Function Of Alzheimer's Disease Mice Research Articles

The bexarotene derivative OAB-14 ameliorates cognitive decline in APP/PS1 transgenic mice by suppressing microglia-mediated neuroinflammation through the PPAR-γ pathway

Neuroinflammation is believed to be a critical process involved in the pathophysiology of Alzheimer's disease (AD). In this study, we investigated the pharmacological ability of OAB-14, a small molecule compound derived from bexarotene, to reduce neuroinflammation and improve cognitive decline in an AD mouse model (in vivo) and its ability to regulate signaling pathways implicated in neuroinflammation in vitro. It was found that OAB-14 significantly improved the cognitive function of 11-month-old AD mice (APP/PS1 transgenic mice) in a dose-dependent manner. Simultaneously, OAB-14 dramatically inhibited the activation of microglia in the cerebral cortex and hippocampus of AD mice and dose-dependently downregulated the expression of nuclear factor kappa B (NF-κB) and NOD-like receptor protein 3 (NLRP3) in the cerebral cortex. At the cellular level, OAB-14 reversed the downregulation of M2 phenotypic markers, including mannose receptor C-type 1 (MRC1) and arginase 1 (ARG1), in lipopolysaccharide (LPS)- or amyloid-β protein oligomer (oAβ1-42)-activated BV2 microglial cells and partially restored their ability to clear Aβ. However, these effects were suppressed when peroxisome proliferator-activated receptor-γ (PPAR-γ) was specifically inhibited by GW9662, a selective PPAR-γ antagonist. These results suggested that OAB-14 could regulate microglial polarization by regulating PPAR-γ signaling, thereby mitigating neuroinflammation and improving cognitive function in AD mice.

Improving Blood Monocyte Energy Metabolism Enhances Its Ability to Phagocytose Amyloid-β and Prevents Alzheimer's Disease-Type Pathology and Cognitive Deficits.

Deficiencies in the clearance of peripheral amyloid β (Aβ) play a crucial role in the progression of Alzheimer's disease (AD). Previous studies have shown that the ability of blood monocytes to phagocytose Aβ is decreased in AD. However, the exact mechanism of Aβ clearance dysfunction in AD monocytes remains unclear. In the present study, we found that blood monocytes in AD mice exhibited decreases in energy metabolism, which was accompanied by cellular senescence, a senescence-associated secretory phenotype, and dysfunctional phagocytosis of Aβ. Improving energy metabolism rejuvenated monocytes and enhanced their ability to phagocytose Aβ in vivo and in vitro. Moreover, enhancing blood monocyte Aβ phagocytosis by improving energy metabolism alleviated brain Aβ deposition and neuroinflammation and eventually improved cognitive function in AD mice. This study reveals a new mechanism of impaired Aβ phagocytosis in monocytes and provides evidence that restoring their energy metabolism may be a novel therapeutic strategy for AD.

The effect of gastric bypass surgery on cognitive function of Alzheimer's disease and the role of GLP1-SGLT1 pathway

ObjectiveGastric bypass surgery has been shown to improve metabolic profiles via GLP1, which may also have cognitive benefits for Alzheimer's disease (AD) patients. However, the exact mechanism requires further investigation. MethodsRoux-en-Y gastric bypass or sham surgery was performed on APP/PS1/Tau triple transgenic mice (an AD mice model) or wild type C57BL/6 mice. Morris Water Maze (MWM) test was used to evaluate the cognitive function of mice and animal tissue samples were obtained for measurements two months after the surgery. Additionally, STC-1 intestine cells were treated with siTAS1R2 and siSGLT1, and HT22 nerve cells were treated with Aβ, siGLP1R, GLP1 and siSGLT1 in vitro to explore the role of GLP1-SGLT1 related signaling pathway in cognitive function. ResultsThe MWM test showed that bypass surgery significantly improved cognitive function in AD mice as measured by navigation and spatial probe tests. Moreover, bypass surgery reversed neurodegeneration, down-regulated hyperphosphorylation of Tau protein and Aβ deposition, improved glucose metabolism, and up-regulated the expression of GLP1, SGLT1, and TAS1R2/3 in the hippocampus. Furthermore, GLP1R silencing down-regulated SGLT1 expression, whereas SGLT1 silencing increased Tau protein deposition and exacerbated dysregulated of glucose metabolism in HT22 cells. However, RYGB did not alter the level of GLP1 secretion in the brainstem (where central GLP1 is mainly produced). Additionally, GLP1 expression was upregulated by RYGB via TAS1R2/3-SGLT1 activation sequentially in the small intestine. ConclusionRYGB surgery could improve cognition function in AD mice through facilitating glucose metabolism and reducing Tau phosphorylation and Aβ deposition in the hippocampus, mediated by peripheral serum GLP1 activation of SGLT1 in the brain. Furthermore, RYGB increased GLP1 expression through sequential activation of TAS1R2/TAS1R3 and SGLT1 in the small intestine.

