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Background: Studies have suggested that cognitive impairment in Alzheimer's disease (AD) is associated with dendritic spine loss, especially in the hippocampus. Fluoxetine (FLX) has been shown to improve cognition in the early stage of AD and to be associated with diminishing synapse degeneration in the hippocampus. However, little is known about whether FLX affects the pathogenesis of AD in the middle-tolate stage and whether its effects are correlated with the amelioration of hippocampal dendritic dysfunction. Previously, it has been observed that FLX improves the spatial learning ability of middleaged APP/PS1 mice., Objective: In the present study, we further characterized the impact of FLX on dendritic spines in the hippocampus of middle-aged APP/PS1 mice., Results: It has been found that the numbers of dendritic spines in dentate gyrus (DG), CA1 and CA2/3 of hippocampus were significantly increased by FLX. Meanwhile, FLX effectively attenuated hyperphosphorylation of tau at Ser396 and elevated protein levels of postsynaptic density 95 (PSD-95) and synapsin-1 (SYN-1) in the hippocampus., Conclusion: These results indicated that the enhanced learning ability observed in FLX-treated middle-aged APP/PS1 mice might be associated with remarkable mitigation of hippocampal dendritic spine pathology by FLX and suggested that FLX might be explored as a new strategy for therapy of AD in the middle-to-late stage., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

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 Aβ40, Aβ42, 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. Using the unbiased stereological methods, we found that FLX prevented the decrease in dendritic spine synapses in the dentate gyrus, CA1/2 and CA3 regions of the hippocampus in the early Alzheimer's disease. This might provide a starting point for further research into new preventative measures and treatments for AD. [ABSTRACT FROM AUTHOR]

• AD mice has more postsynaptic terminal colocalized with microglia in the hippocampi. • Anti-LINGO-1 antibody rescues the loss of postsynaptic terminal in AD hippocampi. • Microglia might participate in the effect of Anti-LINGO-1 antibody in AD. 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. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is closely related to hippocampal synapse loss, which can be alleviated by running exercise. However, further studies are needed to determine whether running exercise reduces synapse loss in the hippocampus in an AD model by regulating microglia. Ten-month-old male wild-type mice and APP/PS1 mice were randomly divided into control and running groups. All mice in the running groups were subjected to voluntary running exercise for four months. After the behavioral tests, immunohistochemistry, stereological methods, immunofluorescence staining, 3D reconstruction, western blotting and RNA-Seq were performed. Running exercise improved the spatial learning and memory abilities of APP/PS1 mice and increased the total number of dendritic spines, the levels of the PSD-95 and Synapsin Ia/b proteins, the colocalization of PSD-95 and neuronal dendrites (MAP-2) and the number of PSD-95-contacting astrocytes (GFAP) in the hippocampi of APP/PS1 mice. Moreover, running exercise reduced the relative expression of CD68 and Iba-1, the number of Iba-1+ microglia and the colocalization of PSD-95 and Iba-1+ microglia in the hippocampi of APP/PS1 mice. The RNA-Seq results showed that some differentially expressed genes (DEGs) related to the complement system (Cd59b , Serping1 , Cfh , A2m , and Trem2) were upregulated in the hippocampi of APP/PS1 mice, while running exercise downregulated the C3 gene. At the protein level, running exercise also reduced the expression of advanced glycation end products (AGEs), receptor for advanced glycation end products (RAGE), C1q and C3 in the hippocampus and AGEs and RAGE in hippocampal microglia in APP/PS1 mice. Furthermore, the Col6a3 , Scn5a , Cxcl5 , Tdg and Clec4n genes were upregulated in the hippocampi of APP/PS1 mice but downregulated after running, and these genes were associated with the C3 and RAGE genes according to protein–protein interaction (PPI) analysis. These findings indicate that long-term voluntary exercise might protect hippocampal synapses and affect the function and activation of microglia, the AGE/RAGE signaling pathway in microglia and the C1q/C3 complement system in the hippocampus in APP/PS1 mice, and these effects may be related to the Col6a3 , Scn5a , Cxcl5 , Tdg and Clec4n genes. The current results provide an important basis for identifying targets for the prevention and treatment of AD. • Voluntary exercise prevented spatial learning and memory decline in APP/PS1 mice. • Voluntary exercise improved the number of dendritic spines and expression of synapse-related proteins in the hippocampi of APP/PS1 mice. • Voluntary exercise reduced the number of microglia, colocalization of synapses and microglia, AGE/RAGE signaling pathway in microglia and C1q/C3 complement system in the hippocampi of APP/PS1 mice. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. • Four-month treadmill exercise improves spatial learning and memory in APP/PS1 mice. • Four-month treadmill exercise increases dendritic spine numbers in the CA1, CA2–3 and DG of APP/PS1 mice. • Running exercise may be an effective means to delay dementia symptoms in AD. [ABSTRACT FROM AUTHOR]