Animal Models Of AD Research Articles

Overexpression of TECPR1 improved cognitive function of P301S-tau mice via activation of autophagy in the early and late process.

Autophagy disorders in AD patients and animal models were well known, however, the effect of P301S-tau on autophagy is not clear. Here, we found that autophagy related protein Tectonin Beta-Propeller Repeat-Containing Protein 1 (TECPR1) decreased in the hippocampus of P301S-tau transgenic mice by proteomics, which was proved invivo and invitro, and P301S-tau induced autophagic deficits in early and late process. TECPR1 overexpression attenuated P301S-tau induced autophagy defects via promoting autophagosome generation and autophagosome and lysosomes fusion. We also found that TECPR1 overexpression ameliorated the behavior disorders of P301S-tau mice with promoting tau degradation, improving synaptic plasticity and neuron loss. Lastly, CQ or 3-MA treatment reversed TECPR1 induced improvement effects on autophagic and cognitive disorders, further proved that, TECPR1 activated the early and late process of autophagy to ameliorate the cognition of P301S-tau mice. Our data suggest that TECPR1 is a potential therapy target for AD.

Potential Neuroprotective Effects of Alpinia officinarum Hance (Galangal): A Review.

Background/Objectives: This review aims to provide a detailed understanding of the current evidence on Alpinia officinarum Hance (A. officinarum) and its potential therapeutic role in central nervous system (CNS) disorders. CNS disorders encompass a wide range of disorders affecting the brain and spinal cord, leading to various neurological, cognitive and psychiatric impairments. In recent years, natural products have emerged as potential neuroprotective agents for the treatment of CNS disorders due to their outstanding bioactivity and favourable safety profile. One such plant is A. officinarum, also known as lesser galangal, a perennial herb from the Zingiberaceae family. Its phytochemical compounds such as flavonoids and phenols have been documented to have a powerful antioxidants effect, capable of scavenging free radicals and preventing oxidative damage. Methods: In this review, we critically evaluate the in vitro and in vivo studies and examine the mechanisms by which A. officinarum exerts its neuroprotective effect. Results: Several studies have confirmed that A. officinarum exerts its neuroprotective effects by reducing oxidative stress and cell apoptosis, promoting neurite outgrowth, and modulating neurotransmitter levels and signalling pathways. Conclusions: Although previous studies have shown promising results in various models of neurological disorders, the underlying mechanisms of A. officinarum in Alzheimer's (AD) and Parkinson's disease (PD) are still poorly understood. Further studies on brain tissue and cognitive and motor functions in animal models of AD and PD are needed to validate the results observed in in vitro studies. In addition, further clinical studies are needed to confirm the safety and efficacy of A. officinarum in CNS disorders.

The Role of Gut Microbiota in the Neuroprotective Effects of Selenium in Alzheimer's Disease.

The objective of the present review was to provide a timely update on the molecular mechanisms underlying the beneficial role of Se in Alzheimer's disease pathogenesis, and discuss the potential role of gut microbiota modulation in this neuroprotective effect. The existing data demonstrate that selenoproteins P, M, S, R, as well as glutathione peroxidases and thioredoxin reductases are involved in regulation of Aβ formation and aggregation, tau phosphorylation and neurofibrillary tangles formation, as well as mitigate the neurotoxic effects of Aβ and phospho-tau. Correspondingly, supplementation with various forms of Se in cellular and animal models of AD was shown to reduce Aβ formation, tau phosphorylation, reverse the decline in brain antioxidant levels, inhibit neuronal oxidative stress and proinflammatory cytokine production, improve synaptic plasticity and neurogenesis, altogether resulting in improved cognitive functions. In addition, most recent findings demonstrate that these neuroprotective effects are associated with Se-induced modulation of gut microbiota. In animal models of AD, Se supplementation was shown to improve gut microbiota biodiversity with a trend to increased relative abundance of Lactobacillus, Bifidobacterium, and Desulfivibrio, while reducing that of Lachnospiracea_NK4A136, Rikenella, and Helicobacter. Moreover, the relative abundance of Se-affected taxa was significantly associated with Aβ accumulation, tau phosphorylation, neuronal oxidative stress, and neuroinflammation, indicative of the potential role of gut microbiota to mediate the neuroprotective effects of Se in AD. Hypothetically, modulation of gut microbiota along with Se supplementation may improve the efficiency of the latter in AD, although further detailed laboratory and clinical studies are required.

