Targeting microglial neurotransmitter receptors as a therapeutic approach for Alzheimer’s disease

Alzheimer’s disease(AD)is a neurodegenerative condition that disrupts nerve cell function due to the misfolding and buildup of proteins,resulting in cognitive loss and aberrant behavior.Microglia cellsare one of the crucial immune cells in the central nervous system.Depending on their activation levels,microglia cells in the degenerative phase of AD can serve either neuroprotective or neurotoxic roles.Microglia cells express several neurotransmitter receptors that play distinct functions in the degenerative progression of AD.These receptors facilitate bidirectional communication between microglia and nerve cells.The neurotransmitter receptors on microglia cells can mediate or affect the neuroprotective or toxic effects of microglia cells,thereby affecting AD pathology.This paper focuses on the gamma-aminobutyric acid,glutaminergic,cannabinoid,cholinergic,and adrenergic receptors on microglia cells and their relationship with AD.Understanding how neurotransmitter receptors on microglia function in AD will be crucial for identifying potential treatment targets.

Modulation of mitochondrial bioenergetics as a therapeutic strategy in Alzheimer＇s disease

Alzheimer’s disease （AD） is an increasingly pressing worldwide public-health, social, political and economic concern. Despite significant investment in multiple traditional therapeutic strategies that have achieved success in preclinical models addressing the pathological hallmarks of the disease, these efforts have not translated into any effective disease-modifying therapies. This could be because interventions are being tested too late in the disease process. While existing therapies provide symptomatic and clinical benefit, they do not fully address the molecular abnormalities that occur in AD neurons. The pathophysiology of AD is complex; mitochondrial bioenergetic deficits and brain hypometabolism coupled with increased mitochondrial oxidative stress are antecedent and potentially play a causal role in the disease pathogenesis. Dysfunctional mitochondria accumulate from the combination of impaired mitophagy, which can also induce injurious inflammatory responses, and inadequate neuronal mitochondrial biogenesis. Altering the metabolic capacity of the brain by modulating/potentiating its mitochondrial bioenergetics may be a strategy for disease prevention and treatment. We present insights into the mechanisms of mitochondrial dysfunction in AD brain as well as an overview of emerging treatments with the potential to prevent, delay or reverse the neurodegenerative process by targeting mitochondria.

Interplay between microglia and environmental risk factors in Alzheimer's disease

Alzheimer s disease,among the most common neurodegenerative disorders,is chara cterized by progressive cognitive impairment.At present,the Alzheimer’s disease main risk remains genetic ris ks,but major environmental fa ctors are increasingly shown to impact Alzheimer’s disease development and progression.Microglia,the most important brain immune cells,play a central role in Alzheimer’s disease pathogenesis and are considered environmental and lifestyle"sensors."Factors like environmental pollution and modern lifestyles(e.g.,chronic stress,poor dietary habits,sleep,and circadian rhythm disorde rs)can cause neuroinflammato ry responses that lead to cognitive impairment via microglial functioning and phenotypic regulation.However,the specific mechanisms underlying interactions among these facto rs and microglia in Alzheimer’s disease are unclear.Herein,we:discuss the biological effects of air pollution,chronic stress,gut micro biota,sleep patterns,physical exercise,cigarette smoking,and caffeine consumption on microglia;consider how unhealthy lifestyle factors influence individual susceptibility to Alzheimer’s disease;and present the neuroprotective effects of a healthy lifestyle.Toward intervening and controlling these environmental risk fa ctors at an early Alzheimer’s disease stage,understanding the role of microglia in Alzheimer’s disease development,and to rgeting strategies to to rget microglia,co uld be essential to future Alzheimer’s disease treatments.

