Early Quality Life Impairment in Alzheimer Disease’s Patients in Geriatric Department: About 214 Cases in Pitié Salpêtrière Hospital of Paris (France)

Alzheimer’s disease (AD) is the most common neurodegenerative disease causing an alteration of life quality in the terminal stage. The purpose was to report 14 years of experience about the early impact on the quality of life of patients with AD. Methodology: Descriptive retrospective study over 14 years in the geriatric department of Pitié Salpêtrière Hospital, using the activity of daily living, Instrumental activity of daily living, neuropsychological inventory and Hoen Yahr scale evaluated at the time of diagnosis of AD according to the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer Disease’s and Related Disorders Association diagnostic criteria. Results: A total of 214 exploitable files had been listed. At the moment of diagnosis, the mean age was 82.1 years with extremes 68 to 95 with sex ratio 1.6 in women’s favor. The mean socio-cultural level was 4.9 with extremes about 0 to 7. There was poly pathology with a mean Cumulative Illness Rate Scale = 4.6 with extremes 0 to 16. the mean cognitive status was moderate = 22.5 with extremes 0 to 30. Quality life showed moderate impairment of IADL = 9.2 with extreme 3 to 11 compared to activity of daily living. The activity of daily living was more affected in 68 - 80-year-olds, while poly pathology impacted more on IADL in men. The cognitive impairment was more deficient in IADL when the MMSE test was low. The common disorders at the NPI were psychological, behavioral and psychotic. Conclusion: At the early diagnosis of Alzheimer’s Disease cognitive deficiencies were predominant and influenced on global Instrumental activity and psychological, behavioral disorders.

A Systematic Review and Meta-Analysis of Randomized Control Trials to Check Role of Non-Steroidal Anti-inflammatory Drugs as Protective Factor in Alzheimer Disease Subjects

Background: Alzheimer’s disease is the major neurodegenerative disease, affecting more than two third cases of dementia in the world. NSAIDs are widely used anti-inflammatory analgesic agents representing 7.7% of worldwide prescriptions of which 90% are in patients over 65 years old. Based on mixed findings observed by different RCTs, a systematic review and meta-analysis were conducted to develop a better understanding of the protective role of Non-steroidal anti-inflammatory drugs (NSAIDs) in AD. Methods: Database search was Pubmed, WebScience, and Embase. RCTs investigating the effect of NSAIDs on AD or test scores assessing cognitive function in people without AD at baseline were included. Three indicators were MMSE Score, ADAS-cog score, and CDR-sob. 10 studies were included in the present Meta-analysis. Results: For the ADAS-cog score, the pooled effect size was -0.31 with 95% CI -0.06 to 0.02, which was statistically significant (p = 0.03). MMSE score difference, the pooled effect size was -0.06 with 95% CI -0.22 to 0.10, which was statistically insignificant (p-value = 0.47). For the MMSE average score, the pooled effect size was -0.002 with 95% CI -0.03 to 0.07, which was statistically insignificant (p-value = 0.87). For the CDR-sob score difference, the pooled effect size calculated using the random effect model was -0.06 with 95% CI -0.39 to 0.05 which was statistically insignificant (p = 0.14). For CDR-sob average score, the pooled effect size calculated using the random effect model was 0.21 with 95% CI -0.09 to 0.51, which was statistically insignificant (p-value = 0.17). Conclusion: Present Meta-analysis shows that NSAIDs in general are not effective in the treatment of AD. They also have no protective effect against the development of AD on their sustained use.

