Treatment Of AD Research Articles

Alzheimer’s Disease: Treatment Today and Tomorrow

Abstract Background and Aims: The scope of treatment in Alzheimer’s Disease has widened in recent times with FDA approval of new drugs. This review looks at established treatments in AD as well as critically analyses the newer drugs available. Methods: Data in this review was gathered from PubMed; Google Scholar and MEDLINE from January-March 2023. Search words used were ‘Alzheimer’s Disease treatment’ and ‘Dementia treatment’. Results: Older time tested drugs like Acetyl Choline Receptor Inhibitors and NMDA Receptor antagonists remain the mainstay of pharmacological treatment in AD. Despite a lot of excitement about newer FDA approved drugs; we have to be cautious in their use. Aducanumab showed good reduction in CSF amyloid levels (biomarker of AD); but this did not necessarily translate into better clinical outcomes of patients. Conclusion: Despite the recent advances and approval of drugs in treatment of AD, we have to exhibit caution while prescribing these drugs. Even with a sound mechanism of action, these drugs do not always show improvement in clinical outcomes. More clinical trials are required for development of drugs in treatment of AD which explore various different mechanisms of action.

Systematic druggable genome-wide Mendelian randomisation identifies therapeutic targets for Alzheimer’s disease

BackgroundAlzheimer’s disease (AD) is the leading cause of dementia. Currently, there are no effective disease-modifying treatments for AD. Mendelian randomisation (MR) has been widely used to repurpose licensed drugs and...

Targeting the post-synaptic proteome has therapeutic potential for psychosis in Alzheimer Disease

Individuals with Alzheimer Disease who develop psychotic symptoms (AD + P) experience more rapid cognitive decline and have reduced indices of synaptic integrity relative to those without psychosis (AD-P). We sought to determine whether the postsynaptic density (PSD) proteome is altered in AD + P relative to AD-P, analyzing PSDs from dorsolateral prefrontal cortex of AD + P, AD-P, and a reference group of cognitively normal elderly subjects. The PSD proteome of AD + P showed a global shift towards lower levels of all proteins relative to AD-P, enriched for kinases, proteins regulating Rho GTPases, and other regulators of the actin cytoskeleton. We computationally identified potential novel therapies predicted to reverse the PSD protein signature of AD + P. Five days of administration of one of these drugs, the C-C Motif Chemokine Receptor 5 inhibitor, maraviroc, led to a net reversal of the PSD protein signature in adult mice, nominating it as a novel potential treatment for AD + P.

Chinese medicine monomers in the treatment of Alzheimer’s disease: Some preclinical findings

AbstractBackgroundMost of the FDA approved drugs for AD are symptom driven and effects are limited. Because AD is a complex disease involving multiple pathological changes, such as senile plaques formed by amyloid‐β (Aβ) deposition, neurofibrillary tangles caused by tau hyperphosphorylation, microglia‐evoked neuroinflammation, synaptic degeneration, and blood‐brain barrier (BBB) disruption. While the current anti‐dementia drugs are mostly single targets, Chinese medicines have great development potential considering their multi‐target anti‐dementia components.MethodSeveral Chinese medicine monomers, including cryptotanshinone (CTS), pterostilbene (PTE), Ginsenoside Compound K (GCK), and glabridin (Gla) were selected to test their safety and efficacy in AD cell models, and to further explore their possible molecular mechanisms and target of action. Aβ42 oligomers (AβO) were used to establish AD cell models. The cytotoxicity of AβO as well as protective effects of Chinese medicine monomers on cell models were evaluated using the MTT assay. The molecular mechanisms and pathways were tested using qRT‐PCR, ELISA, Western blot and immunofluorescence.ResultAβO induced cell injury, apoptosis, and generation of intracellular reactive oxygen species (ROS). In AβO‐induced cell models, CTS significantly reduced tau hyperphosphorylation at Ser202, Ser404, Thr181, and Thr231, and increased the levels of PSD95 and synaptophysin; PTE attenuated cell injury, apoptosis, and ROS generation; GCK diminished inflammatory cytokine production; Gla attenuated cell injury (figure1). Further study found that their mechanisms of action include PI3K/Akt/GSK3β pathway (figure2), BBB permeability and tight junction scaffold protein (figure3), as well as NF‐kB pathway via LRP1 activation (figure4), respectively.ConclusionThese results provides rational basis for the therapeutic application of Chinese medicine monomers in the treatment of AD, and support further evaluation of these multi‐target action potential in AD treatment.