Effects of Broussonetia papyrifera (L.) L'Hér. ex Vent. fruits water extract on hippocampal neurogenesis in the treatment of APP/PS1 transgenic mice.

Background: Adult neurogenesis plays an important role in repairing damaged neurons and improving cognitive impairment in Alzheimer's disease (AD). B. Papyrifera (L.) L'Hér. ex Vent. fruits (BL), a traditional Chinese medicine for tonifying the kidney, has been reported to improve cognitive function in AD mice, but the underlying mechanisms have not been clearly illuminated. This study aimed to provide an overview of the differential compounds in the brain of APP/PS1 mice after BL water extract (BLWE) treatment through metabolomics technology and to elucidate whether the therapeutic effect and mechanism are through the enhancement of neurogenesis. Methods: APP/PS1 transgenic mice were treated with different doses of BLWE. After 6weeks of intragastric injection, the therapeutic effects of BLWE on APP/PS1 transgenic mice were determined by the Morris water maze test, immunohistochemistry, hematoxylin & eosin and Nissl staining, enzyme-linked immunosorbent assay and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. Subsequently, metabolomics technology was used to analyze the regulatory effect of BLWE on differential compounds in the brain of APP/PS1 mice, and on this basis, its molecular mechanism of BLWE was screened. Finally, the protein expression of the Wnt/β-catenin signaling pathway was detected by Western blotting. Results: After BLWE treatment, the learning and memory function of APP/PS1 mice were significantly improved, which was related to the increase in the number of Nestin+/BrdU+ and NeuN+/BrdU+ cells, and the decrease in the number of apoptotic cells in the hippocampus. BLWE treatment could also up-regulate the expression of synapse-associated proteins. Moreover, BLWE could modulate endogenous metabolic compounds in the brains of AD mice, including N-acetyl-aspartate, glutamine, etc. Furthermore, BLWE inhibited the phosphorylation of Tyr216-GSK-3β and β-catenin protein while increased CyclinD1 protein expression. Conclusion: We demonstrated that BLWE can enhance neural stem cells proliferation and improve neurogenesis, thereby efficiently repairing damaged neurons in the hippocampus and ameliorating cognitive impairment in APP/PS1 transgenic mice. The mechanism is at least partly through activating the Wnt/β-catenin signaling pathway.

LncRNA MIR600HG Knockdown Alleviates Cognitive Impairment in Alzheimer's Disease Through NEDD4L Mediated PINK1 Degradation.

Growing evidence has demonstrated that long non-coding RNAs (lncRNAs) play a critical role in Alzheimer's disease (AD), which is characterized by sustained mitochondrial dysfunction, inevitable memory loss, and cognitive decline. However, the potential function of lncRNAs MIR600 Host Gene (MIR600HG) in AD remains unanswered. Our study aimed to investigate the role of MIR600HG and its related molecular mechanism in AD. The expression of MIR600HG was examined by qRT-PCR. The MIR600HG interacting proteins were identified by RNA pull-down assay and mass spectrometry and verified by RNA immunoprecipitation. Immunofluorescence staining was applied to examine the colocalization of PINK1 and NEDD4L. The PINK1 level and the activation of autophagy were detected by immunoblotting. Morris water maze test was performed to evaluate cognitive decline in AD mice model. MIR600HG expression was elevated during aging in two different types of AD transgenic mouse models. Next, we found that increased MIR600HG directly interact with NEDD4L, which promoted PINK1 ubiquitination and degradation, and as well as autophagy activation. Additionally, MIR600HG promoted Aβ production and suppressed Cytochrome C Oxidase activity. Administration of AAV-shMIR600HG restored the Cytochrome C Oxidase activity and inhibited Aβ production. Furthermore, PINK1 overexpression or MIR600HG knockdown significantly ameliorated the cognitive impairment in APP/PS1 mice. PINK1 depletion recovered the spatial memory defect in the AAV-shMIR600HG injected APP/PS1 mice. MIR600HG was increased in AD and promoted AD pathogenesis. Targeting MIR600HG significantly improved cognitive function in AD mice, which could pave the way for exciting new avenues in AD therapeutic strategy research.

DJ-1 affects oxidative stress and pyroptosis in hippocampal neurons of Alzheimer's disease mouse model by regulating the Nrf2 pathway.

