Effects of Xixin Decoction （洗心汤） on the Diversity of Intestinal Flora and Levels of Aβ1-42，LPS，SAA，and ACH in Brain and Intestinal Tissues of Rapidly Aging Model Mice / 中医杂志

ObjectiveTo observe the possible mechanism of Xixin Decoction （洗心汤， XXD） in the prevention and treatment of Alzheimer 's disease（AD）. MethodsFifty rapid aging model mice （SAMP8） were randomly divided into model group， probiotic group， high-， moderate- and low-dose group of XXD， with 10 mice in each group. Another 10 homologous anti-rapid aging mice （SAMR1） were set as control group. After 10 weeks of feeding， the control group and the model group were given 10 ml·kg-1·d-1 of distilled water by gavage， while the probiotic group （0.39 g·kg-1·d-1）， the high-dose group of XXD （5.08 g·kg-1·d-1）， the moderate-dose group of XXD （2.54 g·kg-1·d-1）， and the low-dose group of XXD （1.27 g·kg-1·d-1） were given corresponding drugs or decoctions by gavage， once a day in all groups. After 10 weeks of intragastric administration， Morris water maze was used to detect the spatial learning and memory ability of mice in each group. HE staining was used to observe the pathological changes of hippocampal CA3 region and colon. The levels of β-amyloid 1-42 （Aβ1-42）， lipopolysaccharide （LPS）， serum amyloid A （SAA） and acetylcholine （ACH） in hippocampus and colon were detected by ELISA.The diversity of intestinal flora in mouse feces was detected by 16S rRNA sequencing. ResultsCompared to those in the control group， the levels of Aβ1-42，LPS， SAA increased， while the level of ACH decreased in the model group （P＜0.05 or P＜0.01）. Compared to those in the model group， the escape latency period of the probiotic group was significantly shortened on the 2nd and 5th days， while the escape latency period was shortened， and the residence time in the target platform quadrant increased in the high-dose XXD group during the 2nd to 5th days； the escape latency period was shortened significantly in the moderate-dose XXD group on the 5th day （P＜0.05 or P＜0.01）. Compared to those in the model group， the hippocampal neuron cells in the high- and moderate-dose XXD groups were arranged more closely， with decreased levels of SAA， Aβ1-42 and LPS， increased ACH level， Simpson and Shannon index （P＜0.05 or P＜0.01）； the arrangement of hippocampal neuron cells in the probiotic group and the low-dose XXD group was relatively loose； the proportions of Bacteroidetes and Prevotella were significantly reduced in the probiotic group and the high-dose XXD group， while that of Firmicutes and Lactobacillus significantly increased （P＜0.05 or P＜0.01）. Compared to those in the probiotic group and the high-dose XXD group， the number of goblet cells in the moderate-dose XXD group decreased， and the number of glands in the low-dose XXD group decreased with atrophy. The high-dose XXD group had decreased Aβ1-42 level in the hippocampus， increased ACH level in thehippocampus and colon tissue， and decreased SAA in the colon tissue than the moderate- and low-dose XXD groups （P＜0.05 or P＜0.01）； moreover， the SAA level in the hippocampus was significantly higher in the low-dose XXD group than the high- and moderate-dose groups （P＜0.01）. ConclusionXXD can improve the spatial learning and memory ability of SAMP8， reduce the production and deposition of LPS， SAA and Aβ1-42 in brain and intestine， and increase the content of ACH. The mechanism of its prevention and treatment of AD maybe related to regulating intestinal microecology， affecting flora diversity and improving inflammatory response.

Effect of aqueous extract of Corni Fructus on Aβ_(25-35)-induced brain injury and neuroinflammation in mice with Alzheimer's disease / 中国中药杂志