Multiple target‐based combination therapy of galantamine, memantine and fisetin for the possible treatment of Alzheimer’s disease

AbstractDementia is defined by problems associated with memory, communication, problem‐solving, and other thinking abilities that impair a person’s capacity to carry out daily activities. Alzheimer’s disease is one of the them in which cognitive functions get declined. Globally, more than 44 million people are diagnosed with dementia till 2021. The Pathophysiology of Alzheimer’s disease is degeneration of acetylcholine neurons in the cerebral cortex and hippocampus parts of the brain, enhanced oxidative stress, neuroinflammation, mitochondrial dysfunction. Many clinical and preclinical studies have been reported on the treatment of AD but a very limited number of drugs have found a clinical application. Because regeneration of neurons is a complicated process due to the involvement of multiple pathways, a combination of drugs that can work through multiple pathways could prove to be effective in treating AD. Based on prior studies and different mechanisms involved in the treatment, a new hypothesis has been proposed that a combination of galantamine, memantine and fisetin is anticipated to produce better activity as compared to the current therapies available in market for the treatment of this disease.

Alpha‐secretase ADAM10 as a blood‐based biomarker in Alzheimer’s disease and type 2 diabetes mellitus

AbstractBackgroundAD (Alzheimer’s disease) is a progressive neurodegenerative disease characterized by extensive neuronal losses and deposits of neurofibrillary tangles and senile plaques. Patients with T2DM (type 2 diabetes mellitus) have structural brain changes and cognitive impairment, with a high risk of developing AD. These data suggest that insulin may play a key role in brain activity and memory formation. Based on these findings, AD has been called by some researchers T3DM (type 3 diabetes mellitus) or cerebral diabetes. Our group has been studying peripheral biomarkers for AD since 2010. Among them, our focus is the study of ADAM10 (A Disintegrin And Metalloprotease), an α‐secretase that inhibits the formation of senile plaques and, therefore, is protective against AD. We observed that this protein is decreased in platelets and increased in plasma of elderly people with this dementia compared to cognitively healthy elderly people.MethodThe participants of this research were people aged 60 or over, divided into 4 groups: participants with AD, participants with T2DM, participants with AD and concomitant presence of T2DM and cognitively unimpaired (CU) controls with regular plasma glucose levels. In this work, due to the COVID‐19 pandemic, we are presenting the results of a pilot trial carried out with data collected from 9 participants in each group. Patients’ blood was collected and plasma was used in assays to determine ADAM10 levels using an ADAM10‐specific Enzyme‐Linked Immunosorbent Assay (ELISA) kit (Life Sciences, catalog number LS‐F23768). Results were confirmed using SDS‐PAGE followed by western blotting analyses with the primary antibody anti‐ADAM10 (Ab39180 rabbit, Abcam). A “young control” performed with plasma samples from a young donnor and soroalbumin bands were used as endogen controls to avoid interassay biases in the densitometry analyses.ResultPlasma ADAM10 was elevated in persons with AD and T2DM and these levels were even higher when plasma from patients with both diseases was analysed.ConclusionThis study shows a clinical impact related to a new approach that could be used in the treatment of AD, also observing the metabolic and inflammatory states of the patients. Study also contributes to a better understanding of the biology of the disease itself.

Intranasal Delivery of Leuprolide Acetate Chitosan Nanoparticles for Treatment of Alzheimer’s Disease

Background: Alzheimer’s is one of the primary causes and the most prevalent form of age-related dementia worldwide. There is an urgent surge to find an effective treatment for AD due to its social implications on society. Aim: Present research work aims to develop Chitosan nanoparticles of leuprolide acetate for the treatment of Alzheimer’s disease by delivery through the intranasal route. Methods: Chitosan nanoparticles encapsulating leuprolide acetate were prepared using the ionic ge-lation method and optimized using a central composite design. The optimized nanoparticles were evaluated by DSC study, TEM analysis, release study of the drug in vitro and ex vivo, histopatholo-gy study, and accelerated stability study, In vivo kinetic and dynamic study. Results: The optimized formulation exhibited particle size of 254.3 ± 10.7 nm, % EE of 85.6 ± 0.8 %, and zeta potential of +18.0 ± 0.2 mv. The release of drug from optimized nanoparticles in vitro was in a sustained manner, with only 75.7 % drug released at 48 hours. Higher permeation of the drug from nanoparticles (Papp =5.44 ± 0.34 x 104) was observed in the diffusion study ex vivo. Sheep nasal toxicity and accelerated stability study proved the intranasal safety and stability of the developed formulation. The in vivo drug uptake study indicated a greater brain drug concentration from chitosan nanoparticles than from plain drug solution. The anti-Alzheimer potential was also evident from behavioural studies and histopathology study of rat brain. Conclusion: Thus, the chitosan nanoparticulate formulation of leuprolide acetate was found to have great potential for Alzheimer’s disease management.