Sorl1 knockout inhibits expression of brain-derived neurotrophic factor:involvement in the development of late-onset Alzheimer's disease

Sortilin-related receptor 1(SORL1)is a critical gene associated with late-onset Alzheimer’s disease.SORL1 contributes to the development and progression of this neurodegenerative condition by affecting the transport and metabolism of intracellularβ-amyloid precursor protein.To better understand the underlying mechanisms of SORL1 in the pathogenesis of late-onset Alzheimer s disease,in this study,we established a mouse model of SorI1 gene knockout using cluste red regularly inters paced short palindro mic repeats-associated protein 9 technology.We found that Sorl1-knocko ut mice displayed deficits in learning and memory.Furthermore,the expression of brain-derived neurotrophic factor was significantly downregulated in the hippocampus and co rtex,and amyloidβ-protein deposits were observed in the brains of 5orl1-knockout mice.In vitro,hippocampal neuronal cell synapses from homozygous Sorl1-knockout mice were impaired.The expression of synaptic proteins,including Drebrin and NR2B,was significantly reduced,and also their colocalization.Additionally,by knocking out the Sorl1 gene in N2a cells,we found that expression of the N-methyl-D-aspartate receptor,NR2B,and cyclic adenosine monophosphate-response element binding protein was also inhibited.These findings suggest that SORL1 participates in the pathogenesis of late-onset Alzheimer s disease by regulating the N-methyl-D-aspartate receptor NR2B/cyclic adenosine monophosphate-response element binding protein signaling axis.

Genetic association of urokinase-type plasminogen activator gene rs2227564 site polymorphism with sporadic Alzheimer's disease in the Han Chinese population

A missense C/T polymorphism in exon 6 （the NCBI rslD is rs2227564） of the urokinase-type plasminogen activator gene has been identified as a possible hot spot for Alzheimer＇s disease risk. The present study analyzed urokinase-type plasminogen gene polymorphisms of rs2227564 with sporadic Alzheimer＇s disease by PCR-restriction fragment length polymorphism. Results showed that CC, CT and TT genotype distribution frequencies had significant differences between sporadic Aizheimer＇s disease patients and healthy controls, in-depth analysis of the association between urokinase-type plasminogen gene rs2227564 polymorphisms and sporadic Alzheimer＇s disease indicated that people with the C-positive genotype CC ＋ CT were at a higher risk for developing sporadic Alzheimer＇s disease. These results support the contribution of the polymorphisms of rs2227564 in the urokinase-type plasminogen gene to the pathogenesis of sporadicAIzheimer＇s disease in the Han Chinese population.

The neuroprotective effects of oxygen therapy in Alzheimer’s disease:a narrative review

Alzheimer’s disease(AD)is a degenerative neurological disease that primarily affects the elderly.Drug therapy is the main strategy for AD treatment,but current treatments suffer from poor efficacy and a number of side effects.Non-drug therapy is attracting more attention and may be a better strategy for treatment of AD.Hypoxia is one of the important factors that contribute to the pathogenesis of AD.Multiple cellular processes synergistically promote hypoxia,including aging,hypertension,diabetes,hypoxia/obstructive sleep apnea,obesity,and traumatic brain injury.Increasing evidence has shown that hypoxia may affect multiple pathological aspects of AD,such as amyloid-beta metabolism,tau phosphorylation,autophagy,neuroinflammation,oxidative stress,endoplasmic reticulum stress,and mitochondrial and synaptic dysfunction.Treatments targeting hypoxia may delay or mitigate the progression of AD.Numerous studies have shown that oxygen therapy could improve the risk factors and clinical symptoms of AD.Increasing evidence also suggests that oxygen therapy may improve many pathological aspects of AD including amyloid-beta metabolism,tau phosphorylation,neuroinflammation,neuronal apoptosis,oxidative stress,neurotrophic factors,mitochondrial function,cerebral blood volume,and protein synthesis.In this review,we summarized the effects of oxygen therapy on AD pathogenesis and the mechanisms underlying these alterations.We expect that this review can benefit future clinical applications and therapy strategies on oxygen therapy for AD.

Current concept on the pathogenesis of inflammatory bowel disease-crosstalk between genetic and microbial factors:Pathogenic bacteria and altered bacterial sensing or changes in mucosal integrity take"toll"?

