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Potassium 2-(1-hydroxypentyl)-benzoate promotes long-term potentiation in Aβ1-42-injected rats and APP/PS1 transgenic mice.

ABSTRACT: Potassium 2-(1-hydroxypentyl)-benzoate (dl-PHPB) is a new drug candidate for ischemic stroke. The aim of this study was to investigate the effects of dl-PHPB on memory deficits and long-term potentiation (LTP) impairment in animal models of Alzheimer's disease.The expression of NMDA receptor subunits GluN1 and GluN2B in the hippocampus and cortex of APP/PS1 transgenic mice were detected using Western blot analysis. Memory deficits of the mice were evaluated with the passive avoidance test. LTP impairment was studied in the dentate region of Aβ1-42-injected rats and APP/PS1 transgenic mice.APP/PS1 transgenic mice showed significantly lower levels of GluN1 and p-GluN2B in hippocampus, and chronic administration of dl-PHPB (100 mg · kg(-1) · d(-1), po) reversed the downregulation of p-GluN2B, but did not change GluN1 level in the hippocampus. Furthermore, chronic administration of dl-PHPB reversed the memory deficits in APP/PS1 transgenic mice. In the dentate region of normal rats, injection of dl-PHPB (100 μmol/L, icv) did not change the basal synaptic transmission, but significantly enhanced the high-frequency stimulation (HFS)-induced LTP, which was completely prevented by pre-injection of APV (150 μmol/L, icv). Chronic administration of dl-PHPB (100 mg · kg(-1) · d(-1), po) reversed LTP impairment in Aβ1-42-injected normal rats and APP/PS1 transgenic mice.Chronic administration of dl-PHPB improves learning and memory and promotes LTP in the animal models of Alzheimer's disease, possibly via increasing p-GluN2B expression in the hippocampus.

SUBMITTER: Li PP

PROVIDER: S-EPMC4088280 | biostudies-other | 2014 Jul

REPOSITORIES: biostudies-other

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Nrf2 Ablation Promotes Alzheimer's Disease-Like Pathology in APP/PS1 Transgenic Mice: The Role of Neuroinflammation and Oxidative Stress.

Project description:IntroductionAlzheimer's disease (AD), the most common neurodegenerative disorder, is characterized by the accumulation of amyloid-? (A?) peptide and hyperphosphorylated tau protein. Accumulating evidence has revealed that the slow progressive deterioration of AD is associated with oxidative stress and chronic inflammation in the brain. Nuclear factor erythroid 2- (NF-E2-) related factor 2 (Nrf2), which acts through the Nrf2/ARE pathway, is a key regulator of the antioxidant and anti-inflammatory response. Although recent data show a link between Nrf2 and AD-related cognitive decline, the mechanism is still unknown. Thus, we explored how Nrf2 protects brain cells against the oxidative stress and inflammation of AD in a mouse model of AD (APP/PS1 transgenic (AT) mice) with genetic removal of Nrf2.MethodsThe spatial learning and memory abilities of 12-month-old transgenic mice were evaluated using a Morris water maze test. Hippocampal levels of Nrf2, A?, and p-tauS404 and of astrocytes and microglia were determined by immunostaining. Inflammatory cytokines were determined by ELISA and quantitative real-time polymerase chain reaction (qRT-PCR). Oxidative stress was measured by 8-hydroxydeoxyguanosine immunohistochemistry, and the antioxidant response was determined by qRT-PCR.ResultsThe spatial learning and memory abilities of AT mice were impaired after Nrf2 deletion. A? and p-tauS404 accumulation was increased in the hippocampus of AT/Nrf2-KO mice. Astroglial and microglial activation was exacerbated, followed by upregulation of the proinflammatory cytokines IL-1?, IL-6, and TNF-?.ConclusionOur present results show that Nrf2 deficiency aggravates AD-like pathology in AT mice. This phenotype was associated with increased levels of oxidative and proinflammatory markers, which suggests that the Nrf2 pathway may be a promising therapeutic target for AD.

| S-EPMC7238335 | biostudies-literature

Naringin Dihydrochalcone Ameliorates Cognitive Deficits and Neuropathology in APP/PS1 Transgenic Mice.