Linalool acts as a chemical chaperone by inhibiting amyloid-β aggregation

Linalool is a neuroprotective monoterpene found in essential oils from aromatic plants. Linalool's effectiveness in AD animal models has been established previously, but its mechanisms of action remain unclear. Therefore, this study aims to investigate whether linalool binds directly to the amyloid beta (Aβ) fibrils to understand it's role in preventing neurodegeneration. The anti-aggregation ability of Linalool was determined using Dithiothreitol (DTT), and thermal aggregation assays followed by Thioflavin T (ThT) binding assay. AD animals were treated with Linalool, and Thioflavin T staining was used to check the binding of linalool to Aβ fibrils in rat brain tissue sections. Preliminary studies revealed the anti-aggregation potential of linalool under the thermal and chemical stimulus. Further, in ThT binding assay Linalool inhibited Aβ aggregation, binding directly to Aβ fibrils. The reduced fluorescence intensity of ThT in AD brain tissues following linalool administration, highlights its neuroprotective potential as a therapeutic agent for AD.

Visualization of Microcirculation at Acupoints in vivo of Alzheimer's Disease Animal Model with Photoacoustic Microscope: A Pilot Study.

Alzheimer's disease may be effectively treated with acupoint-based acupuncture, which is acknowledged globally. However, more research is needed to understand the alterations in acupoints that occur throughout the illness and acupuncture treatment. This research investigated the differences in acupoint microcirculation between normal mice and AD animals in vivo. This research also examined how acupuncture affected AD animal models and acupoint microcirculation. 6-month-old SAMP8 mice were divided into two groups: the AD group and the acupuncture group. Additionally, SAMR1 mice of the same month were included as the normal group. The study involved subjecting a group of mice to 28 consecutive days of acupuncture at the ST36 (Zusanli) and CV12 (Zhongwan) acupoints. Following this treatment, the Morris water maze test was conducted to assess the mice's learning and memory abilities; the acoustic-resolution photoacoustic microscope (AR-PAM) imaging system was utilized to observe the microcirculation in CV12 acupoint region and head-specific region of each group of mice. In comparison to the control group, the mice in the AD group exhibited a considerable decline in their learning and memory capabilities (p < 0.01). In comparison to the control group, the vascular in the CV12 region and head-specific region in mice from the AD group exhibited a considerable reduction in length, distance, and diameter r (p < 0.01). The implementation of acupuncture treatment had the potential to enhance the aforementioned condition to a certain degree. These findings offered tangible visual evidence that supports the ongoing investigation into the underlying mechanisms of acupuncture's therapeutic effects.

Roles of HDAC6 in the pathogenesis of Alzheimer’s disease

AbstractBackgroundIt has recently been demonstrated that HDAC6 depletion ameliorates the impairment of memory function and mitochondrial axonal transport induced by the accumulation of Aβ. However, very little is known about molecular mechanisms through which HDAC6 regulates APP processing. Also, it remains controversial whether HDAC6 induces inflammation or reduces it.MethodWe analyzed the expression of HDAC6 in AD patients and 5xFAD mice. We confirmed that HDAC6 regulates BACE1 in primary neurons and NLRP3 inflammasome in primary microglia. And we crossed HDAC6 knock‐out mice with 5xFAD mice and got 5xFAD/HDAC6 KO. We compared 5xFAD (n = 11) and 5xFAD/HDAC6 KO (n = 13). We did a nest building test, open field test, Morris water maze, Y‐maze, passive avoidance, and elevated plus maze. After finishing all these behaviour tests, we sacrificed the mouse and checked protein and mRNA. We did Immunohistochemistry using Aβ plaque, NLRP3 inflammasome and synapse‐related markers. We also did RNA‐seq analysis in these mice’s brains.ResultWe confirmed that the expression of HDAC6 was increased in the AD cortex compared to neuropathologically normal brains. The stability of BACE1 is regulated by its C‐terminal lysine, and HDAC6 deacetylates the C‐terminal lysine of BACE1 by direct binding. Also, HDAC6 deficiency reduced NLRP3 inflammasome activation‐, and subsequent inflammatory responses in microglia. By crossing HDAC6 knock‐out mice with 5xFAD mice, the role of HDAC6 was confirmed in an animal model of AD. HDAC6 deletion improved cognitive function and reduced the protein expression of BACE1 and inflammatory factors in 5xFAD mice. Also, HDAC6‐deficient 5xFAD mice developed fewer dense‐core plaques, IL‐1β, and ASC specks than 5xFAD mice. Furthermore, RNA‐sequencing was analyzed from the hippocampus of 5xFAD and 5xFAD/HDAC6 KO mice. Synapse and neuron development‐related genes were significantly up‐regulated, and type I interferon, immune response, and prion disease‐related genes were down‐regulated in HDAC6‐depleted mice. Finally, we confirmed that the ratio of PSD95 colocalized with C1q was significantly decreased in 5xFAD/HDAC6 KO compared to 5xFAD mice, which suggested that synapse loss was inhibited in AD mice.ConclusionThis study reveals distinct functions of HDAC6 and suggests HDAC6 as a significant regulator in the pathogenesis of AD that could be exploited therapeutically.