The pathogenesis of inflammatory bowel disease （IBD） is only partially understood. Various environmental and host （e.g. genetic-, epithelial-, immune and nonimmune） factors are involved. It is a multifactorial polygenic disease with probable genetic heterogeneity. Some genes are associated with IBD itself, while others increase the risk of ulcerative colitis （UC） or Crohn＇ s disease （CD） or are associated with disease location and/or behaviour. This review addresses recent advances in the genetics of IBD. The article discusses the current information on the crosstalk between microbial and genetic factors （e.g. NOD2/CARD15, SLC22A46A5 and DLG5）. The genetic data acquired in recent years help in understanding the pathogenesis of IBD and can identify a number of potential targets for therapeutic intervention. In the future, genetics may help more accurately diagnose and predict disease course in IBD.

Thrombosis and inflammatory bowel disease-the role of genetic risk factors

Thromboembolism is a significant cause of morbidity and mortality in patients with inflammatory bowel disease （IBD）. Recent data suggest thromboembolism as a disease-specific extraintestinal manifestation of IBD, which is developed as the result of multiple interactions between acquired and genetic risk factors. There is evidence indicating an imbalance of procoagulant, anticoagulant and fibrinolitic factors predisposing in thrombosis in patients with IBD. The genetic factors that have been suggested to interfere in the thrombotic manifestations of IBD include factor V Leiden, factor Ⅱ （prothrombin, G20210A）, methylenetetrahydrofolate reductase gene mutation （MTHFR, 6777T, plasminogen activator inhibitor type 1 （PAI-1） gene mutation and factor X Ⅲ （val34leu）. In this article we review the current data and future prospects on the role of genetic risk factors in the development of thromboembolism in TBD.

Inhibiting 5-hydroxytryptamine receptor 3 alleviates pathological changes of a mouse model of Alzheimer's disease

Extracellular amyloid beta(Aβ) plaques are main pathological feature of Alzheimer’s disease.However,the specific type of neuro ns that produce Aβ peptides in the initial stage of Alzheimer’s disease are unknown.In this study,we found that 5-hydroxytryptamin receptor 3A subunit(HTR3A) was highly expressed in the brain tissue of transgenic amyloid precursor protein and presenilin-1 mice(an Alzheimer’s disease model) and patients with Alzheimer’s disease.To investigate whether HTR3A-positive interneurons are associated with the production of Aβ plaques,we performed double immunostaining and found that HTR3A-positive interneurons were clustered around Aβ plaques in the mouse model.Some amyloid precursor protein-positive or β-site amyloid precursor protein cleaving enzyme-1-positive neurites near Aβ plaques were co-localized with HTR3A interneurons.These results suggest that HTR3A-positive interneurons may partially contribute to the generation of Aβ peptides.We treated 5.0-5.5-month-old model mice with tro pisetron,a HTR3 antagonist,for 8 consecutive weeks.We found that the cognitive deficit of mice was partially reversed,Aβ plaques and neuroinflammation we re remarkably reduced,the expression of HTR3 was remarkably decreased and the calcineurin/nuclear factor of activated T-cell 4 signaling pathway was inhibited in treated model mice.These findings suggest that HTR3A interneurons partly contribute to generation of Aβ peptide at the initial stage of Alzheimer’s disease and inhibiting HTR3 partly reve rses the pathological changes of Alzheimer’s disease.

Hyperbaric Oxygen and Ginkgo Biloba Extract Ameliorate Cognitive and Memory Impairment via Nuclear Factor Kappa-B Pathway in Rat Model of Alzheimer＇s Disease

Background： Hyperbaric oxygen （HBO） and Ginkgo biloba extract （e.g., EGB 761） were shown to ameliorate cognitive and memory impairment in Alzheimcr＇s disease （AD）. However, the exact mechanism remains elusive. The aim of the present study was to investigate the possible mechanisms of HBO and EGB 761 via the function of nuclear factor kappa-B （NF-κB） pathway. Methods： AD rats were induced by injecting β-amyloid 25-35 into the hippocampus. All animals were divided into six groups： Normal. sham. AD model, HBO （2 atmosphere absolute： 60 min/d）, EGB 761 （20 mg·kg^-1 ·d ^-1）, and HBO/EGB 761 groups. Morris water maze tests were used to assess cognitive, and memory capacities of rats： TdT-mediated dUTP Nick-End Labeling staining and Western blotting were used to analyze apoptosis and NF-κB pathway-related proteins in hippocampus tissues. Results： Morris water maze tests revealed that EGB 761 and HBO significantly improved the cognitive and memory ability of AD rats. In addition, the protective effect of combinational therapy （HBO/EGB 761 ） was superior to either HBO or EGB 761 alone. In line. redticed apoptosis with NF-κB pathway activation was observed in hippocampus neurons treated by HBO and EGB 761. Conclusions： Our results suggested that HBO and EGB 761 improve cognitive and memory capacity in a rat model of AD. The protective effects are associated with the reduced apoptosis with NF-κB pathway activation in hippocampus neurons.

