old mice; reduced the elevated levels of soluble Aß40, Aß42, and amyloid plaques in the hippocampus; and prevented the decrease in dendritic spine synapses and in postsynaptic protein PSD-95 density in the dentate gyrus, CA1/2 and CA3 regions of the hippocampus. Our results indicate that reversing synaptic impairment might be considered a promising therapeutic approach for alleviating the cognitive deficits associated with early AD. Moreover, our results suggest that FLX may be a safe and effective drug for delaying the progress of AD, which might provide a starting point for further research into new preventative measures and treatments for AD.

Sex Differences in the White Matter and Myelinated Fibers of APP/PS1 Mice and the Effects of Running Exercise on the Sex Differences of AD Mice.

Previous studies have suggested that changes in the white matter might play an important role in the pathogenic processes of Alzheimer's disease (AD). However, no study has investigated sex differences in these changes. Previous studies found that running exercise could delay both the decline in spatial learning and memory abilities as well as the changes in the white matter during early AD in male mice. However, whether exercise also has an effect on the changes in the white matter in female AD mice remains unknown. To address these questions, 6- and 10-month-old male and female APP/PS1 double transgenic AD mice were used. The 6-month-old male and female APP/PS1 double transgenic AD mice underwent a 4-month running exercise regime. The white matter volume and parameters of the myelinated fibers in the white matter of the 10-month-old exercised and non-exercised male and female AD mice were investigated using electron microscopy and stereological methods. There were no significant differences in the mean escape latencies between the male and female AD mice in the non-exercised groups, but after 4 months of treadmill exercise, the mean escape latencies of the female exercised AD mice had significantly shortened compared with those of the male exercised AD mice. The total white matter volume and most of the parameters of the myelinated fibers of the white matter in the female AD mice were significantly lower than those of the male AD mice. The total length of the myelinated fibers with diameters ranging from 0.6 to 0.7 µm, the axonal diameter of the myelinated fibers and the g-ratio of the myelinated fibers in the white matter of the exercised female AD mice were significantly increased compared with those of the non-exercised female AD mice. There were sex-specific differences in the white matter and myelinated fibers of white matter in the AD mice. Running exercise more effectively delayed the decline in spatial learning and memory abilities and delayed the changes in the myelinated fibers of the white matter in female transgenic mice with early AD than in male transgenic mice.

Running exercise protects against myelin breakdown in the absence of neurogenesis in the hippocampus of AD mice.

Neurogenesis might influence oligodendrogenesis and selectively instruct myelination in the mammalian brain. Running exercise could induce neurogenesis and protect the myelin sheaths in the dentate gyrus of AD mice. It is unclear whether running exercise can protect myelin sheaths in the absence of neurogenesis in the hippocampus of AD mice. Six-month-old male APP/PS1 transgenic mice were randomly assigned to a control group (Tg control) or a running group (Tg runner), and age-matched non-transgenic littermates were used as a wild-type group (WT control). The Tg runner mice were subjected to a running protocol for four months. The behaviors of the mice in the three groups were then assessed using the Morris water maze, and related quantitative parameters of the myelin sheaths within the CA1 field were investigated using unbiased stereological and electron microscopy techniques. Learning and spatial memory performance, CA1 volume, the volumes of the myelinated fibers, and myelin sheaths in the CA1 field were all significantly worse in the Tg control mice than in the WT control mice. Learning and spatial memory performance, CA1 volume and the volume of the myelin sheaths in the CA1 field were all significantly greater in the Tg runner mice than in the Tg control mice. These results reveal demyelinating lesions in the CA1 field of Alzheimer's disease (AD) mice and indicate that running exercise could protect against myelin sheath degeneration in the absence of neurogenesis, thereby reducing CA1 atrophy and delaying the onset and progression of AD.

Effect of running exercise on the number of the neurons in the hippocampus of young transgenic APP/PS1 mice.

