Glutamate receptor delocalization in postsynaptic membrane and reduced hippocampal synaptic plasticity in the early stage of Alzheimer's disease

Mounting evidence suggests that synaptic plasticity provides the cellular biological basis of learning and memory, and plasticity deficits play a key role in dementia caused by Alzheimer's disease. However, the mechanisms by which synaptic dysfunction contributes to the pathogenesis of Alzheimer's disease remain unclear. In the present study, Alzheimer's disease transgenic mice were used to determine the relationship between decreased hippocampal synaptic plasticity and pathological changes and cognitive-behavioral deterioration, as well as possible mechanisms underlying decreased synaptic plasticity in the early stages of Alzheimer's disease-like diseases. APP/PS1 double transgenic(5 XFAD; Jackson Laboratory) mice and their littermates(wild-type, controls) were used in this study. Additional 6-weekold and 10-week-old 5 XFAD mice and wild-type mice were used for electrophysiological recording of hippocampal dentate gyrus. For10-week-old 5 XFAD mice and wild-type mice, the left hippocampus was used for electrophysiological recording, and the right hippocampus was used for biochemical experiments or immunohistochemical staining to observe synaptophysin levels and amyloid beta deposition levels. The results revealed that, compared with wild-type mice, 6-week-old 5 XFAD mice exhibited unaltered long-term potentiation in the hippocampal dentate gyrus. Another set of 5 XFAD mice began to show attenuation at the age of 10 weeks, and a large quantity of amyloid beta protein was accumulated in hippocampal cells. The location of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor and N-methyl-D-aspartic acid receptor subunits in synaptosomes was decreased. These findings indicate that the delocalization of postsynaptic glutamate receptors and an associated decline in synaptic plasticity may be key mechanisms in the early onset of Alzheimer's disease. The use and care of animals were in strict accordance with the ethical standards of the Animal Ethics Committee of Capital Medical University,China on December 17, 2015(approval No. AEEI-2015-182).     

Characterization of hippocampal Cajal-Retzius cells during development in a mouse model of Alzheimer＇s disease （Tg2576）

Cajal-Retzius cells are reelin-secreting neurons in the marginal zone of the neocortex and hippocampus. The aim of this study was to investigate Cajal-Retzius cells in Alzheimer＇s disease pathology. Results revealed that the number of Cajal-Retzius cells markedly reduced with age in both wild type and in mice over-expressing the Swedish double mutant form of amyloid precursor protein 695 （transgenic （Tg） 2576 mice）. Numerous reelin-positive neurons were positive for activated caspase 3 in Tg2576 mice, suggesting that Cajal-Retzius neuronal loss occurred via apoptosis in this Alzheimer＇s disease model. Compared with wild type, the number of Cajal-Retzius cells was significantly lower in Tg2576 mice. Western blot analysis confirmed that reelin levels were markedly lower in Tg2576 mice than in wild-type mice. The decline in Cajal-Retzius cells in Tg2576 mice was found to occur concomitantly with the onset of Alzheimer＇s disease amyloid pathology and related behavioral deficits. Overall, these data indicated that Cajal-Retzius cell loss occurred with the onset and development of Alzheimer＇s disease.     

7.0T nuclear magnetic resonance evaluation of the amyloid beta(1–40) animal model of Alzheimer's disease: comparison of cytology verification

3.0T magnetic resonance spectroscopic imaging is a commonly used method in the research of brain function in Alzheimer's disease.However,the role of 7.0T high-field magnetic resonance spectroscopic imaging in brain function of Alzheimer's disease remains unclear.In this study,7.0T magnetic resonance spectroscopy showed that in the hippocampus of Alzheimer's disease rats,the N-acetylaspartate wave crest was reduced,and the creatine and choline wave crest was elevated.This finding was further supported by hematoxylin-eosin staining,which showed a loss of hippocampal neurons and more glial cells.Moreover,electron microscopy showed neuronal shrinkage and mitochondrial rupture,and scanning electron microscopy revealed small size hippocampal synaptic vesicles,incomplete synaptic structure,and reduced number.Overall,the results revealed that 7.0T high-field nuclear magnetic resonance spectroscopy detected the lesions and functional changes in hippocampal neurons of Alzheimer's disease rats in vivo,allowing the possibility for assessing the success rate and grading of the amyloid beta(1–40) animal model of Alzheimer's disease.     