Effects of lateral ventricular transplantation of bone marrow-derived mesenchymal stem cells modified with brain-derived neurotrophic factor gene on cognition in a rat model of Alzheimer's disease

In the present study, transplantation of bone marrow-derived mesenchymal stem cells modified with brain-derived neurotrophic factor gene into the lateral ventricle of a rat model of Alzheimer＇s disease, resulted in significant attenuation of nerve cell damage in the hippocampal CA1 region. Furthermore, brain-derived neurotrophic factor and tyrosine kinase B mRNA and protein levels were significantly increased, and learning and memory were significantly improved. Results indicate that transplantation of bone marrow-derived mesenchymal stem cells modified with brain-derived neurotrophic factor gene can significantly improve cognitive function in a rat model of Alzheimer＇s disease, possibly by increasing the levels of brain-derived neurotrophic factor and tyrosine kinase B in the hippocampus.

Exogenous brain-derived neurotrophic factor attenuates cognitive impairment induced by okadaic acid in a rat model of Alzheimer's disease

Decreased expression of brain-derived neurotrophic factor（BDNF） plays an important role in the pathogenesis of Alzheimer＇s disease, and a typical pathological change in Alzheimer＇s disease is neurofibrillary tangles caused by hyperphosphorylation of tau. An in vivo model of Alzheimer＇s disease was developed by injecting okadaic acid（2 μL） and exogenous BDNF（2 μL） into the hippocampi of adult male Wister rats. Spatial learning and memory abilities were assessed using the Morris water maze. The expression levels of protein phosphatase 2 A（PP2 A）, PP2 Ac-Yp307, p-tau（Thr231）, and p-tau（Ser396/404） were detected by western blot assay. The expression levels of BDNF, TrkB, and synaptophysin mRNA were measured by quantitative real-time polymerase chain reaction. Our results indicated that BDNF expression was suppressed in the hippocampus of OA-treated rats, which resulted in learning and memory deficits. Intra-hippocampal injection of BDNF attenuated this OA-induced cognitive impairment. Finally, our findings indicated an involvement of the PI3 K/GSK-3β/AKT pathway in the mechanism of BDNF in regulating cognitive function. These results indicate that BDNF has beneficial effect on Alzheimer＇s disease, and highlight the potential of BDNF as a drug target for treatment of Alzheimer＇s disease.

Vascular factors in Alzheimer’s disease

The vascular factor in Alzheimer’s disease (AD), affecting its development and progression, is one of the most urgent problems of modern neuroangiology. The research investigates the characteristics of cerebral angioarchitectonics identified at different stages of AD. The research included 106 patients: 1) The Test Group—47 patients suffering from various stages of AD;2) The Control Group—59 patients suffering from the most common lesions of the brain accompanied by neurodegenerative changes, the development of dementia and cognitive impairment, but not having AD. All the patients underwent: the testing of cognitive functions (MMSE), the determination of severity of dementia (CDR) and AD stages (TDR), computed tomography (CT), magnetic resonance imaging (MRI), scintigraphy of the brain (SG), rheoencephalography (REG), and cerebral multigated angiography (MUGA). Patients with AD different stages showed the following changes in angioarchitectonics and microcirculation: Absence of pronounced atherosclerotic lesions of intracranial vessels, reduction of the capillary bed in the temporal and temporo-parietal regions, development of multiple arteriovenous shunts in the same areas, early venous discharge, abnormal expansion of venous trunks that receive blood from arteriovenous shunts, venous congestion at the border of the frontal and parietal region, increased looping of intracranial arteries. Control Group patients had no combination of the abovementioned changes. These vascular changes are specific for AD and are in fact the vascular factor of this disease;they may also be called dyscirculatory angiopathy of Alzheimer’s type (DAAT). Patients suffering from other diseases that are accompanied by neurodegenerative changes in the brain, dementia and cognitive impairment do not have them.