Investigation on Positive Correlation of Increased Brain Iron Deposition with Cognitive Impairment in Alzheimer Disease by Using Quantitative MR R2' Mapping

Brain iron deposition has been proposed to play an important role in the pathophysiology of Alzheimer disease（AD）.The aim of this study was to investigate the correlation of brain iron accumulation with the severity of cognitive impairment in patients with AD by using quantitative MR relaxation rate R2＇ measurements.Fifteen patients with AD,15 age-and sex-matched healthy controls,and 30 healthy volunteers underwent 1.5T MR multi-echo T2 mapping and T2＊ mapping for the measurement of transverse relaxation rate R2＇（R2＇=R2＊-R2）.We statistically analyzed the R2＇ and iron concentrations of bilateral hippocampus（HP）,parietal cortex（PC）,frontal white matter（FWM）,putamen（PU）,caudate nucleus（CN）,thalamus（TH）,red nucleus（RN）,substantia nigra（SN）,and dentate nucleus（DN） of the cerebellum for the correlation with the severity of dementia.Two-tailed t-test,Student-Newman-Keuls test（ANOVA） and linear correlation test were used for statistical analysis.In 30 healthy volunteers,the R2＇ values of bilateral SN,RN,PU,CN,globus pallidus（GP）,TH,and FWM were measured.The correlation with the postmortem iron concentration in normal adults was analyzed in order to establish a formula on the relationship between regional R2＇ and brain iron concentration.The iron concentration of regions of interest（ROI） in AD patients and controls was calculated by this formula and its correlation with the severity of AD was analyzed.Regional R2＇ was positively correlated with regional brain iron concentration in normal adults（r=0.977,P0.01）.Iron concentrations in bilateral HP,PC,PU,CN,and DN of patients with AD were significantly higher than those of the controls（P0.05）;Moreover,the brain iron concentrations,especially in parietal cortex and hippocampus at the early stage of AD,were positively correlated with the severity of patients＇ cognitive impairment（P0.05）.The higher the R2＇ and iron concentrations were,the more severe the cognitive impairment was.Regional R2＇ and iron concentration in parietal cortex and hippocampus were positively correlated with the severity of AD patients＇ cognitive impairment,indicating that it may be used as a biomarker to evaluate the progression of AD.

Epigenetic basis of Alzheimer disease

Alzheimer disease(AD)is the primary form of dementia that occurs spontaneously in older adults.Interestingly,the epigenetic profile of the cells forming the central nervous system changes during aging and may contribute to the progression of some neurodegenerative diseases such as AD.In this review,we present general insights into relevant epigenetic mechanisms and their relationship with aging and AD.The data suggest that some epigenetic changes during aging could be utilized as biomarkers and target molecules for the prevention and control of AD.

Striatal oxidative damages and neuroinflammation correlate with progression and survival of Lewy body and Alzheimer diseases

Neurodegenerative diseases are a class of chronic and complex disorders featuring progressive loss of neurons in distinct brain areas.The mechanisms responsible for the disease progression in neurodegeneration are not fully illustrated.In this observational study,we have examined diverse biochemical parameters in the caudate and putamen of patients with Lewy body diseases(LBDs)and Alzheimer disease(AD),shedding some light on the involvement of oxidative damage and neuroinflammation in advanced neurodegeneration.We performed Spearman and Mantel-Cox analyses to investigate how oxidative stress and neuroinflammation exert comprehensive effects on disease progression and survival.Disease progression in LBDs correlated positively with poly(ADP-Ribose)and triggering receptors expressed on myeloid cell 2 levels in the striatum of LBD cohorts,indicating that potential parthanatos was a dominant feature of worsening disease progression and might contribute to switching microglial inflammatory phenotypes.Disease progression in AD corresponds negatively with 8-oxo-7,8-dihydro-2′-deoxyguanosine(8-oxo-d G)and myeloperoxidase concentrations in the striatum,suggesting that possible mitochondria dysfunction may be involved in the progression of AD via a mechanism ofβ-amyloid entering the mitochondria and subsequent free radicals generation.Patients with lower striatal 8-oxo-d G and myeloperoxidase levels had a survival advantage in AD.The age of onset also affected disease progression.Tissue requests for the postmortem biochemistry,genetics,and autoradiography studies were approved by the Washington University Alzheimer's Disease Research Center(ADRC)Biospecimens Committee(ethics approval reference number:T1705,approval date:August 6,2019).Recombinant DNA and Hazardous Research Materials were approved by the Washington University Environmental Health&Safety Biological Safety Committee(approval code:3739,approval date:February 25,2020).Radioactive Material Authorization was approved by the Washington University Environmental Health&Safety Radiation Safety Committee(approval code:1056,approval date:September 18,2019).