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

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

Beta 2-adrenergic receptor activation enhances neurogenesis in Alzheimer’s disease mice

Impaired hippocampal neurogenesis is one of the early pathological features of Alzheimer's disease. Enhancing adult hippocampal neurogenesis has been pursued as a potential therapeutic strategy for Alzheimer's disease. Recent studies have demonstrated that environmental novelty activates β2-adrenergic signaling and prevents the memory impairment induced by amyloid-β oligomers. Here, we hypothesized that β2-adrenoceptor activation would enhance neurogenesis and ameliorate memory deficits in Alzheimer's disease. To test this hypothesis, we investigated the effects and mechanisms of action of β2-adrenoceptor activation on neurogenesis and memory in amyloid precursor protein/presenilin 1(APP/PS1) mice using the agonist clenbuterol(intraperitoneal injection, 2 mg/kg). We found that β2-adrenoceptor activation enhanced hippocampal neurogenesis, ameliorated memory deficits, and increased dendritic branching and the density of dendritic spines. These effects were associated with the upregulation of postsynaptic density 95, synapsin 1 and synaptophysin in APP/PS1 mice. Furthermore, β2-adrenoceptor activation decreased cerebral amyloid plaques by decreasing APP phosphorylation at Thr668. These findings suggest that β2-adrenoceptor activation enhances neurogenesis and ameliorates memory deficits in APP/PS1 mice.     

Neurogenesis within the adult hippocampus under physiological conditions and in depression

Adult neurogenesis can only be observed in some specific brain regions. One of these areas is the dentate gyrus of the hippocampal formation. The progenitor cells located in the subgranular layer of the dentate gyrus proliferate, differentiate, and give rise to young neurons that can become integrated into existing neuronal circuits. Under physiological conditions, hippocampal neurogenesis is linked to hippocampal-dependent learning, whereas deficits in adult hippocampal neurogenesis have been shown to correlate with disturbances in spatial learning and memory. This review summarizes the phenomenon of adult hippocampal neurogenesis and the use of suitable markers for the investigation of adult hippocampal neurogenesis. In addition, we focused on the disturbances in neurogenesis that can be seen in depression. Interestingly, several antidepressants have been found to be capable of increasing the rate of hippocampal neurogenesis. Based on that, it can be speculated that factors, which directly or indirectly increase the rate of hippocampal neurogenesis, may be helpful in the treatment of depression.     

Adipose-derived mesenchymal stem cell transplantation promotes adult neurogenesis in the brains of Alzheimer’s disease mice

In the present study,we transplanted adipose-derived mesenchymal stem cells into the hippocampi of APP/PS1 transgenic Alzheimer’s disease model mice.Immunofluorescence staining revealed that the number of newly generated(BrdU+)cells in the subgranular zone of the dentate gyrus in the hippocampus was significantly higher in Alzheimer’s disease mice after adipose-derived mesenchymal stem cell transplantation,and there was also a significant increase in the number of BrdU+/DCX+neuroblasts in these animals.Adipose-derived mesenchymal stem cell transplantation enhanced neurogenic activity in the subventricular zone as well.Furthermore,adipose-derived mesenchymal stem cell transplantation reduced oxidative stress and alleviated cognitive impairment in the mice.Based on these findings,we propose that adipose-derived mesenchymal stem cell transplantation enhances endogenous neurogenesis in both the subgranular and subventricular zones in APP/PS1 transgenic Alzheimer’s disease mice,thereby facilitating functional recovery.     