Soluble p75 neurotrophic receptor as a reliable biomarker in neurodegenerative diseases: what is the evidence?

Neurodegenerative diseases are often misdiagnosed,especially when the diagnosis is based solely on clinical symptoms.The p75 neurotrophic receptor(p75^(NTR))has been studied as an index of sensory and motor nerve development and maturation.Its cleavable extracellular domain(ECD)is readily detectable in various biological fluids including plasma,serum and urine.There is evidence for increased p75NTR ECD levels in neurodegenerative diseases such as Alzheimer’s disease,amyotrophic lateral sclerosis,age-related dementia,schizophrenia,and diabetic neuropathy.Whether p75^(NTR) ECD could be used as a biomarker for diagnosis and/or prognosis in these disorders,and whether it could potentially lead to the development of targeted therapies,remains an open question.In this review,we present and discuss published studies that have evaluated the relevance of this emerging biomarker in the context of various neurodegenerative diseases.We also highlight areas that require further investigation to better understand the role of p75^(NTR) ECD in the clinical diagnosis and management of neurodegenerative disorders.

<i>Ratanasampil</i>(Tibetan Medicine, RNSP) Reduces <i>β</i>-Amyloid Protein (Aβ) and Pro-Inflammatory Factor Levels and Improves Cognitive Functions in Mild-to-Moderate Alzheimer’s Disease (AD) Patients Living at High Altitude

Ratanasampil (RNSP) is a traditional Tibetan medicine used for the treatment of stroke and cerebrovascular diseases. Previous discoveries that RNSP can reduce β-amyloid protein levels and increase learning and memory in Alzheimer’s mouse models (Tg2576) led us to investigate whether RNSP can improve cognitive functions in Alzheimer’s patients. In this study, 146 AD patients living in Qinghai province received either one gram or 0.33 gram daily of RNSP for 16 weeks. Placebo patients received Piracetam. Serum Aβ40 and Aβ42 levels were measured at the beginning of the study and after 4 and 16 weeks of treatment. Compared to the same group before treatment, MMSE scores, ADAS-cog scores and ADL scores were significantly improved (p 0.05, p > 0.05). After 16-week treatment, serum TNF-α, IL-1β, IL-6 and Aβ42 levels were significantly decreased (p < 0. 01) in the high-dose RNSP group, whereas no significant differences were found in the low-dose and placebo groups. The Aβ42/Aβ40 ratio was significantly decreased after 4-week and 16-week treatment in the high-dose RNSP group (p < 0. 05, p < 0.01). Furthermore, serum Aβ42 concentrations had a strong positive correlation with TNF-α, IL-1β and IL-6 levels. There were no observable adverse effects in either treatment or control groups. We conclude that further clinical trials of RNSP in Alzheimer disease are warranted.

Repurposed anti-cancer epidermal growth factor receptor inhibitors: mechanisms of neuroprotective effects in Alzheimer’s disease

Numerous molecular mechanisms are being examined in an attempt to discover disease-modifying drugs to slow down the underlying neurodegeneration in Alzheimer’s disease.Recent studies have shown the beneficial effects of epidermal growth factor receptor inhibitors on the enhancement of behavioral and pathological sequelae in Alzheimer’s disease.Despite the promising effects of epidermal growth factor receptor inhibitors in Alzheimer’s disease,there is no irrefutable neuroprotective evidence in well-established animal models using epidermal growth factor receptor inhibitors due to many un-explored downstream signaling pathways.This caused controversy about the potential involvement of epidermal growth factor receptor inhibitors in any prospective clinical trial.In this review,the mystery beyond the under-investigation of epidermal growth factor receptor in Alzheimer’s disease will be discussed.Furthermore,their molecular mechanisms in neurodegeneration will be explained.Also,we will shed light on SARS-COVID-19 induced neurological manifestations mediated by epidermal growth factor modulation.Finally,we will discuss future perspectives and under-examined epidermal growth factor receptor downstream signaling pathways that warrant more exploration.We conclude that epidermal growth factor receptor inhibitors are novel effective therapeutic approaches that require further research in attempts to be repositioned in the delay of Alzheimer’s disease progression.

