AD-like Changes Research Articles

Emerging signs of Alzheimer-like tau hyperphosphorylation and neuroinflammation in the brain post recovery from COVID-19.

Coronavirus disease 2019 (COVID-19) has been suggested to increase the risk of memory decline and Alzheimer's disease (AD), the main cause of dementia in the elderly. However, direct evidence about whether COVID-19 induces AD-like neuropathological changes in the brain, especially post recovery from acute infection, is still lacking. Here, using postmortem human brain samples, we found abnormal accumulation of hyperphosphorylated tau protein in the hippocampus and medial entorhinal cortex within 4-13 months post clinically recovery from acute COVID-19, together with prolonged activation of glia cells and increases in inflammatory factors, even though no SARS-COV-2 invasion was detected in these regions. By contrast, COVID-19 did not change beta-amyloid deposition and hippocampal neuron number, and had limited effects on AD-related pathological phenotypes in olfactory circuits including olfactory bulb, anterior olfactory nucleus, olfactory tubercle, piriform cortex and lateral entorhinal cortex. These results provide neuropathological evidences linking COVID-19 with prognostic increase of risk for AD.

Central Nervous System Disorders of Marine Mammals: Models for Human Disease?

This article deals with Central Nervous System (CNS) disorders of marine mammals as putative neuropathology and neuropathogenesis models for their human and, to some extent, their animal "counterparts" in a dual "One Health" and "Translational Medicine" perspective. Within this challenging context, special emphasis is placed upon Alzheimer's disease (AD), provided that AD-like pathological changes have been reported in the brain tissue of stranded cetacean specimens belonging to different Odontocete species. Further examples of potential comparative pathology interest are represented by viral infections and, in particular, by "Subacute Sclerosing Panencephalitis" (SSPE), a rare neurologic sequela in patients infected with Measles virus (MeV). Indeed, Cetacean morbillivirus (CeMV)-infected striped dolphins (Stenella coeruleoalba) may also develop a "brain-only" form of CeMV infection, sharing neuropathological similarities with SSPE. Within this framework, the global threat of the A(H5N1) avian influenza virus is another major concern issue, with a severe meningoencephalitis occurring in affected pinnipeds and cetaceans, similarly to what is seen in human beings. Finally, the role of Brucella ceti-infected, neurobrucellosis-affected cetaceans as putative neuropathology and neuropathogenesis models for their human disease counterparts is also analyzed and discussed. Notwithstanding the above, much more work is needed before drawing the conclusion marine mammal CNS disorders mirror their human "analogues".

Folic acid and S-adenosylmethionine reverse Homocysteine-induced Alzheimer’s disease-like pathological changes in rat hippocampus by modulating PS1 and PP2A methylation levels

BackgroundAbnormally elevated homocysteine (Hcy) is recognized as a biomarker and risk factor for Alzheimer’s disease (AD). However, the underlying mechanisms by which Hcy affects AD are still unclear. ObjectivesThis study aimed to elucidate the effects and mechanisms by which Hcy affects AD-like pathological changes in the hippocampus through in vivo and in vitro experiments, and to investigate whether folic acid (FA) and S-adenosylmethionine (SAM) supplementation could improve neurodegenerative injuries. MethodsIn vitro experiments hippocampal neurons of rat were treated with Hcy, FA or SAM for 24 h; while the hyperhomocysteinemia (HHcy) in Wistar rats was established by intraperitoneal injection of Hcy, and FA was added to feed. The expression of β-amyloid (Aβ), phosphorylated tau protein, presenilin 1 (PS1) at the protein level and the activity of protein phosphatase 2A (PP2A) were detected, the immunopositive cells for Aβ and phosphorylated tau protein in the rat hippocampus were also evaluated by immunohistochemical staining. ResultsFA and SAM significantly repressed Hcy-induced AD-like pathological changes in the hippocampus, including the increased tau protein phosphorylation at Ser214, Ser396 and the expression of Aβ42. In addition, Hcy-induced PS1 expression increased at the protein level and PP2A activity decreased, while FA and SAM were able to retard that. ConclusionsThe increase in PS1 expression and decrease in PP2A activity may be the mechanisms underlying the Hcy-induced AD-like pathology. FA and SAM significantly repressed the Hcy-induced neurodegenerative injury by modulating PS1 and PP2A methylation levels.