Virtual Screening of a Marine Natural Product Database for In Silico Identification of a Potential Acetylcholinesterase Inhibitor.

Alzheimer's disease is characterized by amyloid-beta aggregation and neurofibrillary tangles. Acetylcholinesterase (AChE) hydrolyses acetylcholine and induces amyloid-beta aggregation. Acetylcholinesterase inhibitors (AChEI) inhibit this aggregation by binding to AChE, making it a potential target for the treatment of AD. In this study, we have focused on the identification of potent and safe AChEI from the Comprehensive Marine Natural Product Database (CMNPD) using computational tools. For the screening of CMNPD, a structure-based pharmacophore model was generated using a structure of AChE complexed with the co-crystallized ligand galantamine (PDB ID: 4EY6). The 330 molecules that passed through the pharmacophore filter were retrieved, their drug-likeness was determined, and they were then subjected to molecular docking studies. The top ten molecules were selected depending upon their docking score and were submitted for toxicity profiling. Based on these studies, molecule 64 (CMNPD8714) was found to be the safest and was subjected to molecular dynamics simulations and density functional theory calculations. This molecule showed stable hydrogen bonding and stacked interactions with TYR341, mediated through a water bridge. In silico results can be correlated with in vitro studies for checking its activity and safety in the future.

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.

Roles of ApoE4 on the Pathogenesis in Alzheimer's Disease and the Potential Therapeutic Approaches.

The Apolipoprotein E ε4 (ApoE ε4) allele, encoding ApoE4, is the strongest genetic risk factor for late-onset Alzheimer's disease (LOAD). Emerging epidemiological evidence indicated that ApoE4 contributes to AD through influencing β-amyloid (Aβ) deposition and clearance. However, the molecular mechanisms of ApoE4 involved in AD pathogenesis remains unclear. Here, we introduced the structure and functions of ApoE isoforms, and then we reviewed the potential mechanisms of ApoE4 in the AD pathogenesis, including the effect of ApoE4 on Aβ pathology, and tau phosphorylation, oxidative stress; synaptic function, cholesterol transport, and mitochondrial dysfunction; sleep disturbances and cerebrovascular integrity in the AD brains. Furthermore, we discussed the available strategies for AD treatments that target to ApoE4. In general, this review overviews the potential roles of ApoE4 in the AD development and suggests some therapeutic approaches for AD. ApoE4 is genetic risk of AD. ApoE4 is involved in the AD pathogenesis. Aβ deposition, NFT, oxidative stress, abnormal cholesterol, mitochondrial dysfunction and neuroinflammation could be observed in the brains with ApoE4. Targeting the interaction of ApoE4 with the AD pathology is available strategy for AD treatments.

3D bioprinting patient-derived induced pluripotent stem cell models of Alzheimer’s disease using a smart bioink

BackgroundAlzheimer’s disease (AD), a progressive neurodegenerative disorder, is becoming increasingly prevalent as our population ages. It is characterized by the buildup of amyloid beta plaques and neurofibrillary tangles containing hyperphosphorylated-tau. The current treatments for AD do not prevent the long-term progression of the disease and pre-clinical models often do not accurately represent its complexity. Bioprinting combines cells and biomaterials to create 3D structures that replicate the native tissue environment and can be used as a tool in disease modeling or drug screening.MethodsThis work differentiated both healthy and diseased patient–derived human induced pluripotent stems cells (hiPSCs) into neural progenitor cells (NPCs) that were bioprinted using the Aspect RX1 microfluidic printer into dome-shaped constructs. The combination of cells, bioink, and puromorphamine (puro)-releasing microspheres were used to mimic the in vivo environment and direct the differentiation of the NPCs into basal forebrain-resembling cholinergic neurons (BFCN). These tissue models were then characterized for cell viability, immunocytochemistry, and electrophysiology to evaluate their functionality and physiology for use as disease-specific neural models.ResultsTissue models were successfully bioprinted and the cells were viable for analysis after 30- and 45-day cultures. The neuronal and cholinergic markers β-tubulin III (Tuj1), forkhead box G1 (FOXG1), and choline acetyltransferase (ChAT) were identified as well as the AD markers amyloid beta and tau. Further, immature electrical activity was observed when the cells were excited with potassium chloride and acetylcholine.ConclusionsThis work shows the successful development of bioprinted tissue models incorporating patient derived hiPSCs. Such models can potentially be used as a tool to screen promising drug candidates for treating AD. Further, this model could be used to increase the understanding of AD progression. The use of patient derived cells also shows the potential of this model for use in personalized medicine applications.