Back propagation artificial neural network for community Alzheimer's disease screening in China

AIzheimer＇s disease patients diagnosed with the Chinese Classification of Mental Disorders diagnostic criteria were selected from the community through on-site sampling. Levels of macro and trace elements were measured in blood samples using an atomic absorption method, and neurotransmitters were measured using a radioimmunoassay method. SPSS 13.0 was used to establish a database, and a back propagation artificial neural network for Alzheimer＇s disease prediction was simulated using Clementine 12.0 software. With scores of activities of daily living, creatinine, 5-hydroxytryptamine, age, dopamine and aluminum as input variables, the results revealed that the area under the curve in our back propagation artificial neural network was 0.929 （95% confidence interval： 0.868-0.968）, sensitivity was 90.00%, specificity was 95.00%, and accuracy was 92.50%. The findings indicated that the results of back propagation artificial neural network established based on the above six variables were satisfactory for screening and diagnosis of Alzheimer＇s disease in patients selected from the community.

Cellular and molecular mechanisms underlying the action of ginsenoside Rg1 against Alzheimer’s disease

Ginsenoside Rgl inhibits oxidation, aging and ce this study, we pretreated rat brain tissue sections I apoptosis, and improves cognitive function. In with ginsenoside Rgl, and established brain slice models of Alzheimer＇s disease induced by okadaic acid. The results revealed that ginsenoside Rgl pretreatment suppressed the increase in phosphorylated Tau protein expression induced by incubation with okadaic acid, and reduced brain-derived neurotrophic factor expression. These results suggest that ginsenoside Rgl upregulates brain-derived neurotrophic factor expression and inhibits Tau protein phosphorylation in brain slices from a rat model of Alzheimer＇s disease.

The role of small vessel disease in development of Alzheimer's disease

Classically Alzheimer＇s disease and vascular dementia have been considered as two different entities, with their own clinical criteria, but relatively recent epidemiological and clinicopathological studies suggest an overlap between them sharing not only most of the risk factors and some clinical aspects but also pathophysiological mechanisms. Cerebrovascular lesions, especially small vessel disease （lacunar infarcts, white matter hyperintensities and microbleeds）, may magnify the effects of mild Alzheimer＇s disease pathology and promote the progression of cognitive decline and may also be a precursor of neuronal damage and dementia. ＂Vascular hypothesis＂ of Alzheimer＇s disease would open a window for new approaches and treatments.

Synaptic dysfunction in Alzheimer's disease:the effects of amyloid beta on synaptic vesicle dynamics as a novel target for therapeutic intervention

The most prevalent form of dementia in the elderly is Alzheimer＇s disease.A significant contributing factor to the progression of the disease appears to be the progressive accumulation of amyloid-β42（Aβ42）,a small hydrophobic peptide.Unfortunately,attempts to develop therapies targeting the accumulation of Aβ42 have not been successful to treat or even slow down the disease.It is possible that this failure is an indication that targeting downstream effects rather than the accumulation of the peptide itself might be a more effective approach.The accumulation of Aβ42 seems to affect various aspects of physiological cell functions.In this review,we provide an overview of the evidence that implicates Aβ42 in synaptic dysfunction,with a focus on how it contributes to defects in synaptic vesicle dynamics and neurotransmitter release.We discuss data that provide new insights on the Aβ42 induced pathology of Alzheimer＇s disease and a more detailed understanding of its contribution to the synaptic deficiencies that are associated with the early stages of the disease.Although the precise mechanisms that trigger synaptic dysfunction are still under investigation,the available data so far has enabled us to put forward a model that could be used as a guide to generate new therapeutic targets for pharmaceutical intervention.