The purpose of this study was to investigate the effect of aqueous extract of Corni Fructus on β-amyloid protein 25-35(Aβ_(25-35))-induced brain injury and neuroinflammation in Alzheimer's disease(AD) mice to provide an experimental basis for the treatment of AD by aqueous extract of Corni Fructus. Sixty C57BL/6J male mice were randomly divided into a sham group, a model group, a positive control group(huperizine A, 0.2 mg·kg~(-1)), a low-dose aqueous extract of Corni Fructus group(1.3 g·kg~(-1)), a medium-dose aqueous extract of Corni Fructus group(2.6 g·kg~(-1)), and a high-dose aqueous extract of Corni Fructus group(5.2 g·kg~(-1)). The AD model was induced by lateral ventricular injection of Aβ_(25-35) in mice except for those in the sham group, and AD model mice were treated with corresponding drugs by gavage for 24 days. The behavioral test was performed one week before animal dissection. Hematoxylin-eosin(HE) staining was performed to observe the morphology of neurons in the hippocampal region. Flow cytometry was used to detect the apoptosis level of primary hippocampal cells in mice. ELISA kits were used to detect the levels of β-amyloid protein 1-42(Aβ_(1-42)) and phosphorylated microtubule-associated protein Tau(p-Tau) in mouse brain tissues. Immunofluorescence and Western blot were used to detect the expression of related proteins in mouse brain tissues. MTT assay was used to detect the effect of compounds in aqueous extract of Corni Fructus on Aβ_(25-35)-induced N9 cell injury. Molecular docking was employed to analyze the interactions of caffeic acid, trans-p-hydroxy cinnamic acid, isolariciresinol-9'-O-β-D-glucopyranoside, esculetin, and(+)-lyoniresinol with β-amyloid precursor protein(APP), interleukin-6(IL-6), and tumor necrosis factor-α(TNF-α). Aqueous extract of Corni Fructus could improve the learning and memory abilities of Aβ_(25-35)-induced mice by increasing the duration of the autonomous activity, the rate of autonomous alternation, the preference coefficient, and the discrimination coefficient, and reduce Aβ_(25-35)-induced brain injury and neuroinflammation in mice by increasing the expression levels of interleukin-10(IL-10) and B-cell lymphoma-2(Bcl-2) in brain tissues, decreasing the expression levels of Aβ_(1-42), p-Tau, IL-6, TNF-α, cysteine aspartate-specific protease 3(caspase-3), cysteine aspartate-specific protease 9(caspase-9), and Bcl-2-associated X protein(Bax), and decreasing the number of activated glial cells in brain tissues. The results of cell experiments showed that esculetin and(+)-lyoniresinol could improve Aβ_(25-35)-induced N9 cell injury. Molecular docking results showed that caffeic acid, trans-p-hydroxy cinnamic acid, isolariciresinol-9'-O-β-D-glucopyranoside, esculetin, and(+)-lyoniresinol had good binding affinity with APP and weak binding affinity with IL-6 and TNF-α. Aqueous extract of Corni Fructus could ameliorate cognitive dysfunction and brain damage in Aβ_(25-35)-induced mice by reducing the number of apoptotic cells and activated glial cells in the brain and decreasing the expression level of inflammatory factors. Caffeic acid, trans-p-hydroxy cinnamic acid, isolariciresinol-9'-O-β-D-glucopyranoside, esculetin, and(+)-lyoniresinol may be the material basis for the anti-AD effect of aqueous extract of Corni Fructus.

Drofenine as a Kv2.1 inhibitor alleviated AD-like pathology in mice through A β/Kv2.1/microglial NLRP3/neuronal tau axis / 中国药理学与毒理学杂志

OBJECTIVE Alzheimer disease(AD)is a neurodegenerative disease with clinical hallmarks of pro-gressive cognitive impairment.Synergistic effects of Aβ-tau cascade reaction are tightly implicated in AD patholo-gy,and microglial NLRP3 inflammasome activation drives neuronal tauopathy through microglia and neurons cross-talk.However,the underlying mechanism of how Aβ medi-ates NLRP3 inflammasome remains unclear.Shab related potassium channel member 1(Kv2.1)as a voltage gated po-tassium channel widely distributed in the central nervous system and plays an important role in regulating the out-ward potassium flow in neurons and glial cells.In current work,we aimed to explore the underlying mechanism of Kv2.1 in regulating Aβ/NLRP3 inflammasome/tau axis by using a determined Kv2.1 inhibitor drofenine(Dfe).METHODS Cell-based assays including Western blot-ting and immunofluorescence staining against primary microglia or neurons were carried out to expound the role of Kv2.1 channel in NLRP3 inflammasome activa-tion and subsequent neuronal tau hyperphosphorylation.For animal studies,new object recognition,Y-maze and Morris water maze were performed to evaluate the ame-lioration of Kv2.1 inhibition through either Kv2.1 inhibitor Dfe treatment or adeno-associated virus AAV-ePHP-si-Kv2.1injectionon5×FADADmodel mice.Assays of histol-ogy and immunostaining of tissue sections and Western blotting of brain tissues were performed to verify the con-clusion of cellular assays.RESULTS We reported that oligomeric Aβ(o-Aβ)bound to microglial Kv2.1 and pro-moted Kv2.1-dependent potassium leakage to activate NLRP3 inflammasome through JNK/NF-κB pathway sub-sequently resulting in neuronal tauopathy.Treatment of either Kv2.1 inhibitor Dfe or AAV-ePHP-si-Kv2.1 for brain-specific Kv2.1 knockdown deprived o-A β of its capability in inducing microglial NLRP3 inflammasome activation and neuronal tau hyperphosphorylation,while improved the cognitive impairment of 5×FAD AD model mice.CONCLUSION Our results have highly addressed that Kv2.1 channel is required for o-Aβ driving NLRP3 inflammasome activation and neuronal tauopathy in AD model mice and highlighted that Kv2.1 inhibition is a prom-ising therapeutical strategy for AD and Dfe as a Kv2.1 inhibitor shows potential in the treatment of this disease.