Lychee seed saponins improve cognitive function and ameliorate hippocampal neuronal injury in Alzheimer disease rat model induced by Aβ_(25-35) through AKT/GSK3β pathway

OBJECTIVE Lychee seed,a famous traditional Chinese medicine,recently were reported to improve the learning and memory abilities in mice.However,it is still unclear whether lychee seed saponins(LSS)can improve the cognitive function and associated mechanisms.METHODS In present studies,we established the Alzheimer disease(AD)model by injecting Aβ25-35 into the lateral ventricle of rats.Then the spatial learning and memory abilities of LSS-treated rats were evaluated with the Morris water maze,meanwhile the protein expressions of AKT,GSK3β and Tau in the hippocampal neuron were analyzed by immunohistochemistry and Western blotting.RESULTS The results showed LSS can improve the cognitive functions of AD rats through shortening the escape latency,increasing the number across the platform,platform quadrant dwell time and the percentage of the total distance run platform quadrant.The protein expression of AKT was significantly up-regulated and that of GSK3β and Tau were decreased remarkably in the hippocampal CA1 area.CONCLUSION Our study is the first to show that LSS significantly improve the cognitive function and prevent hippocampal neuronal injury of the rats with AD by activation of the PI3K/AKT/GSK3βsignaling pathway,suggesting LSS may be developed into the nutrient supplement for the treatment of AD.

Mirror writing in elderly patients with Alzheimer disease and vascular dementia

BACKGROUND： The results showed that mirror writing （MW） was correlated with the development of written language, so that MW examination may be one of methods to examine the intelligence of elderly people. OBJECTIVE： To study the MW in elderly patients with Alzheimer disease （AD） and vascular dementia （VaD） and take appropriate scale for their evaluation. DESIGN： Taking the written portion of the Chinese Aphasia Examination Scale （1994） for assessment. SETTING： Department of Neurology, Neuropsychological Laboratory, Beijing Hospital. PARTICIPANTS： From March 1998 to January 2001, 33 patients with AD, 30 patients with VaD admitted into Department of Neurology, Beijing Hospital was enrolled into study. Criteria according to the Diagnostic and Statistical Manual of Mental Disorder, 4^th edition （DSM-Ⅳ）, published by the American Psychiatric Association was used to diagnose AD, while criteria according to the National Institute of Neurological Disorders and Stroke-Association Internationale pour 1a Recherche et 1＇ Enseignement en Neurosciences （NINDS-AIREN） and Alzheimer Disease Diagnostic and Treatment Center （ADDCT） were used for diagnosis of VaD. AD group contained 19 males and 14 females aged 60 - 83 years. Twenty-eight males and 2 females, aged 60 - 87 years made up the VaD group. The 63 healthy elderly subjects matched on age and education as controls were enrolled into study. The matched controls were categorized AD control （n =33） and VaD control （n =30）. All patients and controls were understanding and agree with all items of assessment. METHODS： MW examination, Mini Mental State Examination （MMSE）, Hachinski Ischemic Scale, the Global Deterioration Scale （GDS） were examined in all subjects. ① Use the written potion of the Chinese Aphasia examination Scale （1994）, patient using MW for 91% - 100% of dictation had complete MW, those using MW for 51% - 90% of dictation had severe MW, those using MW for 11% - 50% had moderate MW, those using MW for 1% - 10% had mild MW. ② According to the MMSE, the patients were considered to have dementia if they were illiterate and had an MMSE score ≤ 17 score or educated time ≤ 6 years and MMSE ≤ 20 score or educated time 〉 6 years and MMSE ≤ 24 score. ③Using the Hachinski Ischemic Scale to differentiate the AD and VaD, it included 6 items and total 9 scores. 〉 7 score was VaD, 〈 4 score was AD and 4 - 7 score was blended dementia. ④ Using the GDS to assess cognitive function： Standard criteria were divided in 7 degrees： 1 degree： no impairment of cognition and 7 degree： very severe impairment of cognition. MAIN OUTCOME MEASURES： The data of MW examination, evaluation of MMSE, Hachinski Ischemic Scale and the GDS of all assessed subjects. RESULTS： All 63 cases of AD and VaD and 63 healthy controls were entered for analysis. ①Results of MW examination： A total of 17 patients with AD were characterized as using MW, 3 with moderate MW and 14 patients with mild MW. In the corresponding control group, only 2 subjects were characterized as being mild MW. The VaD group has 23 patients with MW, 2 with moderate and 21 patients with mild MW. ② MMSE score： MMSE score of AD group was much lower than that of individuals in control group [（20.15 ± 3.40）, （29.73 ±0.40） score, P 〈 0.01 ], MMSE score of VaD group was much lower than that of individuals in control group [09.33±2.75）, （29.12±0.63） score, P 〈 0.01]. ③Hachinski Ischemic Scale and GDS score： Rating according to the Hachinski Ischemic Scale was higher in VaD patients compared to AD patients [（9.61 ±1.69）, （1.09±0.60） score, P 〈 0.01]. The GDS score did not significantly differ between the AD group and the VaD group. CONCLUSION： ① MW examination could be used as an indicator of intelligence in healthy elderly people and also could be used as one of methods to assess the intelligence in AD and VaD patients. ② Grade of severity of MW may indirectly reflect the degree of dementia.