Modelling of Alzheimer’s disease pathology in the retina ‐ what can we learn from animal models?

AbstractRetinal neurodegeneration and visual dysfunction have been reported in the majority of Alzheimer’s patients, and, in light of the quest for novel biomarkers, the retina has been receiving increasing attention as an organ for diagnosing, monitoring, and understanding disease. Thinning of retinal layers, abnormalities in vasculature, and protein deposition can be imaged at unprecedented resolution, which offers a unique systems biology view on the cellular and molecular changes underlying AD. It makes the retina not only a promising target for biomarker development, but it also suggests that novel fundamental insights into the pathophysiology of AD can be obtained by studying the retina–brain axis.This presentation will show how the visual system, together with retinal imaging techniques and available animal models of AD, constitutes a unique toolbox for fundamental and preclinical studies of AD; and explore how the retina‐brain axis has the potential to revolutionize preclinical research of AD. We will discuss the strengths of the rodent retina as a model organ to investigate Alzheimer’s disease mechanisms. Studies in different AD mouse models will be presented to showcase how retinal imaging can reveal information about the structure, function, and molecular composition of the retina and thereby aid in diagnosing, monitoring, and understanding AD. Furthermore, we will touch upon how the organotypic heterogeneity of the retina versus the brain may hold clues to understanding AD, and how the unique anatomical organization of the visual system offers opportunities to investigate disease propagation along neural connections.

Network pharmacology-based analysis of Jin-Si-Wei on the treatment of Alzheimer's disease

Ethnopharmacological relevanceJin-Si-Wei (JSW), a traditional Chinese medicine (TCM) formula, have cognitive enhancing effect and delay the memory decline in an animal model of AD， which has been reported. However, the therapeutic mechanism of JSW in the treatment of AD remains unclear. Aim of the studyThis study aimed to verify the pharmacodynamics of JSW in the treatment of AD, and to explore its potential mechanism based on network pharmacology, molecular docking and experimental validation both in vitro and in vivo. Materials and methodsIn this study, the underlying mechanism of JSW against AD was investigated by the integration of network pharmacology. Then, the core pathways and biological process of JSW were verified by experiment, including behavioral test and pathological and biochemical assays with 6-month-old APPswe/PS1ΔE9 transgenic (APP/PS1) mice in vivo and verified with Aβ1-42-stimulated SH-SY5Y cells in vitro. At last, molecular docking was used to show the binding activity of each active ingredient to the core genes of JSW treatment in AD. ResultsA Drug-Ingredient-Target network was established, which included 363 ingredients and 116 targets related to the JSW treatment of AD. The main metabolic pathway of JSW treatment for AD is neuroactive ligand-receptor interaction pathway, and biological processes are mainly involved in Aβ metabolic process. In vivo experiments, compared with APP/PS1 mice, the cognitive and memory ability of mice was significantly improved after JSW administration. In brain tissue of APP/PS1 mice, JSW could increase the contents of low-density lipoprotein receptor-related protein 1 (LRP-1), enkephalinase (NEP) and Acetyl choline (ACh), and decrease the contents of Aβ1-42, amyloid precursor protein (APP) and receptor for advanced glycation end products (RAGE), decrease the vitality of cholinesterase (AChE) and choline acetyltransferase (ChAT). Besides, JSW could increase α-secretase expression and decrease β/γ-secretase expression, and improve the number and morphology of synapses in CA1 region of the hippocampus of APP/PS1 mice. In vitro experiments, Drug-Containing Serum (JSW-serum) has a neuroprotective effect by reducing the apoptosis on Aβ1-42-stimulated SH-SY5Y cells. Molecular docking results showed that 2-Isopropyl-8-methylphenanthrene-3,4-dione had strong binding activity with PTGS2, which maybe a potential ingredient for the treatment of AD. ConclusionsJSW improves AD in APP/PS1 mice, and this therapeutic effect may be achieved in part by altering the neuroactive ligand-receptor interaction pathway.