Project description:Alzheimer's disease (AD) is a multi-factorial neurodegenerative disorder with abnormal accumulation of amyloid-β (Aβ) plaques, neuroinflammation and impaired neurogenesis. Mounting evidences suggest that single-target drugs have limited effects on clinical treatment and alternative or multiple targets are required. In recent decades, natural compounds and their derivatives have gained increasing attention in AD drug discovery due to their inherently enormous chemical and structural diversity. In this study, we demonstrated that naringin dihydrochalcone (NDC), a widely used dietary sweetener with strong antioxidant activity, improved the cognitive function of transgenic AD mice. Pathologically, NDC attenuated Aβ deposition in AD mouse brain. Furthermore, NDC reduced periplaque activated microglia and astrocytes, indicating the inhibition of neuroinflammation. It also enhanced neurogenesis as investigated by BrdU/NeuN double labeling. Additionally, the inhibition of Aβ level and neuroinflammation by NDC treatment was also observed in an AD cell model or a microglia cell line. Taken together, our study indicated that NDC might be a potential therapeutic agent for the treatment of AD against multiple targets that include Aβ pathology, neuroinflammation and neurogenesis.

| S-EPMC5996202 | biostudies-literature

miRNA profile in the hippocampus of APP/PS1 transgenic mice

Project description:To explore the miRNAs associated with the memory deficits in Alzheimer's disease, we detected the miRNA profiles in the hippocampus of 6-month-old male APPswe/PS1dE9 (APP/PS1) mice and age-matched wild type C57BL/6 mice.

2019-10-04 | GSE138382 | GEO

Untargeted lipidomics reveals progression of early Alzheimer's disease in APP/PS1 transgenic mice.

Project description:Alzheimer's Disease (AD) is closely connected to aberrant lipid metabolism. However, how early AD-like pathology synchronously influences brain and plasma lipidome in AD mice remains unclear. The study of dynamic change of lipidome in early-stage AD mice could be of great interest for the discovery of lipid biomarkers for diagnosis and monitoring of early-stage AD. For the purpose, an untargeted lipidomic strategy was developed for the characterization of lipids (≤ 1,200 Da) perturbation occurring in plasma and brain in early-stage AD mice (2, 3 and 7 months) by ultra-high performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry. Significant changes were detected in the levels of several lipid species including lysophospholipids, phosphatidylcholines (PCs), phosphatidylethanolamines (PEs) and Ceramides (Cers), as well as other related lipid compounds such as fatty acids (FAs), diacylglycerols (DGs) and triacylglycerols (TGs) in AD mice. In this sense, disorders of lipid metabolism appear to involve in multiple factors including overactivation of phospholipases and diacylglycerol lipases, decreased anabolism of lysophospholipids in plasma and PEs in plasma and brain, and imbalances in the levels of PCs, FAs and glycerides at different ages. We revealed the changing panels of potential lipid biomarkers with the development of early AD. The study raises the possibility of developing lipid biomarkers for diagnosis of early-stage AD.

| S-EPMC7471266 | biostudies-literature

The effect of chronic inflammation on molecular pathways of long-term potentiation in an APP/PS1 mouse model of Alzheimer Disease

Project description:Alzheimer Disease (AD) is the most common cause of dementia and neuroinflammation, initiated by systemic bacterial infection, is believed to contribute significantly to its pathogenesis. Lipopolysaccharide (LPS) is an endotoxin, which stimulates inflammatory reactions by increasing the levels of pro-inflammatory cytokines through binding to Toll like receptor-4 (TLR-4) and CD14, in an NF-κΒ-dependent fashion. These receptors are expressed in the circumventricular organs, choroid plexus and leptomeninges as well as on microglia cells, thereby providing an entry for an innate immune reaction to spread through the cerebral tissue. Here, 9 months old APP695/PS1ΔE9 (APP/PS1) double transgenic mice and wild type littermates were treated with weekly intraperitoneal injections of LPS or PBS over 13 weeks to evaluate the effect of repeated infections on the innate immune response of the hippocampal proteome. The effect on the proteome was evaluated using a quantitative iTRAQ 8-plex proteomics approach, with 3D-LC-MS/MS to gain a deep coverage of the hippocampal proteome. Furthermore, the effect of long-term inflammation on amyloid beta (Aβ) protein level was evaluated using stereological plaque load estimation followed by investigation of protein levels of Aβ40 and Aβ42 by Mesoscale. An effect of infection on proteins involved in long-term potentiation was observed, including p-MAPK, p-CREB and phosphorylation motifs of PKA and 14-3-3. Furthermore the complement system, redox reactions and the activation of retinoid receptors were found significantly changed in APP/PS1 mice infected with LPS. This study provides new insight into the effect of bacterial infections in the development of AD.