Association between apolipoprotein E promoter-219G/T polymorphism and total cholesterol level in patients with Alzheimer disease

BACKGROUND: Many researches have suggested that apolipoprotein E (APOE) and total cholesterol metabolism are closely related with dementia. In the supposed theory, 219 site of APOE promoter region is near gene coding region, so its polymorphism may result in the abnormality of APOE gene and protein expression, and finally lead to dementia. OBJECTIVE: To observe the association between APOE promoter-219G/T polymorphisms with serum total cholesterol in patients with Alzheimer disease, and compare it with non-dementia people. DESIGN: Case-control, comparative observation. SETTING: Department of Neurology, Fengtian Hospital of Shenyang Medical College. PARTICIPANTS: Fifty-five dementia patients including 27 males and 28 females aged (66±3) years and treated in the Department of Neurology, Fengtian Hospital were selected from January 2002 to December 2005 as the Alzheimer disease group. They all diagnosed according to the DSM-Ⅳdiagnostic criteria of Alzheimer disease instituted by American Psychiatry Association in 1994. Meanwhile, 44 none-dementia patients including 21 males and 23 females aged (66±3) years were selected from other clinical departments of Fengtian Hospital as control group. All the participants were informed the detection and agreed. METHODS: Genomic DNA was extracted from the peripheral blood of all subjects, then 'NEST'PCR, DNA sequence and enzyme digestion were adopted to detect the expression of APOE promoter-219 polymorphism, following by biomedical statistics analysis based on the clinical total cholesterol level. MAIN OUTCOME MEASURES: Polymorphism of APOE promoter-219 G/T and total cholesterol level. RESULTS: All 55 dementia patients and 44 non-dementia ones were involved in the result analysis. ①Allele and genotype frequency: The T allele frequency of the Alzheimer disease group was significantly higher than that in the control group [88.2% (97/110), 54.5% (48/88)], while G allele frequency was remarkably lower than that in the control group [11.8%(13/110), 45.5%(40/88), χ2=8.2, P < 0.01]. The TT allele frequency of the Alzheimer disease group was significantly higher than that in the control group [76% (42/55), 48% (21/44)], while GT+GG allele frequency was remarkably lower than that in the control group [24%(13/55), 52%(23/44), χ2=8.7, P < 0.01]. ②Total cholesterol level: The level of the TT genotype patients in the Alzheimer group was obviously higher than that in GT+GG genotype patients (t =2.46, P < 0.05); the cholesterol level in the two genotypes of the control group was similar (P > 0.05). CONCLUSION: TT genotype and allele T in the APOE promoter-219 polymorphisms are the sensitive gene, and genotype TT has a relationship with the increase of total cholesterol level.