Degenerative alterations in noradrenergic neurons of the locus coeruleus in Alzheimer’s disease

Mice carrying mutant amyloid-β precursor protein and presenilin-1 genes (APP/PS1 double transgenic mice) have frequently been used in studies of Alzheimer’s disease; however, such studies have focused mainly on hippocampal and cortical changes. The severity of Alzheimer’s disease is known to correlate with the amount of amyloid-β protein deposition and the number of dead neurons in the locus coeruleus. In the present study, we assigned APP/PS1 double transgenic mice to two groups according to age: young mice (5-6 months old) and aged mice (16-17 months old). Age-matched wild-type mice were used as controls. Immunohistochemistry for tyrosine hydroxylase (a marker of catecholaminergic neurons in the locus coeruleus) revealed that APP/PS1 mice had 23% fewer cells in the locus coeruleus compared with aged wild-type mice. APP/PS1 mice also had increased numbers of cell bodies of neurons positive for tyrosine hydroxylase, but fewer tyrosine hydroxylase-positive fibers, which were also short, thick and broken. Quantitative analysis using unbiased stereology showed a significant age-related increase in the mean volume of tyrosine hydroxylase-positive neurons in aged APP/PS1 mice compared with young APP/PS1 mice. Moreover, the mean volume of tyrosine hydroxylase-positive neurons was positively correlated with the total volume of the locus coeruleus. These findings indicate that noradrenergic neurons and fibers in the locus coeruleus are predisposed to degenerative alterations in APP/PS1 double transgenic mice.     

Shifting equilibriums in Alzheimer's disease: the complex roles of microglia in neuroinflammation,neuronal survival and neurogenesis

Alzheimer's disease is the leading cause of dementia.Its increased prevalence in developed countries,due to the sharp rise in ageing populations,presents one of the costliest challenges to modern medicine.In order to find disease-modifying therapies to confront this challenge,a more complete understanding of the pathogenesis of Alzheimer's disease is necessary.Recent studies have revealed increasing evidence for the roles played by microglia,the resident innate immune system cells of the brain.Reflecting the well-established roles of microglia in reacting to pathogens and inflammatory stimuli,there is now a growing literature describing both protective and detrimental effects for individual cytokines and chemokines produced by microglia in Alzheimer's disease.A smaller but increasing number of studies have also addressed the divergent roles played by microglial neurotrophic and neurogenic factors,and how their perturbation may play a key role in the pathogenesis of Alzheimer's disease.Here we review recent findings on the roles played by microglia in neuroinflammation,neuronal survival and neurogenesis in Alzheimer's disease.In each case,landmark studies have provided evidence for the divergent ways in which microglia can either promote neuronal function and survival,or perturb neuronal function,leading to cell death.In many cases,the secreted molecules of microglia can lead to divergent effects depending on the magnitude and context of microglial activation.This suggests that microglial functions must be maintained in a fine equilibrium,in order to support healthy neuronal function,and that the cellular microenvironment in the Alzheimer's disease brain disrupts this fine balance,leading to neurodegeneration.Thus,an understanding of microglial homeostasis,both in health and across the trajectory of the disease state,will improve our understanding of the pathogenic mechanisms underlying Alzheimer's disease,and will hopefully lead to the development of microglial-based therapeutic strategies to restore equilibrium in the Alzheimer's disease brain.     

Absence of ephrin-A2/A3 increases retinal regenerative potential for Müller cells in Rhodopsin knockout mice