Studies have confirmed that DJ-1 is associated with diseases associated with the nervous system, including Alzheimer's disease (AD). However, the role of DJ-1 in the pathogenesis of AD has not been clarified. To investigate the effect of DJ-1 on brain tissue damage and cognitive function in AD mice and its possible mechanism, 5XFAD transgenic mice were used as AD model mice and DJ-1 in the brain was overexpressed by transfection of a lentiviral containing a specific targeting DJ-1 gene into the bilateral hippocampus of mice. Following lentivirus infection, the Morris water maze test was performed to assess the cognitive function of the mice. When the behavioral evaluation was completed, the brain tissue of the mouse was examined. Pathological changes were observed by hematoxylin-eosin staining. The levels of relevant indicators were analyzed by reverse transcription-quantitative PCR, ELISA and western blotting. Bilateral hippocampal injection of a lentivirus containing DJ-1 significantly increased the expression of DJ-1 in the hippocampus of 5XFAD transgenic mice. Overexpression of DJ-1 in the brain could ameliorate brain tissue damage, β-amyloid protein (Aβ) deposition and cognitive function in 5XFAD mice. Compared with the sham group, the reactive oxygen species activity and malondialdehyde content in the brain tissue of DJ-1 overexpressing 5XFAD mice were significantly decreased, while the superoxide dismutase activity was significantly increased (P<0.05). In addition, DJ-1 overexpression decreased the expression of caspase-1 and the levels of interleukin (IL) 1β and IL-18 in the hippocampus while ameliorating the death of hippocampal neurons in 5XFAD mice and without affecting the expression of caspase-3. Overexpression of DJ-1 resulted in a significant decrease in nuclear factor erythroid 2-related factor 2 (Nrf2) protein expression in the cytoplasmic while significantly increasing the expression of Nrf2 in the nucleus. Simultaneously, DJ-1 overexpression in the brain inhibited the activation of nanoparticles activate the NLR pyrin domain containing 3 inflammatory bodies in brain tissue. Overexpression of DJ-1 in the brain could repair brain tissue damage, Aβ deposition and cognitive function in 5XFAD mice, and its mechanism may be associated with an inhibition of oxidative stress and neuronal pyroptosis by regulating the Nrf2 signaling pathway.

Silencing of aquaporin1 activates the Wnt signaling pathway to improve cognitive function in a mouse model of Alzheimer's disease.

Aquaporins (AQPs) are water channel proteins robustly presenting in the central nervous system (CNS). Increasing evidence suggests the crucial role of AQP1 in the pathogenesis of CNS injury but scarce data are provided for the potential role of AQP1 in Alzheimer's disease (AD). Thus, the present study aimed to investigate the effects of AQP1 on cognitive function in a mouse model of AD. A mouse model of AD was established by using the β-amyloid isoform Aβ1-42, and then assessed by the step-through test and water maze experiment. The expression of AQP1 was quantified in the AD model. The effects of AQP1 on the cognitive function of AD mice and the Wnt signaling pathway were elucidated using gain- and loss-of-function approaches. Furthermore, hippocampal neurons were isolated and treated with Aβ1-42 for in vitro experiments and the effects of the Wnt signaling pathway on hippocampal neuron apoptosis were analyzed with the use of inhibitor or activator of this pathway. AQP1 was highly-expressed in the AD mouse model while AQP1 silencing improved cognitive function in AD mice. Besides, silencing of AQP1 exhibited protective effects on hippocampal neurons in AD mice. Furthermore, AQP1 inhibited the Wnt signaling pathway while AQP1 promoted neuronal apoptosis by inhibiting the Wnt signaling pathway, thereby damaging the cognitive function. AQP1 silencing attenuates the cognitive impairment in AD through activation of the Wnt signaling pathway, highlighting a novel therapeutic target against AD.

Protective effect of paeoniflorin on inflammation and apoptosis in the cerebral cortex of a transgenic mouse model of Alzheimer's disease.

Paeoniflorin, the main active component of the peony plant, exerts various pharmacological effects. Recently, research on the effect of paeoniflorin on the nervous system has gained more attention. The aim of the present study was to determine whether paeoniflorin exerts a protective effect that improves Alzheimer's disease (AD) via inflammation and apoptosis in the cerebral cortex of a transgenic mouse model of AD. Transgenic mice were used to construct the model of AD and were treated with paeoniflorin. The Morris water maze test was used to analyze cognitive function in AD mice. The protein expression levels of nuclear factor‑κB, tumor necrosis factor‑α, interleukin (IL)‑1β, IL‑6 and caspase‑3 were examined with commercial kits. Expression levels of B‑cell lymphoma 2 (Bcl‑2), Bcl‑2‑associated X protein (Bax), phosphorylated (p)‑Akt and p‑p38 mitogen‑activated protein kinase (p‑p38 MAPK) in AD were evaluated by western blotting. The neuroprotective effects of paeoniflorin significantly improved cognitive function and ameliorated patterns of escape distance and escape latency in AD mice. Furthermore, the effects of paeoniflorin decreased inflammation and caspase‑3 activity, and inhibited cell death via increasing the Bcl‑2/Bax ratio and p‑Akt expression levels, and downregulating p‑p38 MAPK expression in AD mice.