Canine Cognitive Dysfunction Is Associated with Alzheimer’s Disease-Related Changes in the Brain Transcriptome and RNA Changes in Plasma Extracellular Vesicles

Chronic, age-related diseases, such as Alzheimer’s disease (AD), can be diffcult to study longitudinally because humans have long lifespans and are highly heterogeneous. Recently, companion dogs have emerged as a promising model of AD because dogs: a) have a shorter lifespan than humans; b) are heterogeneous like humans; c) exposed to diverse human environments; and d) naturally develop canine cognitive dysfunction (CCD), similar to AD. However, the transcriptomic similarities between AD and CCD have not been evaluated, and emerging mechanisms of AD have not been explored in dogs. One such mechanism involves extracellular vesicles (EVs), ~100nm lipid bilayer particles that can package neurodegeneration-relevant cargo (e.g., RNAs, cytokines), export it to other cells, and contribute to aging/AD-relevant processes like inflammation. To better understand CCD and determine if EVs may play a role in it, we generated total transcriptome (RNA-seq) on cortex tissue and EVs isolated from plasma of young, old, and CCD dogs, and we evaluated cytokine expression in corresponding plasma samples via ELISAs. In the animals we studied, we observed functional differences between old healthy and CCD animals, reflected by Canine Dementia Scale scores (CADES; 6 and 57, respectively). In our RNA-seq analyses, we found marked age- and CCD-related transcriptome differences in the cortex (328 and 2673 differentially expressed genes, respectively), which mostly reflected changes in immune activation and neuronal health (similar to what has been observed in AD). Moreover, when we overlapped transcriptome data on the cortex and plasma EVs, we found a significant overlap in genes that were either up- or down-regulated in both samples (344 and 515, respectively). The processes related to these genes reflected changes in regulation of immune responses, as well as synaptic signaling. We also found evidence of CCL5 (RANTES, increased in AD) RNA in plasma EVs only in CCD samples, which corresponded with increased CCL5 expression in the brains of the same animals, although no differences were observed in plasma concentrations. While preliminary in nature, these results suggest that CCD is associated with AD-like transcriptomic changes in the brain, and with AD-relevant changes in EV cargo. Future studies are needed to determine the functional relevance of these data, but our results suggest the possibility of finding specific EV/RNA markers that could predict disease severity in CCD, and perhaps eventually in AD. NIA R01AG078859; CSU Catalyst for Innovative Partnership Award. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

High salt diet exacerbates cognitive deficits and neurovascular abnormalities in APP/PS1 mice and induces AD-like changes in wild-type mice

High salt diet (HSD) is a risk factor of hypertension and cardiovascular disease. Although clinical data do not clearly indicate the relationship between HSD and the prevalence of Alzheimer's disease (AD), animal experiments have shown that HSD can cause hyperphosphorylation of tau protein and cognition impairment. However, whether HSD can accelerate the progression of AD by damaging the function of neurovascular unit (NVU) in the brain is unclear. Here, we fed APP/PS1 mice (an AD model) or wild-type mice with HSD and found that the chronic HSD feeding increased the activity of enzymes related to tau phosphorylation, which led to tau hyperphosphorylation in the brain. HSD also aggravated the deposition of Aβ42 in hippocampus and cortex in the APP/PS1 mice but not in the wild-type mice. Simultaneously, HSD caused the microglia proliferation, low expression of Aqp-4, and high expression of CD31 in the wild-type mice, which were accompanied with the loss of pericytes (PCs) and increase in blood brain barrier (BBB) permeability. As a result, wild-type mice fed with HSD performed poorly in Morris Water Maze and object recognition test. In the APP/PS1 mice, HSD feeding for 8 months worsen the cognition and accompanied the loss of PCs, the activation of glia, the increase in BBB permeability, and the acceleration of calcification in the brain. Our data suggested that HSD feeding induced the AD-like pathology in wild-type mice and aggravated the development of AD-like pathology in APP/PS1 mice, which implicated the tau hyperphosphorylation and NVU dysfunction.

Chronic noise exposure induces Alzheimer's disease-like neuropathology and cognitive impairment via ferroptosis in rat hippocampus.