Network pharmacological analysis of the active molecules in Coeloglossum viride var. bacteatum and their anti-Alzheimer’s disease activity through restoration of energy metabolism and inhibition of inflammation

Coeloglossum viride var. bracteatum is an advanced tonic in Tibetan medicine with anti-inflammatory and neuroprotective effects. Therefore, its anti-AD effects and potential targets should be explored. Firstly, a network pharmacological analysis of its bioactive molecules and their targets related to AD was performed, and the anti-inflammatory and energy metabolism modulating effects of its extract (CE) were investigated in LPS-induced astrocytes and BV2 cellular models. Then, inflammatory factors levels, ATP content and real-time energy metabolism were measured by RT-qPCR and Seahorse extracellular flux assays, respectively. Finally, we established a molecule-target network, as well as a PPI network of CE-related targets with AD-related targets, and identified 178 nodes and 2317 edges, yielding key targets that may play an important role in the treatment of AD. CE attenuated LPS-induced inflammation and apoptosis in astrocytes, while also enhancing energy metabolism in BV2 cells. Mechanistically, CE inhibited LPS-induced enhancement of microglia glycolytic activity and improved energy metabolism by inhibiting the HIF-1α/PKM2 signaling axis. Thus, CE is a potential AD therapeutic agent with anti-inflammatory and energy metabolism modulating activities.

Highly functionalized dispiropyrrolidine embedded indandione hybrids as potent cholinesterase inhibitors

New class of highly functionalized dispiropyrrolidine tethered indandione heterocycles in good yield were obtained through stereo- and regioselective single-pot three component cycloaddition methodology between benzylidene-indandione and non-stabilized azomethine ylide. The ylide generated from active diketone and aminophenylpropanoic acid via dehydration/decarboxylative pathway. The synthesized dispiropyrroldine comprising indandiones were elucidated through 1H and 13C NMR spectroscopic analysis, the stereo and regioselective formation of the dispiropyrrolidine were unequivocally assigned by X-ray diffraction analysis. Compound thus synthesized were assayed as potential inhibitor for the treatment of AD. Spiropyrrolidine 4h that bearing methoxy group on the phenyl ring showed significant activity, IC50 of 3.24 ± 0.25 and 10.25 ± 0.16 μM against acetyl and butyryl cholinesterase enzyme, respectively. The lead compound 4h executed to investigate for their docking simulation that showed strong binding affinity with binding site of the cholinesterase protein.

An Update on Autophagy as a Target in the Treatment of Alzheimer's Disease.

Proteostasis is crucial for the maintenance and proper operation of cells. Under typical circumstances, the ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway are used to clean out undesired, damaged, misfolded, or aggregated proteins. Any dysregulation in the above-mentioned pathways leads to neurodegeneration. One of the most renowned neurodegenerative disorders is AD. This condition is more prevalent in senior people and is frequently linked to dementia, progressive memory loss, and cognitive function decline, which further contributes to cholinergic neuron degradation and synaptic plasticity loss. Extracellular accumulation of amyloid beta plaques and the intraneuronal deposition of misfolded neurofibrillary tangles are two prime pathological reasons for AD. At present, there is no treatment for AD. All that remains available is the symptomatic treatment of this disease. Autophagy is the major mechanism by which the cells degrade the protein aggregates. Deposited immature autophagic vacuoles (AVs) in AD brains suggest interruption of a person's normal autophagy process. This review has briefly covered various forms and mechanisms of autophagy. Furthermore, the discussion in the article is supported by different ways and mechanisms via which autophagy can be stimulated in a beneficial way and can emerge as a novel target in the treatment of various metabolic CNS related disorders. In the current review article, the mTOR-dependent ones are PI3K/Akt/TSC/mTOR, AMPK/TSC/mTOR, and Rag/mTOR pathways and mTOR-independent ones which include Ca2+/calpain, inositol-dependent, cAMP/EPAC/PLC, and JNK1/Beclin-1/PI3K pathways have been discussed in details. The article sheds light on drugs which are validated with details in tabular form from recent updates in clinical trials.