Effects of ginsenoside of stem and leaf combined with choline on learning and memory ability of rat models with Alzheimer diseases

BACKGROUND： Central adrenergic nerve and 5-serotonergic nerve can influence central cholinergic nerve on learning and memory and make easy for study; however, ginsenoside of stem and leaf （GSL） can improve functions of central adrenergic nerve; moreover, 5-serotonergic nerve and the combination with choline can produce synergistic effect and enhance learning and memory ability so as to improve learning and memory disorder of patients with Alzheimer disease （AD）. OBJECTIVE ： To observe the effects of GSL combining with choline on learning and memory of AD model rats DESIGN ： Randomized grouping design and controlled animal study SETIING ： Department of Pharmacology, Taishan Medical College MATERIALS ： The experiment was carried out in the Pharmacological Department of Medical College of Jilin University from October 1996 to January 1997. Forty healthy male Wistar rats of clean grade were randomly divided into 5 groups, including sham-injury group, model group, GSL group, choline group and combination group, with 8 rats in each group. Main medications： GSL with the volume more than 92.8% was provided by Department of Chemistry, Norman Bethune Medical College of Jilin University. Panaxatriol, the main component, was detected with thin layer scanning technique and regarded as the index of GSL quality [（55±1）%, CV= 2%, n = 5]. Choline was provided by the Third Shanghai Laboratory Factory. METHODS ： 150 nmol quinolinic acid was used to damage bilateral Meynert basal nuclei of adult rats so as to establish AD models. Rats in GSL, choline and combination groups were intragastric administrated with 400 mg/kg GSL, 200 mg/kg choline （20 mL/kg）, and both respectively last for 17 days starting from two days before operation. Rats in sham-injury group and model group were perfused with the same volume of distilled water once in each morning for the same days. （1） Passive avoidance step-down test： Five minutes later, rats jumped up safe platform when they were shocked with 36 V alternating current. If rats jumped down from the platform and the feet touched railings, the response was wrong. Numbers of wrong response were recorded within 3 minutes, and then the test was redone after 24 hours. （2） Morris water-maze spatial localization task： Swimming from jumping-off to platform directly was regarded as right response. Additionally, 4 successively right responses were regarded as the standard. Each rat was trained 10 times a day with 120 s per time for 3 successive days. The interval was 30 s. Three days later, numbers of right response were recorded. The training times were increased to 30 for unlearned rats. （3） Measurement of activity of choline acetylase in cerebral cortex： Rats were sacrificed at 17 days after operation to obtain cerebral cortex to measure activity of choline acetylase with radiochemistry technique. （4） Synergistic effect： It was expressed as Q value： Q value = factual incorporative effect/anticipant incorporative effect; Q ≥ 1 was regarded as synergistic effect. Anticipant incorporative effect = （EA＋EB-EA·EB）, EA and EB were single timing effect, respectively in GSL group and choline group. E（step-down test and Morris water maze test） = （x in model group - factual value in medicine groups）/x in model group; E （activity of choline acetylase） = （factual value in medicine groups -xin model group）/xin model group. MAIN OUTCOME MEASURES ： （1） Passive avoidance step-down test and Morris water-maze spatial localization task in the study of learning and memory; （2） activity of choline acetylase. RESULTS ： All 40 rats were involved in the final analysis. （1） Passive avoidance response： At learning phase on first day and retesting phase on the next day, numbers of wrong responses within 3 minutes were more in model group than sham operation group, and there was significant difference [（5.88±1.46）, （2.25±0.87） times; （2.63±1.06）, （0.50±0.53） times; P 〈 0.01]; numbers of wrong responses within 3 minutes were less in combination group than model group, and there was significant difference [learning phase： （1.12±0.83）, （5.88±1.46） times; retesting phase： （0.38±0.74）, （2.63±1.06）times, P 〈 0.01]; moreover, effect was stronger than that in GSL group and choline group. The Q value was 1.07 and 1.59, respectively and it showed synergistic effect. Spatial localization task： Training times were more in model group than sham operation group, and there was significant difference [（2.9±2.5）, （12.6±3.5） times; P 〈 0.01]. Training times were less in combination group than model group, and there was significant difference [（11.8±2.4）, （27.9±2.5） times, P 〈 0.01]; moreover, effect was stronger than that in GSL group and choline group. The Q value was 1.07 and it showed synergistic effect. （3） Activity of choline acetylase： Activity was lower in model group than sham operation group, and there was significant difference [（30.56±8.33）, （61.11 ±8.33） nkat/g; P 〈 0.01]. Activity was higher in combination group than model group and there was significant difference [（50.00±8.33）, （30.56±8.33） nkat/g, P 〈 0.01];moreover, effect was stronger than that in GSL group and choline group. The Q value was 1.5 and it showed synergistic effect. CONCLUSZON： GSL in combination with choline can synergically improve the disorder of learning and memory of AD model rats. Its mechanism may be involved in enhancing the function of central cholinergic system.