Chronic noise exposure poses a remarkable public health concern, drawing attention to its impacts on the brain. Ferroptosis is involved in several brain-related diseases. However, the role of ferroptosis in the effects of chronic noise on the brain remains elusive. This study aimed to investigate the effects of chronic noise exposure on the brain and elucidate the underlying mechanisms. A chronic noise-induced cognitive impairment model in rats was constructed and validated. The pathological state and ferroptosis level of the rat hippocampus were determined using Western blotting and immunohistochemistry. Bioinformatics was employed to investigate the interrelationship between chronic noise exposure and genes. Genetic relationships were analyzed using Mendelian randomization (MR) analysis. Cytoscape was employed for the prediction of upstream molecular and drug targets. In vivo experiments revealed that chronic noise exposure could induce Alzheimer's disease (AD)-like neuropathological changes in rat hippocampus and cognitive impairment. Moreover, protein markers indicative of ferroptosis and levels of lipid peroxidation were quantified to elucidate underlying mechanisms. Thereafter, oxidative stress- and ferroptosis-related differentially expressed genes (DEGs) underwent functional enrichment and PPI network analyses. Additionally, 8 genes with diagnostic significance were identified. In MR analysis, retinoic acid receptor responder 2 (Rarres2) gene exhibited a negative genetic relationship with AD. Chronic noise exposure could induce AD-like neuropathological changes and cognitive impairment via ferroptosis. The results of MR analysis indicated that Rarres2 gene may act as a protective factor in AD. This gene may be upstream of ferroptosis and serve as a target for the prevention and treatment of chronic noise-induced cognitive impairment.

Blockade of HMGB1 Reduces Inflammation and Pruritus in Atopic Dermatitis by Inhibiting Skin Fibroblasts Activation

Introduction: Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by relapsed eczema and serious pruritus. High-mobility group box 1 protein (HMGB1) is a nuclear-binding protein and serves as an alarmin to promote inflammatory responses. Methods: In this study, we established an AD mouse model by topical use of MC903 on ears and then used a specific HMGB1-binding peptide cIY8 and a HMGB1 inhibitor of glycyrrhizin to investigate HMGB1 on fibroblast activation in the pathogenesis of AD-like symptoms. Results: Topical use of cIY8 and oral use of glycyrrhizin significantly improved the MC903-induced AD-like symptoms and pathological changes of the ears and scratching behavior in an AD mouse model; cIY8 treatment inhibited the higher mRNAs of IL-1α, IL-4, IL-5, IL-13, and IL-31 in the ears. In human fibroblasts, HMGB1 caused nuclear translocation of NF-kB, and the nuclear translocation could be inhibited by pre-treatment of HMGB1 with cIY8, suggesting that NF-κB signaling pathway participates in the HMGB1-induced inflammation of AD in fibroblasts and that cIY8 effectively impedes the function of HMGB1. Glycyrrhizin inhibited the Ca2+ signaling induced by ionomycin in mouse primary fibroblasts. The fibroblast-related proteins of α-SMA, Hsp47, and vimentin and the pruritus-related proteins of IL-33 and periostin were increased in the ears of the AD mouse model, the ratio of EdU incorporation became higher in mouse fibroblasts treated with MC903, and the higher proliferation and inflammatory responses of the fibroblasts could be reversed by glycyrrhizin treatment. Conclusions: Fibroblast activation by HMGB1 is one of the critical processes in the development of inflammation and pruritus in the AD mouse model. The specific HMGB1-binding peptide cIY8 and the HMGB1 inhibitor glycyrrhizin inactivate skin fibroblasts to alleviate the inflammation and pruritus in the AD mouse model. Peptide cIY8 may be topically used to treat AD patients in the future.

Nisin a probiotic bacteriocin mitigates brain microbiome dysbiosis and Alzheimer’s disease-like neuroinflammation triggered by periodontal disease

IntroductionPeriodontitis-related oral microbial dysbiosis is thought to contribute to Alzheimer's disease (AD) neuroinflammation and brain amyloid production. Since probiotics can modulate periodontitis/oral dysbiosis, this study examined the effects of a probiotic/lantibiotic, nisin, in modulating brain pathology triggered by periodontitis.MethodsA polymicrobial mouse model of periodontal disease was used to evaluate the effects of this disease on brain microbiome dysbiosis, neuroinflammation, Alzheimer’s-related changes, and nisin’s therapeutic potential in this context.Results16S sequencing and real-time PCR data revealed that Nisin treatment mitigated the changes in the brain microbiome composition, diversity, and community structure, and reduced the levels of periodontal pathogen DNA in the brain induced by periodontal disease. Nisin treatment significantly decreased the mRNA expression of pro-inflammatory cytokines (Interleukin-1β/IL-1 β, Interleukin 6/IL-6, and Tumor Necrosis Factor α/TNF-α) in the brain that were elevated by periodontal infection. In addition, the concentrations of amyloid-β 42 (Aβ42), total Tau, and Tau (pS199) (445.69 ± 120.03, 1420.85 ± 331.40, 137.20 ± 36.01) were significantly higher in the infection group compared to the control group (193.01 ± 31.82, 384.27 ± 363.93, 6.09 ± 10.85), respectively. Nisin treatment markedly reduced the Aβ42 (261.80 ± 52.50), total Tau (865.37 ± 304.93), and phosphorylated Tau (82.53 ± 15.77) deposition in the brain of the infection group.DiscussionNisin abrogation of brain microbiome dysbiosis induces beneficial effects on AD-like pathogenic changes and neuroinflammation, and thereby may serve as a potential therapeutic for periodontal–dysbiosis-related AD.

