Icariin ameliorates memory deficits through regulating brain insulin signaling and glucose transporters in 3×Tg-AD mice.
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ABSTRACT:
SUBMITTER: Yan F
PROVIDER: S-EPMC9241391 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Early diagnosis of Alzheimer's disease (AD) supposedly increases the effectiveness of therapeutic interventions. However, presently available diagnostic procedures are either invasive or require complex and expensive technologies, which cannot be applied at a larger scale to screen populations at risk of AD. We were looking for a biomarker allowing to unveil a dysfunction of molecular mechanisms, which underly synaptic plasticity and memory, before the AD phenotype is manifested and investigated the effects of transcranial direct current stimulation (tDCS) in 3×Tg-AD mice, an experimental model of AD which does not exhibit any long-term potentiation (LTP) and memory deficits at the age of 3 months (3×Tg-AD-3M). Our results demonstrated that tDCS differentially affected 3×Tg-AD-3M and age-matched wild-type (WT) mice. While tDCS increased LTP at CA3-CA1 synapses and memory in WT mice, it failed to elicit these effects in 3×Tg-AD-3M mice. Remarkably, 3×Tg-AD-3M mice did not show the tDCS-dependent increases in pCREB Ser133 and pCaMKII Thr286 , which were found in WT mice. Of relevance, tDCS induced a significant increase of plasma BDNF levels in WT mice, which was not found in 3×Tg-AD-3M mice. Collectively, our results showed that plasticity mechanisms are resistant to tDCS effects in the pre-AD stage. In particular, the lack of BDNF responsiveness to tDCS in 3×Tg-AD-3M mice suggests that combining tDCS with dosages of plasma BDNF levels may provide an easy-to-detect and low-cost biomarker of covert impairment of synaptic plasticity mechanisms underlying memory, which could be clinically applicable. Testing proposed here might be useful to identify AD in its preclinical stage, allowing timely and, hopefully, more effective disease-modifying interventions.
| S-EPMC7349675 | biostudies-literature
Project description:Icariin, a pharmacologically active component isolated from the Chinese herb Epimedium, has been shown to improve spatial learning and memory abilities in Alzheimer's disease (AD) rats through inhibition of Aβ production and tau protein hyperphosphorylation. However, the potential mechanism of icariin-induced protective effects against mitochondrial dysfunctions in AD still remains unclear. In the present study, we investigated the effect of icariin on the modulation of mitochondrial transport and distribution in primary hippocampal cultures from triple-transgenic (3× Tg) AD mice. The results showed that icariin enhanced mitochondrial motility and increased mitochondrial index and mitochondrial length and size in the diseased neurons. Additionally, the expression of the key mitochondrial enzyme, pyruvate dehydrogenase-E1α (PDHE1α), and the post synaptic density protein 95 (PSD95), was preserved in AD neurons after icariin treatment, accompanied by a downregulation of Aβ and phosphorylated tau expression in the corresponding areas. Further study showed that icariin treatment resulted in a decrease in mitochondrial fission protein dynamin-related protein 1 (Drp1) and an increase in fusion protein Mitofusin 2 (Mfn2). These data indicate that icariin can promote mitochondrial transport, protect mitochondria against fragmentation and preserve the expression of mitochondrial and synaptic functional proteins in AD neurons. Thus, icariin may be a potential therapeutic complement for AD and other mitochondrial malfunction-related neuronal degenerative diseases.
| S-EPMC4783897 | biostudies-literature
Project description:Clinical and epidemiological evidence suggests that lifestyle factors, including nutrition, may influence the chances of developing of Alzheimer's disease (AD), and also likely affect the aging process. Whereas it is clear that high-fat diets are increasing both body weight and the risk of developing Alzheimer's disease, to date, there have been very few studies comparing diets high with different sources of calories (i.e., high fat versus high protein versus high carbohydrates) to determine whether dietary composition has importance beyond the known effect of high caloric intake to increase body weight, AD pathology and cognitive deficits. In the current study we examined the effects that different diets high in carbohydrate, protein or fat content, but similar in caloric value, have on the development of cognitive impairment and brain pathology in wild-type and Tg AD model mice. The results demonstrate that long term feeding with balanced diets similar in caloric content but with significant changes in the source of calories, all negatively influence cognition compared to the control diet, and that this effect is more pronounced in Tg animals with AD pathology.