Advance in Traditional Chinese Medicine for Alzheimer's disease by regulating microglia / 中国药理学通报

Microglia, the main immune macrophages in the central nervous system, can be highly involved in the occurrence and development of Alzheimer's disease(AD)through microglia polarization and receptor protein expression. Traditional Chinese Medicine has been demonstrated to have regulatory effects on MG. Many active components in Traditional Chinese herbs play important roles in decreasing β-amyloid peptide(Aβ)accumulation, inhibiting neuro-inflammation and regulating microglia polarization etc. In this study the role of microglia in the pathogenesis of AD and the mechanism by which Traditional Chinese Medicine regulating microglia are reviewed to provide a reference for the treatment of AD.

Histamine H / 中国药理学通报

Aim To determine the effect of histamine H

Improving Blood Monocyte Energy Metabolism Enhances Its Ability to Phagocytose Amyloid-β and Prevents Alzheimer's Disease-Type Pathology and Cognitive Deficits / 神经科学通报·英文版

Deficiencies in the clearance of peripheral amyloid β (Aβ) play a crucial role in the progression of Alzheimer's disease (AD). Previous studies have shown that the ability of blood monocytes to phagocytose Aβ is decreased in AD. However, the exact mechanism of Aβ clearance dysfunction in AD monocytes remains unclear. In the present study, we found that blood monocytes in AD mice exhibited decreases in energy metabolism, which was accompanied by cellular senescence, a senescence-associated secretory phenotype, and dysfunctional phagocytosis of Aβ. Improving energy metabolism rejuvenated monocytes and enhanced their ability to phagocytose Aβ in vivo and in vitro. Moreover, enhancing blood monocyte Aβ phagocytosis by improving energy metabolism alleviated brain Aβ deposition and neuroinflammation and eventually improved cognitive function in AD mice. This study reveals a new mechanism of impaired Aβ phagocytosis in monocytes and provides evidence that restoring their energy metabolism may be a novel therapeutic strategy for AD.

Microglial Depletion does not Affect the Laterality of Mechanical Allodynia in Mice / 神经科学通报·英文版

Mechanical allodynia (MA), including punctate and dynamic forms, is a common and debilitating symptom suffered by millions of chronic pain patients. Some peripheral injuries result in the development of bilateral MA, while most injuries usually led to unilateral MA. To date, the control of such laterality remains poorly understood. Here, to study the role of microglia in the control of MA laterality, we used genetic strategies to deplete microglia and tested both dynamic and punctate forms of MA in mice. Surprisingly, the depletion of central microglia did not prevent the induction of bilateral dynamic and punctate MA. Moreover, in dorsal root ganglion-dorsal root-sagittal spinal cord slice preparations we recorded the low-threshold Aβ-fiber stimulation-evoked inputs and outputs of superficial dorsal horn neurons. Consistent with behavioral results, microglial depletion did not prevent the opening of bilateral gates for Aβ pathways in the superficial dorsal horn. This study challenges the role of microglia in the control of MA laterality in mice. Future studies are needed to further understand whether the role of microglia in the control of MA laterality is etiology-or species-specific.