Intermittent hypoxia therapy ameliorates beta-amyloid pathology via TFEB-mediated autophagy in murine Alzheimer's disease

BackgroundAlzheimer's disease (AD) is the most prevalent neurodegenerative disorder. Impaired autophagy in plaque-associated microglia (PAM) has been reported to accelerate amyloid plaque deposition and cognitive impairment in AD pathogenesis. Recent evidence suggests that the transcription factor EB (TFEB)-mediated activation of the autophagy–lysosomal pathway is a promising treatment approach for AD. Moreover, the complementary therapy of intermittent hypoxia therapy (IHT) has been shown to upregulate autophagy and impart beneficial effects in patients with AD. However, the effect of IHT on PAM remains unknown.Methods8-Month-old APP/PS1 mice were treated with IHT for 28 days. Spatial learning memory capacity and anxiety in mice were investigated. AD pathology was determined by the quantity of nerve fibers and synapses density, numbers of microglia and neurons, Aβ plaque deposition, pro-inflammatory factors, and the content of Aβ in the brain. TFEB-mediated autophagy was determined by western blot and qRT-PCR. Primary microglia were treated with oligomeric Aβ 1–42 (oAβ) combined with IHT for mechanism exploration. Differential genes were screened by RNA-seq. Autophagic degradation process of intracellular oAβ was traced by immunofluorescence.ResultsIn this study, we found that IHT ameliorated cognitive function by attenuating neuronal loss and axonal injury in an AD animal model (APP/PS1 mice) with beta-amyloid (Aβ) pathology. In addition, IHT-mediated neuronal protection was associated with reduced Aβ accumulation and plaque formation. Using an in vitro PAM model, we further confirmed that IHT upregulated autophagy-related proteins, thereby promoting the Aβ autophagic degradation by PAM. Mechanistically, IHT facilitated the nuclear localization of TFEB in PAM, with TFEB activity showing a positive correlation with Aβ degradation by PAM in vivo and in vitro. In addition, IHT-induced TFEB activation was associated with the inhibition of the AKT–MAPK–mTOR pathway.ConclusionsThese results suggest that IHT alleviates neuronal damage and neuroinflammation via the upregulation of TFEB-dependent Aβ clearance by PAM, leading to improved learning and memory in AD mice. Therefore, IHT may be a promising non-pharmacologic therapy in complementary medicine against AD.Graphical

Tirzepatide ameliorates spatial learning and memory impairment through modulation of aberrant insulin resistance and inflammation response in diabetic rats.

Background: One of the typical symptoms of diabetes mellitus patients was memory impairment, which was followed by gradual cognitive deterioration and for which there is no efficient treatment. The anti-diabetic incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) were demonstrated to have highly neuroprotective benefits in animal models of AD. We wanted to find out how the GLP-1/GIP dual agonist tirzepatide affected diabetes's impairment of spatial learning memory. Methods: High fat diet and streptozotocin injection-induced diabetic rats were injected intraperitoneally with Tirzepatide (1.35mg/kg) once a week. The protective effects were assessed using the Morris water maze test, immunofluorescence, and Western blot analysis. Golgi staining was adopted for quantified dendritic spines. Results: Tirzepatide significantly improved impaired glucose tolerance, fasting blood glucose level, and insulin level in diabetic rats. Then, tirzepatide dramatically alleviated spatial learning and memory impairment, inhibited Aβ accumulation, prevented structural damage, boosted the synthesis of synaptic proteins and increased dendritic spines formation in diabetic hippocampus. Furthermore, some aberrant changes in signal molecules concerning inflammation signaling pathways were normalized after tirzepatide treatment in diabetic rats. Finally, PI3K/Akt/GSK3β signaling pathway was restored by tirzepatide. Conclusion: Tirzepatide obviously exerts a protective effect against spatial learning and memory impairment, potentially through regulating abnormal insulin resistance and inflammatory responses.

Intensity-dependent gamma electrical stimulation regulates microglial activation, reduces beta-amyloid load, and facilitates memory in a mouse model of Alzheimer’s disease

BackgroundGamma sensory stimulation may reduce AD-specific pathology. Yet, the efficacy of alternating electrical current stimulation in animal models of AD is unknown, and prior research has not addressed intensity-dependent effects.MethodsThe intensity-dependent effect of gamma electrical stimulation (GES) with a sinusoidal alternating current at 40 Hz on Aβ clearance and microglia modulation were assessed in 5xFAD mouse hippocampus and cortex, as well as the behavioral performance of the animals with the Morris Water Maze.ResultsOne hour of epidural GES delivered over a month significantly (1) reduced Aβ load in the AD brain, (2) increased microglia cell counts, decreased cell body size, increased length of cellular processes of the Iba1 + cells, and (3) improved behavioral performance (learning & memory). All these effects were most pronounced when a higher stimulation current was applied.ConclusionThe efficacy of GES on the reduction of AD pathology and the intensity-dependent feature provide guidance for the development of this promising therapeutic approach.