| S-EPMC5099116 | biostudies-literature
Project description:BackgroundRecent studies indicated that circulatory factors in blood plasma from young animals can reactivate neurogenesis, restore synaptic plasticity, and improve cognitive function in aged animals. Here, we investigated if young plasma could have a possible therapeutic effect for treatment of Alzheimer's disease (AD)-like pathologies and cognitive impairment in triple-transgenic AD (3×Tg-AD) mice.MethodsWe intravenously injected plasma from 2- to 3-month-old C57BL/6 J wild-type mice into 16-17-month-old 3×Tg-AD mice twice a week for 8 weeks. The behavioral tests including open field, novel object recognition, Morris water maze, and reversal Morris water maze were conducted after 4-week plasma injections. The effect of young plasma on tau and Aβ pathologies and on the levels of synaptic proteins and neuroinflammation were assessed by Western blots and immunohistochemical staining.ResultsYoung plasma treatment improved short-term memory in the novel object recognition test and enhanced the spatial learning and memory in Morris water maze test and reversal Morris water maze test. Biochemical studies revealed that young plasma treatment reduced both tau and Aβ pathologies, as well as neuroinflammation in the mouse brain. However, we did not detect any significant changes in levels of synaptic proteins or the dentate gyrus neurogenesis in the mouse brain after the treatment with young plasma.ConclusionsThese data indicate that young blood plasma not only ameliorates tau and Aβ pathologies but also enhances the cognitive function in 3×Tg-AD mice. These findings suggest that transfusion with young blood plasma could be a potentially effective treatment for AD.
| S-EPMC7278124 | biostudies-literature
Project description:Alzheimer's disease (AD) is one of the most common progressive neurodegenerative disorders that cause deterioration of cognitive functions. Recent studies suggested that the accumulation of inflammatory molecules and impaired protein degradation mechanisms might both play a critical role in the progression of AD. Autophagy is a major protein degradation pathway that can be controlled by several HECT-E3 ligases, which then regulates the expression of inflammatory molecules. E3 ubiquitin ligases are known to be upregulated in several neurodegenerative diseases. Here, we studied the expressional change of HECT-E3 ligase using M01 on autophagy and inflammasome pathways in the context of AD pathogenesis. Our results demonstrated that the M01 treatment reversed the working memory deficits in 3xTg-AD mice when examined with the T-maze and reversal learning with the Morris water maze. Additionally, the electrophysiology recordings indicated that M01 treatment enhanced the long-term potentiation in the hippocampus of 3xTg-AD mice. Together with the improved memory performance, the expression levels of the NLRP3 inflammasome protein were decreased. On the other hand, autophagy-related molecules were increased in the hippocampus of 3xTg-AD mice. Furthermore, the protein docking analysis indicated that the binding affinity of M01 to the WWP1 and NEDD4 E3 ligases was the highest among the HECT family members. The western blot analysis also confirmed the decreased expression level of NEDD4 protein in the M01-treated 3xTg-AD mice. Overall, our results demonstrate that the modulation of HECT-E3 ligase expression level can be used as a strategy to treat early memory deficits in AD by decreasing NLRP3 inflammasome molecules and increasing the autophagy pathway.
| S-EPMC9372289 | biostudies-literature
Project description:The reduction of the cerebral glucose metabolism is closely related to the activation of the NOD-like receptor protein 3 (NLRP3) inflammasome in Alzheimer's disease (AD); however, its underlying mechanism remains unclear. In this paper, 18F-flurodeoxyglucose positron emission tomography was used to trace cerebral glucose metabolism in vivo, along with Western blotting and immunofluorescence assays to examine the expression and distribution of associated proteins. Glucose and insulin tolerance tests were carried out to detect insulin resistance, and the Morris water maze was used to test the spatial learning and memory ability of the mice. The results show increased NLRP3 inflammasome activation, elevated insulin resistance, and decreased glucose metabolism in 3×Tg-AD mice. Inhibiting NLRP3 inflammasome activation using CY-09, a specific inhibitor for NLRP3, may restore cerebral glucose metabolism by increasing the expression and distribution of glucose transporters and enzymes and attenuating insulin resistance in AD mice. Moreover, CY-09 helps to improve AD pathology and relieve cognitive impairment in these mice. Although CY-09 has no significant effect on ferroptosis, it can effectively reduce fatty acid synthesis and lipid peroxidation. These findings provide new evidence for NLRP3 inflammasome as a therapeutic target for AD, suggesting that CY-09 may be a potential drug for the treatment of this disease.