To investigate the effect of running exercise on the number of the neurons in the hippocampus of young APP/PS1 mice, twenty 6-month-old male APP/ PS1 transgenic mice were randomly divided into the APP/PS1 control (AD control) group and the APP/PS1 running (AD running) group (10 mice per group), and ten wild-type mice of the littermate were regarded as the wild-type (WT) group. The AD running mice ran on motorized treadmill machiene for 4 months, while the WT mice and AD control mice were housed in standard condition without running. Then, Morris water maze tests (MWM) were used to assess the special learning and memory abilities of mice in three groups. The stereological methods were used to quantitatively evaluate the volume of the hippocampus, CA1/2, CA3 and the dentate gyrus (DG) and count the number of the neurons in CA1/2, CA3 and DG. We found that 4-month running effectively shortened the escape latency of young APP/PS1 control mice in MWM. More importantly, 4-month running effectively increased the volumes of the hippocampus, CA1/2, CA3 and DG and increased the number of neurons in CA1/2, CA3 and DG in young APP/PS1 mice. The present results suggested that 4-month running has significant beneficial effects on the spatial learning and memory capacities of young APP/PS1 mice and could delay the progress of atrophy of hippocampus and the neuron death in CA1/2, CA3 and DG in young APP/PS1 mice.

Effects of exercise on capillaries in the white matter of transgenic AD mice.

Previous studies have shown that exercise can prevent white matter atrophy in APP/PS1 transgenic Alzheimer's disease (AD) mice. However, the mechanism of this protective effect remains unknown. To further understand this issue, we investigated the effects of exercise on the blood supply of white matter in transgenic AD mice. Six-month-old male APP/PS1 mice were randomly divided into a control group and a running group, and age-matched non-transgenic littermates were used as a wild-type control group. Mice in the running group ran on a treadmill at low intensity for four months. Then, spatial learning and memory abilities, white matter and white matter capillaries were examined in all mice. The 10-month-old AD mice exhibited deficits in cognitive function, and 4 months of exercise improved these deficits. The white matter volume and the total length, total volume and total surface area of the white matter capillaries were decreased in the 10-month-old AD mice, and 4 months of exercise dramatically delayed the changes in these parameters in the AD mice. Our results demonstrate that even low-intensity running exercise can improve spatial learning and memory abilities, delay white matter atrophy and protect white matter capillaries in early-stage AD mice. Protecting capillaries might be an important structural basis for the exercise-induced protection of the structural integrity of white matter in AD.

Exercise Prevents Cognitive Function Decline and Demyelination in the White Matter of APP/PS1 Transgenic AD Mice.

BACKGROUND: Whether exercise could delay the cognitive function decline and structural changes in Alzheimer's disease (AD) are not fully understood. METHODS: 6-month-old male APP/PS1 double transgenic mice ran four months and then the effects of exercise on the cognitive function and the white matter of AD were investigated. RESULTS: The mean escape latency of the excercised group was significantly shortened when compared to that of the sedentary group. The percentage of time in target quadrant and the target zone frequency of the exercised group were significantly increased when compared to the sedentary group. The white matter volume, the myelinated fiber volume and axon volume in the white matter of the exercised group were significantly increased when compared to the sedentary group. CONCLUSION: Exercise could improve the cognitive function in AD, and the effects of exercise on the white matter of AD might be one of the structural bases for the protective effect of exercise on the cognitive function of AD. The exercise-induced protection of the white matter in AD might be due to the fact that the exercise prevented the demyelination of the myelinated fibers in the white matter of AD.

Fluoxetine attenuates the impairment of spatial learning ability and prevents neuron loss in middle-aged APPswe/PSEN1dE9 double transgenic Alzheimer's disease mice.

Selective serotonin reuptake inhibitors (SSRIs) have been reported to increase cognitive performance in some clinical studies of Alzheimer's disease (AD). However, there is a lack of evidence supporting the efficacy of SSRIs as cognition enhancers in AD, and the role of SSRIs as a treatment for AD remains largely unclear. Here, we characterized the impact of fluoxetine (FLX), a well-known SSRI, on neurons in the dentate gyrus (DG) and in CA1 and CA3 of the hippocampus of middle-aged (16 to 17 months old) APPswe/PSEN1dE9 (APP/PS1) transgenic AD model mice. We found that intraperitoneal (i.p.) injection of FLX (10 mg/kg/day) for 5 weeks effectively alleviated the impairment of spatial learning ability in middle-aged APP/PS1 mice as evaluated using the Morris water maze. More importantly, the number of neurons in the hippocampal DG was significantly increased by FLX. Additionally, FLX reduced the deposition of beta amyloid, inhibited GSK-3ß activity and increased the level of ß-catenin in middle-aged APP/PS1 mice. Collectively, the results of this study indicate that FLX delayed the progression of neuronal loss in the hippocampal DG in middle-aged AD mice, and this effect may underlie the FLX-induced improvement in learning ability. FLX may therefore serve as a promising therapeutic drug for AD.