Electroacupuncture at ST 36 ameliorates cognitive impairment and beta-amyloid pathology by inhibiting NLRP3 inflammasome activation in an Alzheimer’s disease animal model

BackgroundAlzheimer’s disease (AD) is the most prevalent neurodegenerative disorder leading to cognitive impairment in the elderly, and no effective treatment exists. Increasing evidence has demonstrated that physical therapy and electroacupuncture (EA) effectively improve spatial learning and memory abilities. Nevertheless, the mechanism underlying the effects of EA on AD pathology is largely unexplored. Acupuncture at Zusanli (ST 36) has previously been shown to improve cognitive impairment in AD, but the mechanism is unclear. According to recent studies, EA drives the vagal–adrenal axis from the hindlimb ST 36 acupoint but not from the abdominal Tianshu (ST 25) to curb severe inflammation in mice. This study examined whether ST 36 acupuncture improves cognitive dysfunction in AD model mice by improving neuroinflammation and its underlying mechanism. MethodsMale 5xFAD mice (aged 3, 6, and 9 months) were used as the AD animal model and were randomly divided into three groups: the AD model group (AD group), the electroacupuncture at ST 36 acupoint group (EA-ST 36 group), and the electroacupuncture at ST 25 acupoint group (EA-ST 25 group). Age-matched wild-type mice were used as the normal control (WT) group. EA (10 Hz, 0.5 mA) was applied to the acupoints on both sides for 15 min, 5 times per week for 4 weeks. Motor ability and cognitive ability were assessed by the open field test, the novel object recognition task, and the Morris water maze test. Thioflavin S staining and immunofluorescence were used to mark Aβ plaques and microglia. The levels of NLRP3, caspase-1, ASC, interleukin (IL)-1β, and IL-18 in the hippocampus were assayed by Western blotting or qRT-PCR. ResultsEA at ST 36, but not ST 25, significantly improved motor function and cognitive ability and reduced both Aβ deposition and microglia and NLRP3 inflammasome activation in 5×FAD mice. ConclusionEA stimulation at ST 36 effectively improved memory impairment in 5×FAD mice by a mechanism that regulated microglia activation and alleviated neuroinflammation by inhibiting the NLRP3 inflammatory response in the hippocampus. This study shows that ST 36 may be a specific acupoint to improve the condition of AD patients.

Neuroprotective Effects of Lactoferrin in Alzheimer's and Parkinson's Diseases: A Narrative Review.

Recent advancements in lactoferrin research have uncovered that lactoferrin does function not only as an antimicrobial protein but also as an immunomodulatory, anticancer, and neuroprotective agent. Focusing on neuroprotection, this literature review delineates how lactoferrin interacts in the brain, specifically its neuroprotective effects and mechanisms against Alzheimer's and Parkinson's diseases (AD and PD), the two most common neurodegenerative diseases. The neuroprotective pathways involving surface receptors (heparan sulfate proteoglycan (HSPG) and lactoferrin receptor (LfR)), signaling pathways (extracellular regulated protein kinase-cAMP response element-binding protein (ERK-CREB) and phosphoinositide 3-kinase/Akt (PI3K/Akt)), and effector proteins (A disintegrin and metalloprotease10 (ADAM10) and hypoxia-inducible factor 1α (HIF-1α)) in cortical/hippocampal and dopaminergic neurons are described. These cellular effects of lactoferrin are likely responsible for attenuating cognitive and motor deficits, amyloid-β and α-synuclein accumulation, and neurodegeneration in animal and cellular models of AD and PD. This review also discusses the inconsistent findings related to the neuroprotective effects of lactoferrin against AD. Overall, this review contributes to the existing literature by clarifying the potential neuroprotective effects and mechanisms of lactoferrin in the context of AD and PD neuropathology.