IL-1β, TNF-α and Sambucus nigra Reactive Serum Proteins as Biomarkers of Mild Cognitive Impairment and Alzheimer Disease Progression

Amyloid-β (Aβ) can induce a chronic inflammatory immune response that is associated, amongst many others, to abnormal glycosylation, inducible nitric oxide synthase (iNOS) and nitric oxide (NO). The relation between development of Mild Cognitive Impairment (MCI) and Alzheimer’s disease progression and these serum markers has not been evaluated. Serum levels of iNOs, NO, TNF-α, IL-1β, IL-6, IL-8, IL-10, and IL-12 are determined with commercially available kits. Sialylation of albumin-free serum patterns is determined by Western blot analysis with Sambucus nigra (specific for sialic acid attached to terminal galactose in α2,6 linkage) lectin. Apolipoprotein E (ApoE) haplotype is determined by Western blot using specific anti-ApoE 2, 3 or 4 antibodies. A mini-mental state examination (MMSE) test is also performed in the 10 MCI patients, 19 Alzheimer’s disease (AD) patients and 46 healthy age-matched controls evaluated. The results show an increase of iNOS in MCI and AD but significantly higher NO concentrations are only found in MCI patients. TNF-α and IL-1β concentrations are the only significantly increased cytokines in MCI patients;no differences between control and MCI or AD patients are found in regard to the other cytokines. An abnormal MMSE test result only correlates with a decrease in serum NO concentration in MCI patients. The terminal sialic acid linkage pattern of serum proteins also shows highly significant differences between MCI and AD patient. ApoE3/4 or 4/4 haplotypes are characteristic of MCI and AD patients. Our results imply that increased serum TNF-α, IL-1β, iNOS, NO and alterations of serum proteins glycosylation patterns in adult individuals with an abnormal MMSE test may serve as an early biomarker of MCI and AD development.

Research progress of TREM2 in Alzheimer disease

Alzheimer disease(AD)is a common neurodegenerative disease in the elderly,but nowadays the pathogenesis of AD is unclear.Myeloid cell 2 trigger receptor(TREM2)is one of the most famous and most common rare mutations in neurodegenerative disease research,and its functional site mutation can significantly increase the incidence of AD.In this paper,we summary the structure,localization,and function and related signaling pathways of TREM2,review the latest epidemiological findings of TREM2 associated with the pathogenesis of AD,and speculate on the possible role of TREM2 in the progression of this disease,as well as the expression of TREM2 and the role of soluble TREM2 in AD brain are further elucidated.Based on the potential protective effect of TREM2 in the pathogenesis of AD,Therefore,targeting TREM2 may provide new opportunities and a reference for AD treatment.As the TREM2 variant appears to be widely involved in neurodegenerative diseases,there is an urgent need to further study the function of TREM2 in the brain and to find its ligands involved in TREM2-mediated signaling transduction and its specific role in AD pathogenesis.