Exendin-4 ameliorates tau hyperphosphorylation and cognitive impairment in type 2 diabetes through acting on Wnt/β-catenin/NeuroD1 pathway

Background Type 2 diabetes (T2D) is an independent risk factor for Alzheimer's disease (AD). Exendin-4 (Ex-4), a widely used glucagon-like peptide-1 receptor agonist drug in the treatment of T2D, has been demonstrated the therapeutic effects on diabetic encephalopathy (DE). Especially, the Ex-4 ameliorates the tau hyperphosphorylation and cognitive impairment in DE. And these crucial alterations are also important bridge between T2D and AD. However, its unique mechanism is unclear.Methods The db/db mice, high-fat-diet (HFD) / streptozotocin (STZ)—induced diabetic (HF-diabetic) mice, and high-glucose-damaged (HGD) HT-22 hippocampal cells were enrolled to examine the effects of Ex-4 on AD-like changes in T2D. The Novel object recognition test (NORT) and Morris water maze test (MWMT) were conducted to evaluate the cognitive impairment. The Dickkopf-1 (DKK1) was employed to weaken the activation of the Wnt/β-catenin pathway to explore the mechanism of Ex-4 in protecting the brain functions. The JASPAR was based to predict the interaction between NeuroD1 and the promoter region of Ins2. Moreover, the chromatin immunoprecipitation coupled with quantitative polymerase chain reaction (ChIP-qPCR) and luciferase reporter assays were performed.Results Ex-4 alleviated the tau hyperphosphorylation, increased the brain-derived insulin, and improved the PI3K/AKT/GSK3-β signalling in db/db mice, HF-diabetic mice, and HGD HT-22 hippocampal neuronal cells. The NORT and MWMT indicated that Ex-4 alleviated the learning and memory deficits in HF-diabetic mice. The inhibitor Dickkopf-1 (DKK1) of the Wnt/β-catenin pathway significantly blocked the protective effects of Ex-4. Regarding further molecular mechanisms, NeuroD1 was affected by Ex-4 in vivo and in vitro, and the knockdown or overexpression of NeuroD1 suggested its crucial role in promoting the brain insulin by Ex-4. Meanwhile, the ChIP‒qPCR and luciferase reporter assays confirmed the combination between NeuroD1 and the promoter region of the insulin-encoding gene Ins2. And this interaction could be promoted by Ex-4.ConclusionsOur study proposes that Ex-4 alleviates tau hyperphosphorylation and cognitive dysfunction by increasing Ins2-derived brain insulin through the Wnt/β-catenin/NeuroD1 signaling in T2D. And its also show new lights on part of the progress and mechanism on treatment targets for the DE in T2D.

Caffeic Acid, a Polyphenolic Micronutrient Rescues Mice Brains against Aβ-Induced Neurodegeneration and Memory Impairment.