| S-EPMC10045645 | biostudies-literature
Project description:BackgroundShen-Zhi-Ling oral liquid (SZL) is an herbal formula known for its efficacy of nourishing "heart and spleen", and is used for the treatment and prevention of middle- and early-stage dementia. This study investigated the effects of SZL on amelioration of AD, and examined whether the underlying mechanisms from the perspective of neuroprotection are related to brain glucose metabolism.MethodsFirstly, LC-MS/MS was used to analysis the SZL mainly enters the blood component. Then, the effects of SZL on cognitive and behavioral ability of APP/PS1 double transgenic mice and amyloid protein characteristic pathological changes were investigated by behavioral study and morphological observation. The effects of SZL on the ultrastructure of mitochondria, astrocytes, and micrangium related to cerebral glucose metabolism were observed using transmission electron microscopy. Then, micro-PET was also used to observe the effects of SZL on glucose uptake. Furthermore, the effects of SZL on insulin signaling pathway InR/PI3K/Akt and glucose transporters (GLUT1 and GLUT3) were observed by immunohistochemistry, Western-blot and RT-qPCR. Finally, the effects of SZL on brain glucose metabolism and key enzyme were observed. In vitro, the use of PI3K and/or GSK3β inhibitor to observe the effects of SZL drug-containing serum on GLUT1 and GLUT3.ResultsIn vivo, SZL could significantly ameliorate cognitive deficits, retarded the pathological damage, including neuronal degeneration, Aβ peptide aggregation, and ultrastructural damage of hippocampal neurons, improve the glucose uptake, transporters and glucolysis. Beyond that, SZL regulates the insulin signal transduction pathway the insulin signal transduction pathway InR/PI3K/Akt. Furthermore, 15% SZL drug-containing serum increased Aβ42-induced insulin signal transduction-pathway related indicators and GLUT1 and GLUT3 expression in SH-SY5Y cells. The improvement of GLUT1 and GLUT3 in the downstream PI3K/Akt/GSK3β signaling pathway was reversed by the use of PI3K and/or GSK3β inhibitor.ConclusionsIn summary, our results demonstrated that improving glucose uptake, transport, and glycolysis in the brain may underlie the neuroprotective effects of SZL, and its potential molecular mechanism may be related to regulate the insulin signal transduction pathway.
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Project description:Alzheimer's disease (AD), a common form of dementia, is caused in part by the aggregation and accumulation in the brain of amyloid β (Aβ), a product of the proteolytic cleavage of amyloid precursor protein (APP) in endosomes. Trafficking of APP, such as surface-intracellular recycling, is an early critical step required for Aβ generation. Less is known, however, about the molecular mechanism regulating APP trafficking. This study investigated the mechanism by which SPIN90, along with Rab11, modulates APP trafficking, Aβ motility and accumulation, and synaptic functionality. Brain Aβ deposition was lower in the progeny of 5xFAD-SPIN90KO mice than in 5xFAD-SPIN90WT mice. Analysis of APP distribution and trafficking showed that the surface fraction of APP was locally distinct in axons and dendrites, with these distributions differing significantly in 5xFAD-SPIN90WT and 5xFAD-SPIN90KO mice, and that neural activity-driven APP trafficking to the surface and intracellular recycling were more actively mobilized in 5xFAD-SPIN90KO neurons. In addition, SPIN90 was found to be cotrafficked with APP via axons, with ablation of SPIN90 reducing the intracellular accumulation of APP in axons. Finally, synaptic transmission was restored over time in 5xFAD-SPIN90KO but not in 5xFAD-SPIN90WT neurons, suggesting SPIN90 is implicated in Aβ production through the regulation of APP trafficking.