Network pharmacology-based analysis of Chinese herbal NaoDeSheng formula for application to Alzheimer disease

OBJECTIVE To predict the potential targets and uncover the mechanisms of Nao De Sheng formula for the treatment of Alzheimer disease.METHODS Firstly,we collected the constituents in Nao De Sheng formula and key targets toward Alzheimer disease.Then,druglikeness,oral bioavailability and blood-brain barrier permeability were evaluated to find drug-like and lead-like constituents for central nervous system diseases treatment.Finallly,we were attempted to predict the targets of constituents and find potential multi-target compounds from Nao De Sheng formula by combining the advantages of machine learning,molecular docking and pharmacophore mapping together.RESULTS Constituenttarget network,constituent-target-target network and targetbiological pathway network were built to explain the network pharmacology of the constituents in NaoD eS heng formula.CONCLUSION To the best of our knowledge,we were the first to study the mechanism of Nao De Sheng formula for potential efficacy for Alzheimer disease treatment by means of the virtual screening and network pharmacology methods.

Erzhi pills ameliorates cognitive dysfunction and alter proteomic profiles of hippocampus in ovariectomized Alzheimer disease model rats induced by D-galactose and Aβ1-40 injection

OBJECTIVE Erzhi pills is a clas⁃sic prescription of Chinese medicine originated from Fu Shou Jing Fang in Ming dynasty,with the effects of nourishing kidney-Yin and hemosta⁃sis,black hair,strengthening muscles and bones.As a classical prescription for nourishing kidney-Yin,Erzhi pills has been used to treat senile dementia in China for many years.Herein,our study aimed to investigate the protective effects of Erzhi pills in rat models of Alzheimer disease(AD)induced by ovariectomy as well as D-galactose and Aβ1-40 injection and to explore its potential mechanism.METHODS The model of AD rats was established by ovariectomy com⁃bined with D-galactose and Aβ1-40 injection.Ovariectomized rats were randomly divided into four groups:model group,estradiol valerate(0.80 mg·kg-1)group,Erzhi pills high(1.50 mg·kg-1)and low(0.75 mg·kg-1)doses group.In addition,rats of sham operation were selected as the sham operated group.Except for the sham oper⁃ated group,rats were injected intraperitoneally with D-galactose(100 mg·kg-1 per day,for 49 d)on the 8th day,then they were given intracerebro⁃ventricular injection of Aβ1-40(10μg per rat,1 g·L-1)on the 36th day,while the corresponding drugs were given by gastrointestinal administra⁃tion on the 22nd day.In our study,Morris water maze test was used to evaluate the learning and memory abilities,while ELISA kit was used to an⁃alyze serum estrogen level.The morphology of hippocampal neuron cells was observed by HE staining,and Nissl staining was utilized to ob⁃serve the Nissl body in cytoplasm.Then,the ex⁃pression of ERβpositive cells and hippocampal Aβ1-40 and p-Tau404 proteins was determined by immunohistochemistry.In order to further explore the molecular mechanism of Erzhi pills preven⁃tion and treatment of AD,proteomics was used to find potential targets and related pathways,Western blotting was used to verify the expres⁃sion of candidate differential protein.According to the results of proteomics in our experiment,Western blotting was used to detect the protein expression of PI3K,Akt,Bcl-2,Bcl-xl,Bad,14-3-3 and GSK3β.RESULTS The escape latency was significantly shortened,the number of crossing platform was increased,the neuron arrange⁃ment was more orderly and with less nuclear pycnosis in rats of Erzhi pills groups compared to the model group.In rats treated with Erzhi pills,the number of neurons,Nissl bodies,the estro⁃gen levels and ERβpositive cells were increased,while the number of Aβ1-40 and p-Tau404 positive cells was significantly decreased.Proteomics found that there were more than one hundred differentially expressed proteins of rats treated with Erzhi pills,which were involved in 48 signal⁃ing pathways.Among these proteins,five of them were involved in the PI3K/Akt signal path⁃way.As the down-stream protein of PI3K/Akt sig⁃naling pathway,the content of 14-3-3 protein was significantly increased.Western blotting analysis showed that the expression of p-GSK3β/GSK3βand Bad was decreased,while that of p-Akt/Akt,p-PI3K/PI3K,14-3-3,Bcl-xl and Bcl-2 was up-regulated in rats from the Erzhi pills groups compared with the model group.CON⁃CLUSION Erzhi pills can improve estrogen levels,alter proteomics expression of the hippocampus and activate PI3K/Akt pathway in AD rats,reduce Aβaggregation,inhibit the hyperphos⁃phorylation of Tau protein,maintain the morphol⁃ogy of hippocampal neurons and decrease the apoptosis of hippocampal neurons,thereby improving the learning and memory abilities of ovariectomized AD rats induced by D-galactose and Aβ1-40 injection.This study may provide an experimental basis for the clinical treatment of Erzhi pills.