Oxidative stress plays an important role in cognitive dysfunctions and is seen in neurodegeneration and Alzheimer's disease (AD). It has been reported that the polyphenolic compound caffeic acid possesses strong neuroprotective and antioxidant effects. The current study was conducted to investigate the therapeutic potential of caffeic acid against amyloid beta (Aβ1-42)-induced oxidative stress and memory impairments. Aβ1-42 (5 μL/5 min/mouse) was administered intracerebroventricularly (ICV) into wild-type adult mice to induce AD-like pathological changes. Caffeic acid was administered orally at 50 mg/kg/day for two weeks to AD mice. Y-maze and Morris water maze (MWM) behavior tests were conducted to assess memory and cognitive abilities. Western blot and immunofluorescence analyses were used for the biochemical analyses. The behavioral results indicated that caffeic acid administration improved spatial learning, memory, and cognitive abilities in AD mice. Reactive oxygen species (ROS) and lipid peroxidation (LPO) assays were performed and showed that the levels of ROS and LPO were markedly reduced in the caffeic acid-treated mice, as compared to Aβ-induced AD mice brains. Moreover, the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) were regulated with the administration of caffeic acid, compared to the Aβ-injected mice. Next, we checked the expression of ionized calcium-binding adaptor molecule 1 (Iba-1), glial fibrillary acidic proteins (GFAP), and other inflammatory markers in the experimental mice, which suggested enhanced expression of these markers in AD mice brains, and were reduced with caffeic acid treatment. Furthermore, caffeic acid enhanced synaptic markers in the AD mice model. Additionally, caffeic acid treatment also decreased Aβ and BACE-1 expression in the Aβ-induced AD mice model.

Human umbilical cord mesenchymal stem cell treatment alleviates symptoms in an atopic dermatitis-like mouse model

BackgroundAtopic dermatitis (AD) is one of the most common immune and inflammatory skin disorders, leading to insufferable itching and skin abnormalities that seriously affect life quality of patients. There are still huge unmet needs for long-term and effective disease control, despite currently available therapies. Evidenced by some preclinical and clinical studies of AD treatment with stem cells, stem cell treatment could significantly and effectively ameliorate AD symptoms.ObjectivesTo elucidate underlying mechanisms of how stem cells therapy alleviates AD-like symptoms.MethodsAn AD-like mouse model was constructed and treated with mesenchymal stem cells (MSCs) subcutaneously or subcutaneously combined with intravenously. The differentially expressed genes were sorted out from RNA sequencing results of dorsal skin and blood.ResultsTwo injection routes of MSCs could alleviate AD-like symptoms and pathologic changes of the skin and immune organs. RNA sequencing of dorsal skin sections and blood provided gene expression signatures for amelioration of skin defects, inflammatory and immune modulation by MSCs, as well as common AD molecular markers for the skin and blood, which may benefit for clinical diagnosis. IL-1β and its signaling pathway were specifically found to be associated with the development of AD-like dermatitis lesions. MSC treatment effectively inhibited the JAK-STAT pathway and receptors of IL-4, IL-13, IL-17, and IgE.ConclusionsMSC therapy could regulate abnormal immune and inflammatory status in AD. Mechanistic exploration will contribute to the development of personalized AD treatment based on MSCs.

The involvement of NLRP3 inflammasome in CUMS-induced AD-like pathological changes and related cognitive decline in mice

BackgroundNumerous studies have found that inhibiting the expression of NLRP3 inflammasome can significantly improve depressive-like behaviors in mice, but the research on its effect on cognitive decline in depression and its mechanism is still lacking. This study aimed to elucidate the role of NLRP3 inflammasome in cognitive decline in depression and explore the common neuro-immunological mechanisms of depression and Alzheimer’s disease (AD).MethodsMale C57BL/6 mice were subjected to chronic unpredictable mild stress (CUMS) for 5 weeks, treatment group was administered with the NLRP3 inhibitor MCC950 (10 mg/kg, i.p.), fluoxetine served as positive control. Then, the mice were assessed for cognitive behaviors and depression-like behaviors, and changes of microglia and neurons in hippocampus and levels of Aβ metabolic pathway and tau protein were measured. To explore the mechanism of NLRP3 activation on neurons, we performed in vitro studies using BV2 microglia and mouse primary neurons. Furthermore, we focused on the role of NLRP3 inflammasome in the function of neurons and the expression of AD pathological indicators.ResultsCUMS induced depressive-like behaviors and cognitive decline in mice, which could be reversed by inhibiting NLRP3 inflammasome. MCC950, a specific NLRP3 inhibitor, alleviated CUMS-induced neuron injury and AD-like pathological changes, including the abnormal expression of Aβ metabolic pathway and the hyper-phosphorylation of tau protein. LPS (1 μg/mL) + ATP (1 mM) treatment activated the expression of NLRP3 inflammasome and IL-1β in vitro. In vitro experiment also proved that inhibiting the expression of NLRP3 inflammasome in microglia can restore the Aβ metabolic pathway to normal, decrease neuronal tau protein phosphorylation and protect neurons.ConclusionsInhibition of NLRP3 inflammasome effectively alleviated CUMS-induced depressive-like behaviors and cognitive decline in mice, and inhibited the activation of AD physiological indicators.