Development of the "hidden" multi-target-directed ligands by AChE/BuChE for the treatment of Alzheimer's disease.

Accumulation of evidences suggested that excessive amounts of AChE and BuChE in the brain of AD patients at the different stage of AD, which could hydrolyze ACh and accelerated Aβ aggregation. To develop new "hidden" multifunctional agents through AChE/BuChE would be a promising strategy to treat AD. To this end, firstly, a series of chalcone derivatives with chelating property was designed and synthesized. The in vitro results showed that compound 3f indicated significant selective MAO-B inhibitory activity (IC50=0.67μM) and remarkable anti-inflammatory property. It also significantly inhibited self-induced Aβ1-42 aggregation and showed remarkable neuroprotective effects on Aβ25-35-induced PC12cell injury. Furthermore, compound 3f was a selective metal chelator and could inhibit Cu2+-induced Aβ1-42 aggregation. Based on this, the carbamate fragment was introduced to compound 3f to obtain carbamate derivatives. The biological activity results exhibited that compound 4b showed good BBB permeability, good AChE inhibitory potency (IC50=5.3μM), moderate BuChE inhibitory potency (IC50=12.4μM), significant MAO-B inhibitory potency, anti-inflammation potency on LPS-induced BV-2cells and neuroprotective effects on Aβ25-35-induced PC12cell injury. Compared with 3f, compound 4b did not show obvious chelation property. Significantly, compound 4b could be activated by AChE/BuChE following inhibition of AChE/BuChE to liberate an active multifunctional chelator 3f, which was consistent with our original intention. More importantly, compounds 3f and 4b presented favorable ADME properties and good stability in artificial gastrointestinal fluid, blood plasma and rat liver microsomes. The in vivo results suggested that compound 4b (0.0195μg/mL) could significantly improve dyskinesia and reaction capacity of the AlCl3-induced zebrafish AD model by increasing the level of ACh. Together our data suggest that compound 4b was a promising "hidden" multifunctional agent by AChE/BuChE, and this strategy deserved further development for the treatment of AD.

Therapeutic potential of aromatic plant extracts in Alzheimer's disease: Comprehensive review of their underlying mechanisms.

The aim of this review is to outline recent advancements in the application and mechanistic studies of aromatic plant extracts in Alzhermer`s disease (AD) to demonstrate their value in the management of this disease. AD is a neurodegenerative disease with a complex pathogenesis characterized by severe cognitive impairment. Currently, there are very few drugs available for the treatment of AD, and treatments are primarily focused on symptom relief. Aromatherapy is a traditional complementary alternative therapy that focuses on the prevention and treatment of the disease through the inhalation or transdermal administration of aromatic plant extracts. Over the past few years, studies on the use of aromatic plant extracts for the treatment of AD have been increasing and have demonstrated a definitive therapeutic effect. We systematically summarized in vitro, in vivo, and clinical studies focusing on the potential use of aromatic plant extracts in the treatment of AD in PubMed, ScienceDirect, Google Scholar, and the Chinese National Knowledge Infrastructure from 2000 to 2022. Our literature survey indicatesthat aromatic plant extracts exert anti-AD effects by modulating pathological changes through anti-amyloid, anti-tau phosphorylation, anti-cholinesterase, anti-inflammation, and anti-oxidative stress mechanisms (Figure 1). This review provides a future strategy for the research of novel anti-AD drugs from aromatic plant extracts.

New Treatment of Alzheimers Disease

Alzheimers disease is a major degenerative disease characterized by impaired memory, aphasia, apraxia and the changes of personality and behavior. As the population ages, the incidence of AD is increasing. According to an analysis of 10000 people with up to 30 years of follow-up data, elderly over 55 years old, the risk of dementia increased nearly four- fold if they have three or more chronic diseases at the age of 55. The pathogenesis of AD has not been fully studied, a lot of mechanisms such as neuroinflammation, mitochondrial dysfunction, abnormal metabolic are related to the pathology of AD. The abnormal deposition of A and hyperphosphorylation of Tau protein are identified mechanism of AD. Finding new drugs for AD has always been a research hotpot, preclinical work of new anti-AD drugs is being carried out on a large scale in the world. However, in all types of new developing drugs for AD, the failure rate is about 99%. The drugs approved to treat AD such as acetylcholinesterase inhibitors and glutamate receptor antagonists, only slow symptoms other than change the progression of this disease. Deep researches are required to study the pathogenesis of AD, developing drugs that can reverse the progression is the key to the treatment for AD. This review introduces new developing therapy and potential targets of future research into treatments of AD.