Kai-Xin-San protects against mitochondrial dysfunction in Alzheimer’s disease through SIRT3/NLRP3 pathway

BackgroundKai-Xin-San (KXS) has been reported to have a good curative impact on dementia. The purpose of the study was to determine whether KXS might ameliorate cognitive deficits in APP/PS1 mice and to evaluate its neuroprotective mechanism.MethodsAPP/PS1 mice were employed as an AD animal model; Aβ1–42 and KXS-containing serum were used in HT22 cells. Four different behavioral tests were used to determine the cognitive ability of mice. Nissl staining was utilized to detect hippocampal neuron changes. ROS, SOD, and MDA were used to detect oxidative stress levels. Transmission electron microscopy and Western blot were used to evaluate mitochondrial morphology, mitochondrial division, and fusion state. Western blotting and immunofluorescence identified PSD95, BDNF, NGF, SYN, SIRT3, and NLRP3 inflammasome levels.ResultsThe results indicated that KXS protected APP/PS1 mice against cognitive impairments. KXS suppressed neuronal apoptosis and oxidative stress among APP/PS1 mice. KXS and KXS-containing serum improved mitochondrial dysfunction and synaptic and neurotrophic factors regarding APP/PS1 mice. In addition, KXS and KXS-containing serum enhanced mitochondrial SIRT3 expression and reduced NLRP3 inflammasome expression in APP/PS1 mice.ConclusionKXS improves cognitive dysfunction among APP/PS1 mice via regulating SIRT3-mediated neuronal cell apoptosis. These results suggested that KXS was proposed as a neuroprotective agent for AD progression.

Attenuation of Alzheimer’s brain pathology in 5XFAD mice by PTH1-34, a peptide of parathyroid hormone

BackgroundAlzheimer’s disease (AD) and osteoporosis are two distinct diseases but often occur in the same patient. Their relationship remains poorly understood. Studies using Tg2576 AD animal model demonstrate bone deficits, which precede the brain phenotypes by several months, arguing for the independence of bone deficits on brain degeneration and raising a question if the bone deficits contribute to the AD development. To address this question, we investigated the effects of PTH1-34, a peptide of parathyroid hormone analog and a well-recognized effective anabolic therapy drug for patients with osteoporosis, on 5XFAD animal model.Methods5XFAD mice, an early onset β-amyloid (Aβ)-based AD mouse model, were treated with PTH1-34 intermittently [once daily injection of hPTH1–34 (50 μg/Kg), 5 days/week, starting at 2-month old (MO) for 2–3 month]. Wild type mice (C57BL/6) were used as control. The bone phenotypes were examined by microCT and evaluated by measuring serum bone formation and resorption markers. The AD relevant brain pathology (e.g., Aβ and glial activation) and behaviors were assessed by a combination of immunohistochemical staining analysis, western blots, and behavior tests. Additionally, systemic and brain inflammation were evaluated by serum cytokine array, real-time PCR (qPCR), and RNAscope.ResultsA reduced trabecular, but not cortical, bone mass, accompanied with a decrease in bone formation and an increase in bone resorption, was detected in 5XFAD mice at age of 5/6-month old (MO). Upon PTH1-34 treatments, not only these bone deficits but also Aβ-associated brain pathologies, including Aβ and Aβ deposition levels, dystrophic neurites, glial cell activation, and brain inflammatory cytokines, were all diminished; and the cognitive function was improved. Further studies suggest that PTH1-34 acts on not only osteoblasts in the bone but also astrocytes in the brain, suppressing astrocyte senescence and expression of inflammatory cytokines in 5XFAD mice.ConclusionsThese results suggest that PTH1-34 may act as a senolytic-like drug, reducing systemic and brain inflammation and improving cognitive function, and implicate PTH1-34’s therapeutic potential for patients with not only osteoporosis but also AD.

Exploring the Latent Mechanism of Huanglian Jiedu Decoction Formula for Anti-atopic Dermatitis by Systems Pharmacology.