2018-11-21 | PXD005785 | Pride

Abnormalities of plasma cytokines and spleen in senile APP/PS1/Tau transgenic mouse model.

Project description:The blood-based diagnosis has a potential to provide an alternative approach for easy diagnosis of Alzheimer's disease (AD) with less invasiveness and low-cost. However, present blood-based AD diagnosis mainly focuses on measuring the plasma A? level because no other biomarkers are found to possess evident transport mechanisms to pass the blood-brain barrier. In order to avoid diagnosing non-demented individuals with A? abnormality, finding additional biomarkers to supplement plasma A? is essential. In this study, we introduce potential neurodegenerative biomarkers for blood-based diagnosis. We observed severe splenomegaly and structural destruction in the spleen with significantly decreased B lymphocytes in senile APPswe, PS1M146V and TauP301L transgenic mice. We also found that inflammatory cytokines associated with splenic dysfunction were altered in the plasma of these mice. These findings suggest potential involvement of the splenic dysfunction in AD and the importance of biomarker level alterations in the plasma as putative diagnostic targets for AD.

| S-EPMC4621607 | biostudies-literature

Anodal Transcranial Direct Current Stimulation Can Improve Spatial Learning and Memory and Attenuate A?42 Burden at the Early Stage of Alzheimer's Disease in APP/PS1 Transgenic Mice.

Project description:Alzheimer's disease (AD) is an irreversible progressive neurodegenerative disease. Intervention in the early stage of AD is a new path for AD treatment that is being explored. The behavioral and pathological effects of anodal transcranial direct current stimulation (AtDCS) at the early stage of AD in the mouse model, amyloid precursor protein (APP)/presenilin-1 (PS1) transgenic mice, were investigated based on our previous studies. Thirty-three 6-month-old male APP/PS1 mice were randomly divided into the model group (AD group), model + sham stimulation group (ADST group) and stimulation group (ADT group). Eleven 6-month-old male C57 wild-type mice were randomly selected as a control group (CTL group). The ADT group received 10 AtDCS sessions. The Morris water maze (MWM) task and novel object recognition (NOR) task were used to test mouse memory. Nissl staining, Western blot (WB), immunohistochemistry and immunofluorescence staining of ?-amyloid (A?42), glial fibrillary acidic protein (GFAP) and NF200 were conducted for pathological analysis. The ADT group and the CTL group had a shorter escape latency and more platform-region crossings than the AD group and ADST group in the MWM. There was no significant difference in the discrimination index among the groups in the NOR task. Pathological analysis showed visible differences between the AD group and ADT group. This study revealed that early-stage APP/PS1 transgenic mice did not show recognition memory impairment. AtDCS effectively improved spatial learning and memory in the early-stage APP/PS1 transgenic mouse model of AD, alleviating A? burden and having a protective effect on neurons. AtDCS could improve AD-related symptoms by activating many glial cells to promote the degradation and clearance of A? or directly affecting production and degradation of A? to reduce glial activation. AtDCS is an effective means of early intervention in the early stage of AD.

| S-EPMC7239315 | biostudies-literature

Synaptic changes in the dentate gyrus of APP/PS1 transgenic mice revealed by electron microscopy.