Müller cells(MC) are considered dormant retinal progenitor cells in mammals.Previous studies demonstrated ephrin-As act as negative regulators of neural progenitor cells in the retina and brain.It remains unclear whether the lack of ephrin-A2/A3 is sufficient to promote the neurogenic potential of MC.Here we investigated whether the MC is the primary retinal cell type expressing ephrin-A2/A3 and their role on the neurogenic potential of Müller cells.In this study, we showed that ephrin-A2/A3 and their receptor EphA4 were expressed in retina and especially enriched in MC.The level of ephrin As/EphA4 expression increased as the retina matured that is correlated with the reduced proliferative and progenitor cell potential of MC.Next, we investigated the proliferation in primary MC cultures isolated from wild-type and A2~(–/–) A3~(–/–) mice by 5-ethynyl-2′-deoxyuridine(EdU) incorporation.We detected a significant increase of EdU~+ cells in MC derived from A2~(–/–) A3~(–/–) mice.Next, we investigated the role of ephrin-A2/A3 in mice undergoing photoreceptor degeneration such as Rhodopsin knockout(Rho~(–/–)) mice.To further evaluate the role of ephrin-A2/A3 in MC proliferation in vivo, EdU was injected intraperitoneally to adult wild-type, A2~(–/–) A3~(–/–), Rho~(–/–) and Rho~(–/–) A2~(–/–) A3~(–/–) mice and the numbers of EdU~+ cells distributed among different layers of the retina.Ephrin As/EphA4 expression was upregulated in the retina of Rho~(–/–) mice compared to the wild-type mice.In addition, cultured MC derived from ephrin-A2~(–/–) A3~(–/–) mice also expressed higher levels of progenitor cell markers and exhibited higher proliferation potential than those from wild-type mice.Interestingly, we detected a significant increase of EdU~+ cells in the retinas of adult ephrin-A2~(–/–) A3~(–/–) mice mainly in the inner nuclear layer; and these EdU~+ cells were co-localized with MC marker, cellular retinaldehyde-binding protein, suggesting some proliferating cells are from MC.In Rhodopsin knockout mice(Rho~(–/–) A2~(–/–) A3~(–/–) mice), a significantly greater amount of EdU~+ cells were located in the ciliary body, retina and RPE than that of Rho~(–/–) mice.Comparing between 6 and 12 weeks old Rho~(–/–) A2~(–/–) A3~(–/–) mice, we recorded more EdU~+ cells in the outer nuclear layer in the 12-week-old mice undergoing severe retinal degeneration.Taken together, Ephrin-A2/A3 are negative regulators of the proliferative and neurogenic potentials of MC.Absence of ephrin-A2/A3 promotes the migration of proliferating cells into the outer nuclear layer and may lead to retinal cell regeneration.All experimental procedures were approved by the Animal Care and Use Committee at Schepens Eye Research Institute, USA(approval No.S-353-0715) on October 24, 2012.     

Korean red ginseng promotes hippocampal neurogenesis in mice

Neurogenesis in the adult hippocampus plays a major role in cognitive ability of animals including learning and memory.Korean red ginseng (KRG) has long been known as a medicinal herb with the potential to improve learning and memory;however,the mechanisms are still elusive.Therefore,we evaluated whether KRG can promote cognitive function and enhance neurogenesis in the hippocampus.Eight-week-old male C57BL/6 mice received 50 mg/kg of 5-bromo-2′-deoxyuridine (BrdU) intraperitoneally and 100 mg/kg of KRG or vehicle orally once a day for 14 days.Pole,Rotarod and Morris water maze tests were performed and the brains were collected after the last behavioral test.Changes in the numbers of BrdU- and BrdU/ doublecortin (DCX;a marker for neuronal precursor cells and immature neurons)-positive cells in the dentate gyrus and the gene expression of proliferating cell nuclear antigen (a marker for cell differentiation),cerebral dopamine neurotrophic factor and ciliary neurotrophic factor in the hippocampus were then investigated.KRG-treated mice came down the pole significantly faster and stood on the rotarod longer than vehicle-treated mice.The Morris water maze test showed that KRG administration enhanced the learning and memory abilities significantly.KRG also significantly increased BrdU- and BrdU/DCX-positive cells in the dentate gyrus as well as the proliferating cell nuclear antigen,cerebral dopamine neurotrophic factor and ciliary neurotrophic factor mRNA expression levels in the hippocampus compared to vehicle.Administration of KRG promotes learning and memory abilities,possibly by enhancing hippocampal neurogenesis.This study was approved by the Pusan National University Institutional Animal Care and Use Committee (approval No.PNU-2016-1071) on January 19,2016.     