Atopic dermatitis (AD) is a chronic inflammatory skin disease, which does not have a specific drug presently. Huanglian jiedu decoction (HJD) is one of the effective traditional Chinese medicine prescriptions. The real material and mechanisms of HJD for AD are not clear. Network pharmacology and in vivo experiments were used to explore the real material and mechanisms of HJD for AD. A systems' pharmacology approach that provides a comprehensive analysis of bioactive compounds, targets, and pathway interactions was employed to elucidate the molecular pathogenesis of HJD for AD. First, the compound databases were constructed for HJD, and compound targets were predicted. Then, the hub targets of HJD were selected by degree centrality analysis and validated using the molecular docking method. Finally, Compound-Target and Target-Pathway networks were constructed to explore the latent mechanism of HJD for AD. Then, animal models of AD were established, the pathology of the skin lesions was observed, and RT-PCR and ELISA methods were used to verify the key targets in the serum of AD mice. The results showed that 60 bioactive compounds (palmatine, wogonin, cavidine, etc.) of HJD interacting with 169 related hub targets (PTGS2, HSP90AA1, etc.) were authenticated. HJD potentially participates in response to stimuli, biological regulation, and reproduction through the PI3K-Akt signaling pathway, MAPK signaling pathway, Ras signaling pathway, and Fc epsilon RI signaling pathway, which are interrelated to the pathogenesis of AD. Compared with the control group, the thickening of the epidermis in the model group was obvious with inflammatory cells infiltrating, the levels of PI3K, AKT, JNK, ERK, IL-4 and TNF-α were up-regulated; and 6.4g/kg and 12.8g/kg HJD could significantly reduce the thickening of the epidermis and infiltration of inflammatory cells, down-regulate the levels of PI3K, AKT, JNK, ERK, IL-4 and TNF-α in the AD mice. HJD might exert its anti-AD effects by downregulating key indicators (PI3K, AKT, JNK, ERK, IL-4, and TNF-α) in the PI3K/AKT and MAPK pathways. Our study could help us understand the compound and mechanism of HJD for AD. Moreover, it had a guidance function to change the traditional arrangement of formula for HJD.

Treatment of Alzheimer’s disease by modulation of microglial neuroinflammation by nasal anti‐CD3 mAb

AbstractBackgroundNeuroinflammation and microglial activation play a role in AD as shown pathologically and by microglial PET imaging (Zhou et al, Front Immunol 2021). We found that nasal anti‐CD3 mAb induced IL‐10‐secreting T cells in the cervical lymph node that migrate to the brain, suppress microglial inflammation and ameliorate disease in a model of progressive MS (Mayo et a,l Brain 2016). In humans we found that nasal anti‐CD3 (Foralumab) decreased inflammation and accelerated resolution of lung inflammation in patients with mild COVID‐19 (Moreira et al, Front Immunol 2021) and modulated microglial activation in progressive MS as measured by microglial PET imaging (Chitnis et al, unpublished). We thus tested nasal anti‐CD3 in animal models of AD.MethodWe treated AD mice (3xTg and APP/PS1) with nasal anti‐CD3, isotype control antibody or PBS 3x/week for 6 months (3xTg) or 3x/week for 2 months (APP/PS1) and investigated cognitive behavior (Morris water maze and Y‐maze), microglia gene profile using a Nanostring myeloid codeset and T cell infiltration in the brain by immunofluorescence.ResultWe found that microglia lose their homeostatic (M0) signature and acquire a neurodegenerative (MGnD) signature in animal models of AD. In 3xTg mice, we found that nasal anti‐CD3 restored the M0 signature by increasing the expression of Cx3cr1, Mafb, and Jun, and lessened the MGnD signature by decreasing the expression of Trem2, Nos2 and Ccl5. Nasal anti‐CD3 improved cognition in 3xTg mice as measured by the Y‐maze and Morris water maze tests and in APP/PS1 mice as measured by the Y‐maze test. Nasal anti‐CD3 induced migration of T cells to the brain which interacted with microglia.ConclusionNasal anti‐CD3 restores the microglial M0 signature and improves behavior in animal models of AD. Based on these results and the successful administration of nasal anti‐CD3 to subjects with progressive MS and COVID‐19, phase 1 trials of nasal Foralumab are planned in subjects with mild AD to assess safety, clinical effects and microglial activation as measured by microglial PET imaging. Nasal anti‐CD3 is a novel approach to treat AD by targeting microglial inflammation.

Ameliorative effect of vanillin on scopolamine-induced dementia-like cognitive impairment in a mouse model.

Alzheimer's disease (AD) is the most common form of dementia, which is among the top five causes of death in the United States. It is a neurodegenerative disorder that causes permanent loss of memory and cognition. The current pharmacotherapy for AD is based on providing symptomatic relief only and has many side effects. There is a need for a safer, disease-modifying drug for the treatment of AD. The PASS online software was used to screen phytoconstituents based on their predicted effects on various AD-related targets. Vanillin was selected as the compound of interest, as it has not been researched elaborately on any animal model of AD. The acetylcholinesterase inhibitory activity of vanillin was established in vitro. Thereafter, ameliorative effect of vanillin was evaluated using the exteroceptive memory model in scopolamine-induced cognitive impairment mice model. Vanillin showed an acetylcholinesterase inhibitory activity in vitro, and the IC50 value was calculated to be 0.033 mM. Vanillin significantly reversed the memory and behavioral deficits caused by scopolamine as demonstrated by significant improvement in memory in negative reinforcement, elevated plus maze, and spatial learning paradigms. Vanillin also proved to have a nootropic effect. Also, vanillin proved to have significantly better antioxidant and acetylcholinesterase inhibitory effects in vivo than donepezil hydrochloride. The potential anti-AD activity of vanillin was also confirmed by the reduction in IL-6 levels and TNF-α levels. Our results suggest that vanillin is a safe and effective natural drug candidate having a great potential for the treatment of AD. However, more research is required to evaluate its effect on A beta plaques and Tau neurofibrillary tangles in vivo.