Targeting Peripheral μ-opioid Receptors or μ-opioid Receptor-Expressing Neurons Does not Prevent Morphine-induced Mechanical Allodynia and Anti-allodynic Tolerance / 神经科学通报·英文版

The chronic use of morphine and other opioids is associated with opioid-induced hypersensitivity (OIH) and analgesic tolerance. Among the different forms of OIH and tolerance, the opioid receptors and cell types mediating opioid-induced mechanical allodynia and anti-allodynic tolerance remain unresolved. Here we demonstrated that the loss of peripheral μ-opioid receptors (MORs) or MOR-expressing neurons attenuated thermal tolerance, but did not affect the expression and maintenance of morphine-induced mechanical allodynia and anti-allodynic tolerance. To confirm this result, we made dorsal root ganglia-dorsal roots-sagittal spinal cord slice preparations and recorded low-threshold Aβ-fiber stimulation-evoked inputs and outputs in superficial dorsal horn neurons. Consistent with the behavioral results, peripheral MOR loss did not prevent the opening of Aβ mechanical allodynia pathways in the spinal dorsal horn. Therefore, the peripheral MOR signaling pathway may not be an optimal target for preventing mechanical OIH and analgesic tolerance. Future studies should focus more on central mechanisms.

Physiological Roles of β-amyloid in Regulating Synaptic Function: Implications for AD Pathophysiology / 神经科学通报·英文版

The physiological functions of endogenous amyloid-β (Aβ), which plays important role in the pathology of Alzheimer's disease (AD), have not been paid enough attention. Here, we review the multiple physiological effects of Aβ, particularly in regulating synaptic transmission, and the possible mechanisms, in order to decipher the real characters of Aβ under both physiological and pathological conditions. Some worthy studies have shown that the deprivation of endogenous Aβ gives rise to synaptic dysfunction and cognitive deficiency, while the moderate elevation of this peptide enhances long term potentiation and leads to neuronal hyperexcitability. In this review, we provide a new view for understanding the role of Aβ in AD pathophysiology from the perspective of physiological meaning.

Preliminary study on the effect of IVIG with different Aβ antibody on cognitive function of Alzheimer′s disease model mice / 中国输血杂志

【Objective】 To investigate the effect of intravenous immunoglobulin(IVIG) with different Aβ antibody content on the cognitive function of Alzheimer′s disease model mice. 【Methods】 IVIG from 8 domestic blood products companies were selected. Enzyme-linked immunosorbent assay(ELISA) was used to detect the content of Aβ40/42 antibody. Three kinds of IVIG with high, middle and low Aβ42/40 antibody levels were selected to treat 3xTg-AD mice. Forty 3-month-old 3xTg-AD mice were randomly divided into 4 groups with 10 mice in each group(half male and half female). Three treat groups were intraperitoneally injected with three kinds of IVIG with 1g·kg-1 for 12 weeks(twice a week). The controls were injected with the same volume of saline. Behavioral tests were performed immediately by using the mouse behavior analysis system after a total of 24 injections. 【Results】 The concentrations of antibodies(μg/mL) against Aβ40 monomer in IVIG ranged 0.7±0.05 to 3.1±0.05, concentrations of antibodies against Aβ40 oligomer ranged 11.7±0.7 to 32.0±2.2, concentrations of antibodies against Aβ42 monomer ranged 1.8±0.1 to 27.9±0.3, and concentrations of antibodies against Aβ42 oligomeric ranged 2.3±0.1 to 49.4±2. High(IVIG-1), medium(IVIG-8) and low(IVIG-6) IVIG were selected for mice study. In the open field test, the time of four groups of mice entering the central area(s) was 0.5±0.9, 23.4±6.1(P<0.0001), 4.6±2.8 and 2.6±2.3, respectively; the number of feces(grains) was 1.6±0.7(P<0.0001), 1.2±0.4(P<0.0001), 2.4±0.5(P<0.001) and 3.8±0.8, respectively. In the novel object recognition test, the scores of exploring new objects were 71.3±29.5(P<0.05), 71.8±20.5(P<0.05), 75.9±26.9(P<0.01) and 25.6±23.7, respectively. In the Barnes maze test, the time of exploring the target hole in the IVIG-8 group was significantly longer than that in the control on the 6th day(50.3±19.3 vs 21±14.6, P<0.05) and the 13th day(58.2±20.9 vs 19.2±15.9, P<0.005), but there was no significant difference between the IVIG-1, 6 groups and the control. 【Conclusion】 There is a significant difference in the level of Aβ40/42 antibody among 8 kinds of domestic IVIG. Domestic IVIG could improve the cognitive function of 3-month-old 3xTg-AD mice after continuous intervention for 3 months. The improvement effect, however, was related to the Aβ antibody in IVIG, but not to the antibody concentration.