Low glucose induced Alzheimer's disease-like biochemical changes in human induced pluripotent stem cell-derived neurons is due to dysregulated O-GlcNAcylation.

Sporadic Alzheimer's disease (sAD) is the leading type of dementia. Brain glucose hypometabolism, along with decreased O-GlcNAcylation levels, occurs before the onset of symptoms and correlates with pathogenesis. Heretofore, the mechanisms involved and the roles of O-GlcNAcylation in sAD pathology largely remain unknown due to a lack of human models of sAD. Human cortical neurons were generated from pluripotent stem cells (PSCs) and treated with glucose reduction media. We found a narrow window of glucose concentration that induces sAD-like phenotypes in PSC-derived neurons. With our model, we reveal that dysregulated O-GlcNAc, in part through mitochondrial dysfunction, causes the onset of sAD-like changes. We demonstrate the therapeutic potential of inhibiting O-GlcNAcase in alleviating AD-like biochemical changes. Our results suggest that dysregulated O-GlcNAc might be a direct molecular link between hypometabolism and sAD-like alternations. Moreover, this model can be exploited to explore molecular processes and for drug development. Lowering glucose to a critical level causes AD-like changes in cortical neurons. Defective neuronal structure and function were also recapitulated in current model. Dysregulated O-GlcNAcylation links impaired glucose metabolism to AD-like changes. Mitochondrial abnormalities correlate with O-GlcNAcylation and precede AD-like phenotype. Our model provides a platform to study sAD as a metabolic disease in human neurons.

Garden Cress (Lepidium sativum) Seeds Ameliorated Aluminum-Induced Alzheimer Disease in Rats Through Antioxidant, Anti-Inflammatory, and Antiapoptotic Effects.

Bioaccumulation of aluminum in the brain is associated with adverse neuroinflammatory and neurodegenerative changes, such as those seen in Alzheimer's disease (AD). This study aimed to assess the impact of the administration of Lepidium sativum (LS) extract on behavioral, biochemical, and cerebral histopathological changes in rats with AlCl3-induced AD and explore the mechanism behind this effect. This study was conducted on 40 male albino rats divided into four groups (n=10): LS (control, 20 mg/kg body weight for 8 weeks), AD (AlCl3, 10 mg/kg body weight), and an LS-treated AD group. Behavioral assessment included radial armed maze and active avoidance training tests. Proinflammatory cytokines, oxidant/antioxidant markers, Aβ, AchE, tau protein, TGFβ1, homocysteine, folic acid, and vitamin B12 were biochemically assessed in the serum. The cerebral cortex was histopathologically examined. AlCl3 administration significantly impaired rats' memory, indicating AD-like behavioral changes, significantly increased (P<0.001) oxidative stress markers, enhanced proinflammatory cytokines, and significantly increased AChE (P<0.001) adding to cytotoxic effects and neuronal loss in the cerebral cortex. LS administration significantly improved the antioxidant parameters, reduced proinflammatory cytokines, and alleviated AD-associated histopathological changes. LS ameliorated AlCl3-induced changes through its antioxidant, anti-inflammatory, and antiapoptotic effects, suggesting that it has a neuroprotective effect.

Precocious emergence of cognitive and synaptic dysfunction in 3xTg-AD mice exposed prenatally to ethanol.

Alzheimer's disease (AD) is the most common cause of dementia, affecting approximately 50 million people worldwide. Early life risk factors for AD, including prenatal exposures, remain underexplored. Exposure of the fetus to alcohol (ethanol) is not uncommon during pregnancy, and may result in physical, behavioral, and cognitive changes that are first detected during childhood but result in lifelong challenges. Whether or not prenatal ethanol exposure may contribute to Alzheimer's disease risk is not yet known. Here we exposed a mouse model of Alzheimer's disease (3xTg-AD), bearing three dementia-associated transgenes, presenilin1 (PS1M146V), human amyloid precursor protein (APPSwe), and human tau (TauP301S), to ethanol on gestational days 13.5-16.5 using an established binge-type maternal ethanol exposure paradigm. We sought to investigate whether prenatal ethanol exposure resulted in a precocious onset or increased severity of AD progression, or both. We found that a brief binge-type gestational exposure to ethanol during a period of peak neuronal migration to the developing cortex resulted in an earlier onset of spatial memory deficits and behavioral inflexibility in the progeny, as assessed by performance on the modified Barnes maze task. The observed cognitive changes coincided with alterations to both GABAergic and glutamatergic synaptic transmission in layer V/VI neurons, diminished GABAergic interneurons, and increased β-amyloid accumulation in the medial prefrontal cortex. These findings provide the first preclinical evidence for prenatal ethanol exposure as a potential factor for modifying the onset of AD-like behavioral dysfunction and set the groundwork for more comprehensive investigations into the underpinnings of AD-like cognitive changes in individuals with fetal alcohol spectrum disorders.