Effects of Electroacupuncture on the Correlation between Serum and Central Immunity in AD Model Animals.

Objective The goal was to investigate the connection between neuroinflammation in the brain and serum inflammatory markers as Alzheimer's disease progressed. We also sought to determine whether electroacupuncture had an effect on inflammatory markers found in blood and other brain regions. Methods As an animal model for AD, we used senescence-accelerated mouse prone 8 (SAMP8) mice. To examine the effects and probable mechanism of electroacupuncture, we used HE staining, immunofluorescence staining, western blotting, and enzyme-linked immunosorbent assay. Results Electroacupuncture therapy protected neurons, significantly downregulated the Iba-1 level in the hippocampus (p value was 0.003), frontal lobe cortex (p value was 0.042), and temporal lobe cortex (p value was 0.013) of the AD animal model, all of which had significantly lower levels of IL-6 (p value was 0.001), IL-1β (p value was 0.001), and TNF-α (p value was 0.001) in their serum. Conclusion The amounts of IL-6, IL-1β, and TNF-α detected in the serum were strongly linked to the levels discovered in the hippocampus and the frontal lobes of the brain, respectively. A better understanding of the electroacupuncture process as well as the course of Alzheimer's disease and the therapeutic benefits of electroacupuncture may be gained by using biomarkers such as serum inflammatory marker biomarkers.

Patchouli alcohol ameliorates the learning and memory impairments in an animal model of Alzheimer's disease via modulating SIRT1

BackgroundAlzheimer's disease (AD) is one of the most prevalent neurodegenerative diseases. Patchouli alcohol (PA), a major active ingredient isolated from Pogostemonis Herba, exhibits extensive bioactivity in the central nervous system (CNS) and exerts neuroprotective effects. PurposeThis study aimed to investigate the anti-AD effects of PA in an animal model of AD and to elucidate the underlying molecular mechanisms. MethodsThe gas chromatography (GC) was used to determine the ability of PA to pass the blood-brain barrier (BBB) in rats after oral administration. The sporadic AD rat model was established by intracerebroventricularly (ICV) injection with streptozotocin (STZ). PA (25 and 50 mg/kg) was given to rat orally once daily for 42 consecutive days. Morris water maze (MWM) test was performed to determine the learning and memory functions of the STZ-induced AD rats. EX527, a silent information regulator 1 (SIRT1) selective inhibitor, was used to investigate the involvement of SIRT1 in the anti-AD effects of PA in rats. ResultsPA could penetrate the BBB. MWM test results showed that PA could significantly ameliorate the learning and memory deficits induced by STZ in rats. Meanwhile, PA enhanced the expression of SIRT1, and markedly alleviated the tau pathology by inhibiting the hyperacetylation (at the site of Lys174) and hyperphosphorylation (at the sites of Thr181, Thr205, Ser396 and Ser404) of tau protein. PA also efficiently suppressed the activation of microglia and astrocytes, and the beta-amyloid (Aβ) expression and the deacetylation of nuclear factor-kappa B (NF-κB) at Lys 310 (K310) in the STZ-treated AD rats. EX527, a SIRT1 selective inhibitor, could partially abolish the cognitive deficits improving effect of PA and inhibit the down-regulation of acetylated tau and acetylated NF-κB p65, suggesting that PA exhibited neuroprotective effects against AD via upregulating SIRT1. ConclusionThis study reported for the first time that PA could penetrate the BBB to exert its protective effects on the brain after a single-dose oral administration. The current experimental findings also amply demonstrated that PA could improve the cognitive and memory impairments in the STZ-induced AD rat model. The underlying mechanisms involve the alleviations of neuroinflammation, tau pathology and Aβ deposition via modulating of SIRT1 and NF-κB pathways. All these findings strongly suggest that PA is a promising naturally occurring compound worthy of further development into an anti-AD pharmaceutical.