Changes in Ileal Flora Induced by Qishengwan in Treatment of Alzheimer's Disease： An Exploration Based on "Interior-Exterior Relationship Between Heart and Small Intestine" / 中国实验方剂学杂志

ObjectiveTo explore the effect of Qishengwan on ileal flora during its treatment of Alzheimer's disease （AD） under the guidance of the theory of "interior-exterior relationship between heart and small intestine". MethodThe AD model was established by bilateral intraventricular injection of β-amyloid 1-42 （Aβ1-42）. The rats were then randomly divided into the blank group， sham-operated group， model group， low-， medium-， and high-dose （5.6， 11.2，22.4 g·kg-1·d-1） Qishengwan groups， and donepezil （0.46 mg·kg-1·d-1） group. After medication for 28 successive days， the spatial memory ability of rats was observed in water maze test， and the levels of Aβ1-42， nuclear transcription factor-κB （NF-κB）， tumor necrosis factor-α （TNF-α）， and interleukin-6 （IL-6） in the hippocampus were analyzed by enzyme-linked immunosorbent assay （ELISA）. Additionally， the contents of the ileum were collected and subjected to 16SrRNA-sequencing analysis for figuring out the changes in ileal flora. ResultCompared with the blank group and sham-operated group， the model group exhibited significantly reduced stay time in the target quadrant and number of target quadrant and platform crossings （P<0.05， P<0.01） and elevated Aβ1-42 content in the hippocampus （P<0.01） and central inflammatory factors NF-κB， TNF-α， and IL-6 （P<0.05， P<0.01）. Compared with the model group， Qishengwan at each dose significantly alleviated the impaired spatial memory function （P<0.05， P<0.01）， improved the deposition of Aβ1-42 in the hippocampus of rats （P<0.05， P<0.01）， and reduced the expression of central nervous system inflammatory factors （P<0.05， P<0.01）， thus exerting a good therapeutic effect on AD rats. The 16SrRNA-sequencing analysis results showed that the structure of the ileal flora in the model group was significantly separated from those in the blank group and sham-operated group. The abundance of Lachnospiraceae NK4A136 group was significantly increased （P<0.01）， while that of Escherichia-Shigella was reduced （P<0.05， P<0.01）. Qishengwan at each dose significantly changed the ileal flora structure and regulated the relative abundance of Lachnospiraceae NK4A136 group， Escherichia-Shigella， and Ruminococcaceae. ConclusionQishengwan has a positive therapeutic effect on AD. It can significantly enhance the memory and cognitive abilities in AD rats， which may be related to its regulation of the structure of rat ileal flora and the relative abundance of Lachnospiraceae NK4A136 group， Escherichia-Shigella， and Ruminococcaceae， the attenuation of the central neuroinflammatory response， and the reduction of central Aβ1-42 deposition.

Mechanism of Linggui Zhugantang in Repairing Blood-brain Barrier Injury of Alzheimer's Disease / 中国实验方剂学杂志