PHPB Attenuated Cognitive Impairment in Type 2 Diabetic KK-Ay Mice by Modulating SIRT1/Insulin Signaling Pathway and Inhibiting Generation of AGEs.

Diabetes mellitus (DM) has been recognized as an increased risk factor for cognitive impairment, known as diabetic encephalopathy (DE). Hyperglycemia and insulin resistance are the main initiators of DE, which is related to the accumulation of advanced glycation end products (AGEs). Potassium 2-(1-hydroxypentyl)-benzoate (PHPB), a derivative of 3-n-butylphthalide (dl-NBP), has emerged various properties including improved mitochondrial function, antioxidant, anti-neuroinflammation, and neuroprotective effects. The present study aimed to investigate the neuroprotective effect of PHPB against AGEs accumulation in type 2 diabetic KK-Ay mice model with DE and further explore the underlying mechanisms. The results showed that PHPB markedly ameliorated the spatial learning ability of KK-Ay mice in the Morris water maze and decreased AD-like pathologic changes (Tau hyperphosphorylation) in the cortex. Furthermore, we found that PHPB treatment significantly reduced AGEs generation via up-regulation of glyoxalase-1 (GLO1) protein and enhancement of methylglyoxal (MG) trapping, while there was no obvious difference in levels of glucose in plasma or brain, contents of total cholesterol (TC), triglycerides (TG), and plasma insulin. Also, PHPB treatment improved the insulin signaling pathway by increasing sirtuin1 (SIRT1) deacetylase activity and attenuated oxidative stress evidenced by elevating glucose-6-phosphate dehydrogenase (G-6-PD) protein expression, promoting the production of reduced glutathione (GSH) and reduced nicotinamide adenine dinucleotide phosphate (NADPH), restoring mitochondrial membrane potential, increasing adenosine triphosphate (ATP) generation, and reducing malondialdehyde (MDA) levels in the brain. Taken together, PHPB exhibited a beneficial effect on DE, which involved modulating the SIRT1/insulin signaling pathway and reducing oxidative stress by inhibiting the generation of AGEs.

Triptolide injection reduces Alzheimer's disease-like pathology in mice.

Triptolide is an epoxidized diterpene lactone isolated from Tripterygium wilfordii. Studies have shown that triptolide exerts organ-protective effects. However, it remains unknown whether triptolide improves Alzheimer's disease (AD)-like presentations. Thirty healthy 8-week-old male C57BL/6J mice were randomly divided into control (n = 10), model (n = 10), and triptolide (n = 10) groups. Amyloid-β (Aβ)42 was injected bilaterally into the ventricles of mice in the model group. Triptolide was injected intraperitoneally daily after injecting Aβ42 (a total of 30 days) in the triptolide group. Learning and memory were tested using the Morris water maze test. The deposition of Aβ42 in the hippocampus was detected using immunohistochemical staining. In the hippocampus, three synaptic-associated proteins-gephyrin, collybistin, and GABRA1 -were detected by western blotting. Furthermore, we used ELISA to detect proinflammatory cytokines, including TNF-α and IL-1β, in the blood and hippocampus. Moreover, superoxide dismutase (SOD), malondialdehyde (MDA), and GSH levels were measured using the corresponding kits. We found that triptolide improved spatial learning and memory in AD-like mice. Additionally, triptolide maintained the expression of gephyrin, collybistin, and GABRA1 and reduced Aβ in these mice. Additionally, triptolide reduced the expression of inflammatory cytokines and decreased oxidative damage in AD-like mice. Our study suggests that triptolide attenuates AD-like changes in the mouse brain.

Molecular alteration of the proteasome contributes to AD-like pathology in the brain of HFD-STZ diabetic rats.