Diagnosis of Alzheimer’s Disease Using EEG

A progressive neurologic disorder which causes the brain to contract and brain cells to die is known as Alzheimer’s disease. An issue related to this is always there that is to recognise it at its earliest stages. It can be acknowledged once the patient suffers from Mild Cognitive Impairment (MCI) and at that stage it cannot be cured as treatment of AD is not available right now that can alter its effect, they can only hinder its advancement. The base of this research paper are journal articles published on brain signals and diagnosis based on image processing of AD that are published in recent years. The field of magneto encephalogram (MEG) signal processing and electroencephalogram (EEG) are reviewed. The following methods are examined for image analysis: magnetic resonance imaging (MRI), functional MRI, structural MRI and diffusion tensor MRI. Detection and Diagnosis of AD during the early onset of a disease using computer and AI based technologies will influence the future of the treatment of this disease to a greater extent. These technological advancements will serve the doctors by aiding in the process of early diagnosis. In the medical world the earlier we make a diagnosis the better it is for the patient. These will help in creating a well thought and timed treatment of the disease. Hence, reducing its effects and progression

Research Progress in Pharmacological Action of Dehydroevodiamine

Dehydroevodiamine is a traditional Chinese medicine monomer extracted from the herb Fructus officinalis, which can inhibit inflammation and reduce oxidative stress. Dehydroevodiamine has anti-amnesia effect in nervous system. Dehydroevodiamine can reduce memory dysfunction, perhaps by activating antioxidant stress and inhibiting the production of brain Aβ. The combination of acetylcholinesterase with dehydroevodiamine is relatively stable, which is expected to be a potential drug for the treatment of AD. In the cardiovascular system, dehydroevodiamine can lower blood pressure and slow down the heart rate. In gastric diseases, dehydroevodiamine has the effect of protecting gastric mucosa and improving gastric ulcer. dehydroevodiamine can reduce arthritis; dehydroevodiamine has antitumor effect. Some studies have also shown that dehydroevodiamine plays a role in liver-related diseases, but the mechanism is not completely clear. We intend to search the literature related to dehydroevodiamine officinalis and review the pharmacological research progress of dehydroevodiamine officinalis on related diseases.

Compensatory remodeling of a septo-hippocampal GABAergic network in the triple transgenic Alzheimer’s mouse model

BackgroundAlzheimer’s disease (AD) is characterized by a progressive loss of memory that cannot be efficiently managed by currently available AD therapeutics. So far, most treatments for AD that have the potential to improve memory target neural circuits to protect their integrity. However, the vulnerable neural circuits and their dynamic remodeling during AD progression remain largely undefined.MethodsCircuit-based approaches, including anterograde and retrograde tracing, slice electrophysiology, and fiber photometry, were used to investigate the dynamic structural and functional remodeling of a GABAergic circuit projected from the medial septum (MS) to the dentate gyrus (DG) in 3xTg-AD mice during AD progression.ResultsWe identified a long-distance GABAergic circuit that couples highly connected MS and DG GABAergic neurons during spatial memory encoding. Furthermore, we found hyperactivity of DG interneurons during early AD, which persisted into late AD stages. Interestingly, MS GABAergic projections developed a series of adaptive strategies to combat DG interneuron hyperactivity. During early-stage AD, MS-DG GABAergic projections exhibit increased inhibitory synaptic strength onto DG interneurons to inhibit their activities. During late-stage AD, MS-DG GABAergic projections form higher anatomical connectivity with DG interneurons and exhibit aberrant outgrowth to increase the inhibition onto DG interneurons.ConclusionWe report the structural and functional remodeling of the MS-DG GABAergic circuit during disease progression in 3xTg-AD mice. Dynamic MS-DG GABAergic circuit remodeling represents a compensatory mechanism to combat DG interneuron hyperactivity induced by reduced GABA transmission.