Effective DNA epitope chimeric vaccines for Alzheimer's disease using a toxin-derived carrier protein as a molecular adjuvant

Active amyloid-beta (Aβ) immunotherapy is under investigation to prevent or treat Alzheimer disease (AD). We describe here the immunological characterization and protective effect of DNA epitope chimeric vaccines using 6 copies of Aβ1-15 fused with PADRE or toxin-derived carriers. These naked 6Aβ15-T-Hc chimeric DNA vaccines were demonstrated to induce robust anti-Aβ antibodies that could recognize Aβ oligomers and inhibit Aβ oligomer-mediated neurotoxicity, result in the reduction of cerebral Aβ load and Aβ oligomers, and improve cognitive function in AD mice, but did not stimulate Aβ-specific T cell responses. Notably, toxin-derived carriers as molecular adjuvants were able to substantially promote immune responses, overcome Aβ-associated hypo-responsiveness, and elicit long-term Aβ-specific antibody response in 6Aβ15-T-Hc-immunized AD mice. These findings suggest that our 6Aβ15-T-Hc DNA chimeric vaccines can be used as a safe and effective strategy for AD immunotherapy, and toxin-derived carrier proteins are effective molecular adjuvants of DNA epitope vaccines for Alzheimer's disease.

Hypoxia Increases Aβ-Induced Tau Phosphorylation by Calpain and Promotes Behavioral Consequences in AD Transgenic Mice

Chronic hypoxia has been reported to contribute to the development of Alzheimer's disease (AD). However, the mechanism of hypoxia in the pathogenesis of AD remains unclear. The purpose of this study was to investigate the effects of chronic hypoxia treatment on β-amyloid, tau pathologies, and the behavioral consequences in the double transgenic (APP/PS1) mice. Double transgenic mice (APP/PS1 mice) were treated with hypoxia, and spatial learning and memory abilities of mice were assessed in the Morris water maze. β-amyloid level and plaque level in APP/PS1 double transgenic mice were detected by immunohistochemistry. Protein tau, p35/p25, cyclin-dependent kinase 5 (CDK5), and calpain were detected by western blotting analysis. Chronic hypoxia treatment decreased memory and cognitive function in AD mice. In addition, chronic hypoxia treatment resulted in increased senile plaques, accompanying with increased tau phosphorylation. The hypoxia-induced increase in the tau phosphorylation was associated with a significant increase in the production of p35 and p25 and upregulation of calpain, suggesting that hypoxia induced aberrant CDK5/p25 activation via upregulation of calpain. Our results showed that chronic hypoxia exposure accelerates not only amyloid pathology but also tau pathology via calpain-mediated tau hyperphosphorylation in an AD mouse model. These pathological changes possibly contribute to the hypoxia-induced behavioral change in AD mice.

MiR‐206 regulates brain‐derived neurotrophic factor in Alzheimer disease model

Alzheimer disease (AD) brains are deficient in brain-derived neurotrophic factor (BDNF), which regulates synaptic plasticity and memory. MicroRNAs (miRNAs) are ∼22-nucleotide small noncoding RNAs that control a variety of physiological and disease processes. Here, we show that miR-206 regulates BDNF and memory function in AD mice. Expression of miRNAs was analyzed in Tg2576 AD transgenic mice and human AD brain samples. Regulation of BDNF by a selected miRNA was validated by in silico prediction, target gene luciferase assay, and dendritic spine responses in neurons. AM206, a neutralizing inhibitor of miR-206 (antagomir), was injected into the third ventricle of Tg2576 mice, after which memory function, synaptogenesis, neurogenesis, and target gene expression were assessed. For noninvasive delivery, antagomirs were administered intranasally. The brains of Tg2576 mice and the temporal cortex of human AD brains had increased levels of miR-206. This miRNA targeted BDNF transcripts, and AM206 prevented the detrimental effects of amyloid-β42 on BDNF and dendritic spine degeneration in Tg2576 neurons. Injection of AM206 into the cerebral ventricles of AD mice increased the brain levels of BDNF and improved their memory function. In parallel, AM206 enhanced the hippocampal synaptic density and neurogenesis. Furthermore, intranasally administered AM206 also reached the brain and increased BDNF levels and memory function in AD mice. Our findings demonstrate a novel miRNA-dependent regulation of BDNF in AD and suggest possible therapeutic approaches, such as noninvasive intranasal delivery of AM206.