Retinal regeneration requires dynamic Notch signaling

Retinal damage in the adult zebrafish induces Müller glia reprogramming to produce neuronal progenitor cells that proliferate and differentiate into retinal neurons.Notch signaling,which is a fundamental mechanism known to drive cell-cell communication,is required to maintain Müller glia in a quiescent state in the undamaged retina,and repression of Notch signaling is necessary for Müller glia to reenter the cell cycle.The dynamic regulation of Notch signaling following retinal damage also directs proliferation and neurogenesis of the Müller glia-derived progenitor cells in a robust regeneration response.In contrast,mammalian Müller glia respond to retinal damage by entering a prolonged gliotic state that leads to additional neuronal death and permanent vision loss.Understanding the dynamic regulation of Notch signaling in the zebrafish retina may aid efforts to stimulate Müller glia reprogramming for regeneration of the diseased human retina.Recent findings identified DeltaB and Notch3 as the ligand-receptor pair that serves as the principal regulators of zebrafish Müller glia quiescence.In addition,multi-omics datasets and functional studies indicate that additional Notch receptors,ligands,and target genes regulate cell proliferation and neurogenesis during the regeneration time course.Still,our understanding of Notch signaling during retinal regeneration is limited.To fully appreciate the complex regulation of Notch signaling that is required for successful retinal regeneration,investigation of additional aspects of the pathway,such as post-translational modification of the receptors,ligand endocytosis,and interactions with other fundamental pathways is needed.Here we review various modes of Notch signaling regulation in the context of the vertebrate retina to put recent research in perspective and to identify open areas of inquiry.     

Differentiating between Alzheimer's disease,amnestic mild cognitive impairment,and normal aging via diffusion kurtosis imaging

Diffusion kurtosis imaging can be used to assess pathophysiological changes in tissue structure and to diagnose central nervous system diseases. However, its sensitivity in assessing hippocampal differences between patients with Alzheimer's disease and those with amnestic mild cognitive impairment has not been characterized. Here, we examined 20 individuals with Alzheimer's disease(11 men and 9 women, mean73.2 ± 4.49 years), 20 with amnestic mild cognitive impairment(10 men and 10 women, mean 71.55 ± 4.77 years), and 20 normal controls(11 men and 9 women, mean 70.45 ± 5.04 years). We conducted diffusion kurtosis imaging, using a 3.0 T magnetic resonance scanner,to compare hippocampal differences among the three groups. The results demonstrated that the right hippocampal volume and bilateral mean kurtosis were remarkably smaller in individuals with Alzheimer's disease compared with those with amnestic mild cognitive impairment and normal controls. Further, the mean kurtosis was lower in the amnestic mild cognitive impairment group compared with the normal control group. The mean diffusion in the left hippocampus was lower in the Alzheimer's disease group than in the amnestic mild cognitive impairment and normal control groups, while the mean diffusion in the right hippocampus was lower in the Alzheimer's disease group than in the normal control group. Fractional anisotropy was similar among the three groups. These results verify that bilateral mean kurtosis and mean diffusion are sensitive to the diagnosis of Alzheimer's disease and amnestic mild cognitive impairment. This study was approved by the Ethics Review Board of Affiliated Sixth People's Hospital of Shanghai Jiao Tong University, China on May 4, 2010(approval No. 2010(C)-6).     

Acupuncture and moxibustion reduces neuronal edema in Alzheimer’s disease rats

To examine the possible correlation of aberrant Wnt signaling and pathological changes in Alzheimer's disease, we established a rat model of Alzheimer's disease and measured axin and β-catenin expression in the hippocampus. Rats were pretreated with moxibustion or electroacu-puncture, or both, at Baihui(GV20) and Shenshu(BL23). Axin expression was lower, β-catenin expression was greater, and neuronal cytoplasmic edema was visibly prevented in the rats that had received the pretreatments. Our results suggest that the mechanism underlying the neuro-protective effect of acupuncture and moxibustion in Alzheimer's disease is associated with axin and β-catenin expression in the Wnt signal transduction pathway.     

Tooth loss inhibits neurogenesis in the dentate gyrus of adult mice

Tooth loss has been shown to affect learning and memory in mice and increases the risk of Alz- heimer＇s disease. The dentate gyrus is strongly associated with cognitive function. This study hypothesized that tooth loss affects neurons in the dentate gyrus. Adult male mice were randomly assigned to either the tooth loss group or normal control group. In the tooth loss group, the left maxillary and mandibular molars were extracted. Normal control mice did not receive any intervention. Immunofluorescence staining revealed that the density and absorbance of double- cortinand neuronal nuclear antigen-positive cells were lower in the tooth loss group than in the normal control group. These data suggest that tooth loss may inhibit neurogenesis in the dentate gyrus of adult mice.     