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Project description:BackgroundThis study sought to explore the mechanism underlying the therapeutic effects of electroacupuncture (EA) on spatial memory deficits caused by surgery.MethodsHepatic apex resection was performed under propofol-based total intravenous anesthesia. Male Sprague-Dawley rats were subjected to EA treatment or EA + mitochondrial division inhibitor-1 (mdivi-1) treatment once a day for three consecutive days after surgery. The Morris water maze test was used to evaluate the spatial memory of the rats after surgery. Tissue from the hippocampus of each rat was frozen and used for transcriptomic and proteomic analyses to identify potential targets for EA treatment. Western blotting was used to confirm the protein expression levels. The levels of reactive oxygen species (ROS) and adenosine triphosphate (ATP) were detected using commercial kits. The rat mitochondria were then isolated, and the activity of mitochondrial complex V was assessed.ResultsEA attenuated surgery-induced spatial memory deficits on postoperative day 3, while these effects were reversed by treatment with the mdivi-1 (P<0.05). Ribonucleic acid (RNA)-sequencing revealed that EA upregulated multiple metabolic pathways and the phosphatidylinositol 3‑kinas/protein kinase B signaling pathway. The proteomic and western blotting results suggested that the EA treatment substantially downregulated coiled-coil-helix-coiled-coil-helix domain containing 3 (ChChd3) expression in the hippocampus. The EA treatment significantly increased the autophagy-related protein levels, including phosphatase and tensin homolog-induced kinase 1, Parkin, MAP1LC3 (LC3), and Beclin1, and inhibited the production of ROS and inflammatory cytokine interleukin-1β in the hippocampus (P<0.05).ConclusionsThese results suggest that EA ameliorates postoperative spatial memory deficits and protects hippocampus from oxidative stress and inflammation through enhanced autophagy in an animal model of perioperative neurocognitive disorders (PNDs).
| S-EPMC9929787 | biostudies-literature
Project description:AimStreptozotocin (STZ) is widely used to induce oxidative damage and to impair glucose metabolism, apoptosis, and tau/A? pathology, eventually leading to cognitive deficits in both in vitro and in vivo models of Alzheimer's disease (AD). In this study, we constructed a cell-based platform using STZ to induce stress conditions mimicking the complicated pathologies of AD in vitro, and evaluated the anti-amyloid effects of a small molecule, N-(1,3-benzodioxol-5-yl)-2-[5-chloro-2-methoxy(phenylsulfonyl)anilino]acetamide (LX2343) in the amelioration of cognitive deficits in AD model mice.MethodsCell-based assays for screening anti-amyloid compounds were established by assessing A? accumulation in HEK293-APPsw and CHO-APP cells, and A? clearance in primary astrocytes and SH-SY5Y cells after the cells were treated with STZ in the presence of the test compounds. Autophagic flux was observed using confocal laser scanning microscopy. APP/PS1 transgenic mice were administered LX2343 (10 mg·kg-1·d-1, ip) for 100 d. After LX2343 administration, cognitive ability of the mice was evaluated using Morris water maze test, and senile plaques in the brains were detected using Thioflavine S staining. ELISA assay was used to evaluate A? and sAPP? levels, while Western blot analysis was used to measure the signaling proteins in both cell and animal brains.ResultsLX2343 (5-20 ?mol/L) dose-dependently decreased A? accumulation in HEK293-APPsw and CHO-APP cells, and promoted A? clearance in SH-SY5Y cells and primary astrocytes. The anti-amyloid effects of LX2343 were attributed to suppressing JNK-mediated APPThr668 phosphorylation, thus inhibiting APP cleavage on one hand, and inhibiting BACE1 enzymatic activity with an IC50 value of 11.43±0.36 ?mol/L, on the other hand. Furthermore, LX2343 acted as a non-ATP competitive PI3K inhibitor to negatively regulate AKT/mTOR signaling, thus promoting autophagy, and increasing A? clearance. Administration of LX2343 in APP/PS1 transgenic mice significantly ameliorated cognitive deficits and markedly ameliorated the A? pathology in their brains.ConclusionLX2343 ameliorates cognitive dysfunction in APP/PS1 transgenic mice via both A? production inhibition and clearance promotion, which highlights the potential of LX2343 in the treatment of AD.
| S-EPMC5057240 | biostudies-literature