Diabetes-related cognitive impairment has been shown in diverse epidemiological investigations and lab-based studies, although the underlying pathological mechanisms remain unclear. Unbalanced protein homeostasis may contribute to cognitive decline by inducing abnormal protein aggregation in the diabetic brain. This study aimed to determine possible changes in the proteasome, which is an important pathway involved in abnormal protein degradation. To this end, we examined potential alterations of proteasomal subunits and hydrolytic activity in the brain of diabetic rats fed with high-fat diet combined with small doses of streptozotocin (STZ). Furthermore, lactacystin were used to inhibit proteasomal activity in vivo and typical Alzheimer's disease (AD)-like pathologies were detected, including amyloid-beta, tau phosphorylation, and oxidative protein changes. Our results showed that proteasomal activity increased in the brains of diabetic rats compared to age-matched control rats. After proteasome inhibition, the levels of tau phosphorylation and protein oxidative modification significantly increased; however, no changes were detected in the pathway involved in amyloid production. These results indicated that changes in protein homeostasis balance in diabetes play a role in some typical AD-like changes, especially in oxidative protein degradation, providing evidence that prevention of diabetes-induced protein imbalance may be a potential therapeutic target.

Cognitive dysfunctions and spontaneous EEG alterations induced by hippocampal amyloid pathology in rats

PurposeWe aimed to determine the effects of different doses of amyloid-beta (Aβ) peptide on learning and memory, and whether the changes in brain oscillations induced by dose-dependent accumulation of Aβ could be used as biomarkers to detect early stages of Alzheimer's disease (AD). Material and methodsMale albino Wistar rats aged 3 months were randomly divided into four groups (n ​= ​12/group) obtained by i. h. Injection (to the dorsal hippocampus) of saline or different doses of 0.01 ​μg/μl, 0.1 ​μg/μl, and 1 ​μg/μl of Aβ. After two weeks of recovery period, open field and novel object recognition tests were performed and spontaneous EEG recordings were obtained. Later, hippocampus tissues were collected for Western blot and ELISA analysis. ResultsA significant decrement in recognition memory was observed in 0.1 ​μg/μl, and 1 ​μg/μl injected groups. In addition, Aβ accumulation induced significant decrement of the expression of NeuN, SNAP-25, SYP, and PSD-95 proteins, and led to the increment of GFAP expression in hippocampus. Moreover, we detected remarkable alterations in spontaneous brain activity. The hippocampal Aβ levels were negatively correlated with hippocampal gamma power and positively correlated with hippocampal theta power. Also, we observed significant changes in coherence values, indicating the functional connectivity between different brain regions, after the accumulation of Aβ. Especially, there was a significant correlation between changes in frontohippocampal theta coherence and in frontotemporal theta coherence. ConclusionsOur findings indicate that Aβ peptide induces AD-like molecular changes at certain doses, and these changes could be detected by evaluating brain oscillations.

MicroRNA-195 rescues the impaired MS-dCA1 neural circuit and spatial memory in rats with chronic cerebral hypoperfusion

Chronic cerebral hypoperfusion (CCH) is a common risk factor for vascular dementia and Alzheimer’s disease (AD). The previous studies have shown that CCH-induced multiple AD-like pathological changes in the hippocampus and cortex through downregulating the microRNA-195 (miR-195) expression. However, whether and how miR-195 participates in the dysfunction of the medial septum (MS)-dorsal hippocampal CA1 (dCA1) neural circuit following CCH is still obscure. In the present study, we found that miR-195 was downregulated in the MS region of CCH rats. Moreover, using electrophysiological recording and immunofluorescence staining technique, we found that the knockdown of miR-195 through the injection of lenti- AMO-195 into the MS region led to a pathological change that mimicked the damage to the MS-dCA1 neural circuit in CCH rats, including the decreased input-output (I/O) curve, increased paired-pulse ratio (PPR), decreased numbers of ChAT+ and PV+ neurons in MS, and diminished theta rhythm in the hippocampus. More importantly, exogenously supplemented miR-195 into the MS region rescued the damaged neural circuit in MS-dCA1 of CCH rats by injecting lenti-pre-miR-195. Gain-of-function of miR-195 in the MS region significantly improved the cognitive dysfunction in CCH rats assessed by the Morris water maze test. In conclusion, knockdown of miR-195 in the MS region can impair MS-dCA1 neural circuit function, while upregulation of miR- 195 can rescue the impaired function of MS-dCA1 neural circuit and spatial memory ability in CCH rats. This provides a valuable reference for future anti-dementia therapy involving miR-195.