ObjectiveTo observe the effect of Linggui Zhugantang （LG） on the blood-brain barrier （BBB） model of Alzheimer's disease （AD） in vitro and to explore the mechanism of LG in repairing the BBB injury in AD. MethodA total of 50 male SPF rats were randomized into five groups： high-dose （4.8 g·kg-1）， medium-dose （2.4 g·kg-1）， and low-dose （1.2 g·kg-1） LG groups， western medicine （0.5 g·kg-1 donepezil hydrochloride） group， and normal group （normal saline of equivalent volume）. They received （ig） corresponding drugs twice a day for 7 d. Drug-containing serum was respectively collected from the abdominal aorta 1 h after the last administration. The BBB injury of AD in vitro was induced with the cell co-culture method， and 6 groups were designed： normal group， model group， high-， medium-， and low-dose LG groups， and western medicine group. The model group was added with 100 μL amyloid β1-42 （Aβ1-42， final concentration： 5 μmol·L-1）， and high-dose， medium-dose， and low-dose LG groups and the western medicine group were added with corresponding 10% drug-containing serum in addition to the 100 μL Aβ1-42 （final concentration： 5 μmol·L-1）. Cell survival rate was detected by methyl thiazolyl tetrazolium （MTT） assay， expression of BBB-related skeleton proteins （claudin-5， ZO-1， occludin）， matrix metalloproteinase-2 （MMP-2）， and matrix metalloproteinase-9 （MMP-9） by Western blot， and content of inflammatory factors interleukin-1β （IL-1β）， interleukin-6 （IL-6）， and tumor necrosis factor-α （TNF-α） by enzyme-linked immunosorbent assay （ELISA）. BBB Aβ transporter low-density lipoprotein receptor-related protein 1 （LRP-1） and advanced glycation end product receptor （RAGE） at different time points in high-dose， medium-dose， and low-dose LG groups were determined by Real-time PCR and Western blot. ResultCell survival rate of the model group was lower than that of the normal group （P<0.05） and the survival rates of the western medicine group and high-dose LG group was higher than that in the model group （P<0.05）. The skeleton proteins were down-regulated and MMP-2 and MMP-9 were up-regulated in the model group compared with those in the normal group （P<0.05）. The expression of skeleton proteins was higher （P<0.05） and that of MMP-2 and MMP-9 was lower （P<0.05） in the western medicine group and high-dose LG group than in the model group. Compared with the model group， only the medium-dose LG group showed the up-regulation （P<0.05） of claudin-5 （P<0.05） and the decrease （P<0.05） of MMP-2. IL-1β， IL-6， and TNF-α in the model group were up-regulated （P<0.05） compared with those in the normal group， and those inflammatory factors in the western medicine group and high-dose and medium-dose LG groups were lower （P<0.05） than those in the model group. LRP-1 expression was up-regulated and RAGE expression was down-regulated at 3 h compared with those at 0 h （P<0.05）， while the expression of the two became stable at 6， 12， 24， 36 h. At 3 h， LRP-1 expression was down-regulated and RAGE expression was up-regulated in model group compared with those in the normal group at 3 h （P<0.05）. Moreover， the LRP-1 content was higher and RAGE content was lower in the western medicine group and high-dose LG group than in the model group. ConclusionLG can repair the BBB injury in vitro by inhibiting the expression of inflammatory factors and MMP-2， MMP-9， promoting the expression of skeletal proteins， and regulating the balance of transporters.

Impairment of the autophagy-lysosomal pathway in Alzheimer's diseases: Pathogenic mechanisms and therapeutic potential

Alzheimer's disease (AD), the most common neurodegenerative disorder, is characterized by memory loss and cognitive dysfunction. The accumulation of misfolded protein aggregates including amyloid beta (Aβ) peptides and microtubule associated protein tau (MAPT/tau) in neuronal cells are hallmarks of AD. So far, the exact underlying mechanisms for the aetiologies of AD have not been fully understood and the effective treatment for AD is limited. Autophagy is an evolutionarily conserved cellular catabolic process by which damaged cellular organelles and protein aggregates are degraded via lysosomes. Recently, there is accumulating evidence linking the impairment of the autophagy-lysosomal pathway with AD pathogenesis. Interestingly, the enhancement of autophagy to remove protein aggregates has been proposed as a promising therapeutic strategy for AD. Here, we first summarize the recent genetic, pathological and experimental studies regarding the impairment of the autophagy-lysosomal pathway in AD. We then describe the interplay between the autophagy-lysosomal pathway and two pathological proteins, Aβ and MAPT/tau, in AD. Finally, we discuss potential therapeutic strategies and small molecules that target the autophagy-lysosomal pathway for AD treatment both in animal models and in clinical trials. Overall, this article highlights the pivotal functions of the autophagy-lysosomal pathway in AD pathogenesis and potential druggable targets in the autophagy-lysosomal pathway for AD treatment.

Targeting whole body metabolism and mitochondrial bioenergetics in the drug development for Alzheimer's disease

Aging is by far the most prominent risk factor for Alzheimer's disease (AD), and both aging and AD are associated with apparent metabolic alterations. As developing effective therapeutic interventions to treat AD is clearly in urgent need, the impact of modulating whole-body and intracellular metabolism in preclinical models and in human patients, on disease pathogenesis, have been explored. There is also an increasing awareness of differential risk and potential targeting strategies related to biological sex, microbiome, and circadian regulation. As a major part of intracellular metabolism, mitochondrial bioenergetics, mitochondrial quality-control mechanisms, and mitochondria-linked inflammatory responses have been considered for AD therapeutic interventions. This review summarizes and highlights these efforts.