Project description:Numerous studies have reported widespread synaptic dysfunction or loss in early stages of both Alzheimer disease (AD) patients and animal models; it is widely accepted that synapse loss is the major structural correlate of cognitive dysfunction. Elucidation of the changes that may affect synapses is crucial for understanding the pathogenic mechanisms underlying AD, but ultrastructural preservation of human postmortem brain tissue is often poor, and classical methods for quantification of synapses have significant technical limitations. We previously observed changes in dendritic spines in plaque-free regions of the neuropil of the dentate gyrus of double-transgenic APP/PS1 (amyloid precursor protein/presenilin 1) model mice by light microscopy. Here, we used electron microscopy to examine possible synaptic alterations in this region. We used standard stereologic techniques to determine numbers of synapses per volume. We were able to reconstruct and analyze thousands of synapses and their 3-dimensional characteristics using a focused ion beam/scanning electron microscope and 3-dimensional reconstruction software (EspINA), which performs semiautomated segmentation of synapses. Our results show that both numbers of synapses per volume and synaptic morphology are affected in plaque-free regions of APP/PS1 mice. Therefore, changes in the number and morphology of synapses seem to be widespread alterations in this animal model.

| S-EPMC3678882 | biostudies-other

Contribution of genetic and dietary insulin resistance to Alzheimer phenotype in APP/PS1 transgenic mice.

Project description:According to epidemiological studies, type-2 diabetes increases the risk of Alzheimer's disease. Here, we induced hyperglycaemia in mice overexpressing mutant amyloid precursor protein and presenilin-1 (APdE9) either by cross-breeding them with pancreatic insulin-like growth factor 2 (IGF-2) overexpressing mice or by feeding them with high-fat diet. Glucose and insulin tolerance tests revealed significant hyperglycaemia in mice overexpressing IGF-2, which was exacerbated by high-fat diet. However, sustained hyperinsulinaemia and insulin resistance were observed only in mice co-expressing IGF-2 and APdE9 without correlation to insulin levels in brain. In behavioural tests in aged mice, APdE9 was associated with poor spatial learning and the combination of IGF-2 and high-fat diet further impaired learning. Neither high-fat diet nor IGF-2 increased ?-amyloid burden in the brain. In male mice, IGF-2 increased ?-amyloid 42/40 ratio, which correlated with poor spatial learning. In contrast, inhibitory phosphorylation of glycogen synthase kinase 3?, which correlated with good spatial learning, was increased in APdE9 and IGF-2 female mice on standard diet, but not on high-fat diet. Interestingly, high-fat diet altered ? isoform expression and increased phosphorylation of ? at Ser202 site in female mice regardless of genotype. These findings provide evidence for new regulatory mechanisms that link type-2 diabetes and Alzheimer pathology.

| S-EPMC3823075 | biostudies-literature

Neuropathological and behavioral features of an APP/PS1/MAPT (6xTg) transgenic model of Alzheimer's disease.

Project description:Alzheimer's disease is associated with various brain dysfunctions, including memory impairment, neuronal loss, astrocyte activation, amyloid-β plaques, and neurofibrillary tangles. Transgenic animal models of Alzheimer's disease have proven to be invaluable for the basic research of Alzheimer's disease. However, Alzheimer's disease mouse models developed so far do not fully recapitulate the pathological and behavioral features reminiscent of Alzheimer's disease in humans. Here, we investigated the neurobehavioral sequelae in the novel 6xTg mouse model of Alzheimer's disease, which was developed by incorporating human tau containing P301L mutation in the widely used 5xFAD mouse model of Alzheimer's disease. At 11-months-old, 6xTg mice displayed the core pathological processes found in Alzheimer's disease, including accumulation of amyloid-β plaque, extensive neuronal loss, elevated level of astrocyte activation, and abnormal tau phosphorylation in the brain. At 9 to 11-months-old, 6xTg mice exhibited both cognitive and non-cognitive behavioral impairments relevant to Alzheimer's disease, including memory loss, hyperlocomotion, anxiety-like behavior, depression-like behavior, and reduced sensorimotor gating. Our data suggest that the aged 6xTg mouse model of Alzheimer's disease presents pathological and cognitive-behavioral features reminiscent of Alzheimer's disease in humans. Thus, the 6xTg mouse model of Alzheimer's disease may be a valuable model for studying Alzheimer's disease-relevant non-cognitive behaviors.

| S-EPMC9175339 | biostudies-literature

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