Neural stem cell transplantation alleviates functional cognitive deficits in a mouse model of tauopathy

The mechanisms of the transplantation of neural stem cells(NSCs)in the treatment of Alzheimer’s disease remain poorly understood.In this study,NSCs were transplanted into the hippocampal CA1 region of the rTg(tau P301L)4510 mouse model,a tauopathy model that is thought to reflect the tau pathology associated with Alzheimer’s disease.The results revealed that NSC transplantation reduced the abnormal aggregation of tau,resulting in significant improvements in the short-term memory of the tauopathy model mice.Compared with wild-type and phosphate-buffered saline(PBS)-treated mice,mice that received NSC transplantations were characterized by changes in the expression of multiple proteins in brain tissue,particularly those related to the regulation of tau aggregation or misfolding.Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analysis and Gene Ontology(GO)function analysis revealed that these proteins were primarily enriched in pathways associated with long-term potentiation,neurogenesis,and other neurobiological processes.Changes in the expression levels of key proteins were verified by western blot assays.These data provided clues to improve the understanding of the functional capacity associated with NSC transplantation in Alzheimer’s disease treatment.This study was approved by the Beijing Animal Ethics Association and Ethics Committee of Beijing Institute of Technology(approval No.SYXK-BIT-school of life science-2017-M03)in 2017.     

Dab2 attenuates brain injury in APP/PS1 mice via targeting transforming growth factor-beta/SMAD signaling简

Transforming growth factor-beta(TGF-β)type II receptor(TβRII)levels are extremely low in the brain tissue of patients with Alzheimer’s disease.This receptor inhibits TGF-β1/SMAD signaling and thereby aggravates amyolid-beta deposition and neuronal injury.Dab2,a specific adapter protein,protects TβRII from degradation and ensures the effective conduction of TGF-β1/SMAD signaling.In this study,we used an adenoviral vector to overexpress the Dab2 gene in the mouse hippocampus and investigated the regulatory effect of Dab2 protein on TGF-β1/SMAD signaling in a mouse model of Alzheimer’s disease,and the potential neuroprotective effect.The results showed that the TβRII level was lower in APP/PS1 mouse hippocampus than in normal mouse hippocampus.After Dab2 expression,hippocampal TβRII and p-SMAD2/3 levels were significantly increased,while amyloid-beta deposition,microglia activation,tumor necrosis factor-βand interleulin-6 levels and neuronal loss were significantly attenuated in APP/PS1 mouse brain tissue.These results suggest that Dab2 can exhibit neuroprotective effects in Alzheimer’s disease by regulating TGF-β1/SMAD signaling.     

Optogenetics-induced activation of glutamate receptors improves memory function in mice with Alzheimer's disease

Optogenetics is a combination of optics and genetics technology that can be used to activate or inhibit specific cells in tissues. It has been used to treat Parkinson's disease, epilepsy and neurological diseases, but rarely Alzheimer's disease. Adeno-associated virus carrying the CaMK promoter driving the optogenetic channelrhodopsin-2(CHR2) gene(or without the CHR2 gene, as control) was injected into the bilateral dentate gyri, followed by repeated intrahippocampal injections of soluble low-molecular-weight amyloid-β1–42 peptide(Aβ1–42).Subsequently, the region was stimulated with a 473 nm laser(1–3 ms, 10 Hz, 5 minutes). The novel object recognition test was conducted to test memory function in mice. Immunohistochemical staining was performed to analyze the numbers of NeuN and synapsin Ia/b-positive cells in the hippocampus. Western blot assay was carried out to analyze the expression levels of glial fibrillary acidic protein, NeuN,synapsin Ia/b, metabotropic glutamate receptor-1 a(mGluR-1 a), mGluR-5, N-methyl-D-aspartate receptor subunit NR1, glutamate receptor 2, interleukin-1β, interleukin-6 and interleukin-10. Optogenetic stimulation improved working and short-term memory in mice with Alzheimer's disease. This neuroprotective effect was associated with increased expression of NR1, glutamate receptor 2 and mGluR-5 in the hippocampus, and decreased expression of glial fibrillary acidic protein and interleukin-6. Our results show that optogenetics can be used to regulate the neuronal-glial network to ameliorate memory functions in mice with Alzheimer's disease. The study was approved by the Animal Resources Committee of Jinan University, China(approval No. LL-KT-2011134) on February 28, 2011.