Polysaccharide Krestin Prevents Alzheimer's Disease-type Pathology and Cognitive Deficits by Enhancing Monocyte Amyloid-β Processing / 神经科学通报·英文版

Deficits in the clearance of amyloid β protein (Aβ) by the peripheral system play a critical role in the pathogenesis of sporadic Alzheimer's disease (AD). Impaired uptake of Aβ by dysfunctional monocytes is deemed to be one of the major mechanisms underlying deficient peripheral Aβ clearance in AD. In the current study, flow cytometry and biochemical and behavioral techniques were applied to investigate the effects of polysaccharide krestin (PSK) on AD-related pathology in vitro and in vivo. We found that PSK, widely used in therapy for various cancers, has the potential to enhance Aβ uptake and intracellular processing by human monocytes in vitro. After administration of PSK by intraperitoneal injection, APP/PS1 mice performed better in behavioral tests, along with reduced Aβ deposition, neuroinflammation, neuronal loss, and tau hyperphosphorylation. These results suggest that PSK holds promise as a preventive agent for AD by strengthening the Aβ clearance by blood monocytes and alleviating AD-like pathology.

A nanocleaner specifically penetrates the blood‒brain barrier at lesions to clean toxic proteins and regulate inflammation in Alzheimer's disease

Insurmountable blood‒brain barrier (BBB) and complex pathological features are the key factors affecting the treatment of Alzheimer's disease (AD). Poor accumulation of drugs in lesion sites and undesired effectiveness of simply reducing A

Abdominal acupoint thread embedding therapy based on "brain-intestinal connection" for mild-to-moderate Alzheimer's disease and its effects on serum levels of APP and Aβ / 中国针灸

OBJECTIVE@#To compare the clinical efficacy of abdominal acupoint thread embedding therapy based on "brain-intestinal connection" combined with donepezil hydrochloride tablets and oral donepezil hydrochloride tablets alone for mild-to-moderate Alzheimer's disease (AD) and observe its effects on amyloid precursor protein (APP) and β-amyloid protein@*METHODS@#Sixty patients with AD were randomly divided into an observation group (30 cases, 3 cases dropped off) and a control group (30 cases, 3 cases dropped off). The patients in the control group were treated with donepezil hydrochloride tablets (5 mg per day); based on the treatment in the control group, the patients in the observation group were treated with abdominal acupoint thread embedding therapy at Zhongwan (CV 12), Xiawan (CV 10), Huaroumen (ST 24), Wailing (ST 26), Daheng (SP 15), etc., once every 10 days. Both groups were treated for 2 months. The mini-mental state examination (MMSE), Alzheimer's disease assessment scale-cognitive subscale (ADAS-Cog), activity of daily living scale (ADL), neuropsychiatric inventory questionnaire (NPI) as well as the serum levels of APP and Aβ@*RESULTS@#After treatment, the MMSE scores in the two groups were higher than those before treatment (@*CONCLUSION@#The abdominal acupoint thread embedding therapy based on the theory of "brain-intestinal connection" combined with donepezil hydrochloride tablets can improve cognitive function, self-care ability of daily life and mental behavior, and reduce the serum levels of APP and Aβ

Danggui Shaoyaosan Inhibits Neuroinflammation in AD Rats by Regulating NLRP3/Caspase-1 Pathway / 中国实验方剂学杂志

Objective:To investigate the neuroprotective effect of Danggui Shaoyaosan （DSS） in a rat model of amyloid-<italic>β</italic>-peptide_1-42 （A<italic>β</italic>_1-42）-induced Alzheimer's disease （AD） as well as its regulatory effect on NOD-like receptor protein 3 （NLRP3）/cysteinyl aspartate-specific protease-1 （Caspase-1） signaling pathway. Method:The AD animal model was established via intracerebral injection of A<italic>β</italic>_1-42 and treated with different concentrations of DSS after the division of rats into the sham operation group， model group， as well as the high-， medium-， and low-dose DSS groups. Morris water maze test was conducted to determine the learning and memory abilities of rats. The morphology and function of neurons were detected by hematoxylin-eosin （HE） staining and Golgi staining， followed by immunofluorescence co-localization of NLRP3 inflammasome activation. The mRNA expression levels of interleukin （IL）-1<italic>β</italic> and IL-18 were measured by Real-time polymerase chain reaction （Real-time PCR）， and the protein expression levels of NLRP3， Caspase-1， and IL-1<italic>β </italic>were assayed by Western blot. Result:Compared with the sham operation group， the model group exhibited significantly decreased learning and memory abilities （<italic>P</italic><0.01）， impaired neuronal morphology and function， up-regulated IL-1<italic>β</italic> and IL-18 mRNA expression， enhanced NLRP3 inflammasome activation， and elevated NLRP3， Caspase-1， and IL-1<italic>β</italic> protein expression （<italic>P</italic><0.01）. Compared with the model group， DSS at both medium and high doses remarkably improved the learning and memory abilities of AD rats （<italic>P</italic><0.05， <italic>P</italic><0.01）， restored neuronal morphology and function， down-regulated the mRNA expression levels of inflammatory factors IL-1<italic>β</italic> and IL-18， reduced the activation of NLRP3 inflammasomes， and lowered the protein expression levels of NLRP3， Caspase-1， and IL-1<italic>β</italic> （<italic>P</italic><0.01）. Conclusion:DSS inhibits inflammasome activation and neuroinflammatory response possibly by regulating the NLRP3/Caspase-1 signaling pathway， thus exerting the neuroprotective effect.

Hops extract alleviates Aβ-injury to osteoblasts through antioxidant pathway / 药学实践杂志

Objective To explore the effects of Humulus lupulus L. extract (HLE) and its mechanism on improving bone formation of Aβ-injured osteoblasts. Methods Osteoblasts isolated from 24 h-old Wistar rats were injured by Aβ1-42 oligomer and intervened with HLE. The proliferation, differentiation and bone mineralization of osteoblasts were determined by MTT assay, alkaline phosphatase (ALP) activity assay and alizarin red staining, respectively. The apoptosis of osteoblasts was detected by flow cytometer. The expression levels of bone formation related proteins, and proteins of Nrf2 and FoxO1 pathways were measured by Western blotting analysis. The intranuclear expression of FoxO1 protein was detected by immunofluorescence. Results HLE significantly improved the cell proliferation, ALP activity and bone mineralization, and inhibited the apoptosis of Aβ-injured osteoblasts. HLE also significantly promoted the expressions of collagen type Ι (COL-I) and osteopontin (OPN) in Aβ-injured osteoblasts. HLE notably activated the Nrf2 and FoxO1 signaling pathways in Aβ-injured osteoblasts by promoting the expressions of related proteins and maintained bone metabolism through relieving oxidative stress. Conclusion This study confirms that HLE can alleviate Aβ-injury to osteoblasts, and preliminarily clarifies the mechanism being related to antioxidation, which provides a new reference for the mechanism research and drugs development for anti-osteoporosis.

Two-dimensional Nanomaterials against β-Amyloid in the Treatment of Alzheimer’s Disease / 中国生物化学与分子生物学报

Alzheimer’s disease (AD) is a prevalent progressive neurodegenerative disorder among the elderly. In the scientific community, the β-amyloid (Aβ) hypothesis is currently a widely-accepted model for AD pathogenesis. Removing Aβ, inhibiting Aβ aggregation and depolymerizing Aβ fibrils are proposed to provide useful strategies for the treatment of AD. However, most current drugs used for anti-Aβ therapy usually have inherent drawbacks that may limit their clinical applications. With the rise of nanotechnology nowadays, the application of two-dimensional nanomaterials in medicine has rapidly attracted much attention from researchers. Two-dimensional nanomaterials not only have excellent physical and chemical properties, as well as good biocompatibility, but also can easily cross either the cell membrane or blood-brain barrier. Recently, it has been found that many two-dimensional nanomaterials can inhibit Aβ aggregation or depolymerize Aβ fibrils by intermolecular interaction, near-infrared photothermal effect, photocatalytic oxidation, chelation of copper ions, drug delivery and other mechanisms, implying its great potential in treating AD. This review will focus on the research of graphene and graphene-like two-dimensional nanomaterials such as molybdenum disulfide, graphitic carbon nitride, and black phosphorus used for anti-Aβ therapy in the treatment of AD.