Effects of LW-AFC,a new formula derived from Liuwei Dihuang decoction,on intestinal microbiome in senescence-accelerated mouse prone 8 strain,a mouse model of Alzheimer disease

OBJECTIVE To investigate the effects of LW-AFC,a new formula derived fromLiuwei Dihuang decoction,on gut microbiota and the behavior of learning and memory of SAMP8 mice,a mouse model of Alzheimer Disease(AD),and identify the specific intestinal microbiota correlating with cognitive ability.METHODS Morris-water maze test,novel object recognition test and shuttle-box test were conducted to observe the ability of learning and memory.16S rRNA amplicon sequencing(Illumina,San Diego,CA,USA)was employed to investigate gut microbiota.RESULTS The treatment of LW-AFC improved cognitive impairments of SAMP8 mice,including spatial learning and memory ability,active avoidance response,and object recognition memory capability.Our data indicated that there were significantly 8 increased and 12 decreased operational taxonomic units(OTUs)in the gut microbiota of SAMP8 mice compared with senescence accelerated mouse resistant 1(SAMR1) strains,the control of SAMP8 mice.The treatment of LW-AFC altered 22(16 increased and 6 decreased)OTUs in SAMP8 mice and among them,15 OTUs could be reversed by LW-AFC treatment resulting in a microbial composition similar to that of SAMR1 mice.We further showed that there were7(3 negative and 4 positive correlation)OTUs significantly correlated with all the three types of cognitive abilities,at the order level,including Bacteroidales,Clostridiales,Desulfovibrionales,CW040,and two unclassified orders.LW-AFC had influences on bacterial taxa correlated with the abilities of learning and memory in SAMP8 mice and restored them to SAMR1 mice.CONCLUSION The effects of LW-AFC on improving cognitive impairments of SAMP8 mice might be via modulating intestinal microbiome and LW-AFC could be used as a potential anti-AD agent.

Effects of polygonatum polysaccharide on p38 MAPK/N-cadherin in zebrafish with Alzheimer disease

OBJECTIVE To study the effect of polygonatum polysaccharide on zebrafish with Alzheimer disease.METHODS Zebrafish were trained in T maze for 7 d.The 40 zebrafish successfully trained were divided into 4 groups:blank group,model group,positive group and polygonatum polysaccharide group.Model group,positive group and polygonatum polysaccharide group were put in AlCl3100μg·L^(-1) for 6 d.The positive group was exposed to Huperzine A solution 4μg·L^(-1),and the polygonatum polysaccharide group was exposed to polygonatum polysaccharide solution 6 g·L^(-1) for 6 d.The model group was not treated,and the blank group was not treated.Each stage of zebrafish was recorded by video,and the time of each group in the EC region was analyzed.After administration,the brain tissue was taken out and the expression of N-cadherin,P38 and p-P38 protein factors was determined by Western blotting.RESULTS In behavior,the analysis of the time spent in the EC area,the blank group,the positive group and the polygonatum polysaccharide group were compared with the model group,respectively,there were statistically significant differences(P<0.05).At the protein level,compared with the model group,the P38 and p-P38 proteins in the positive group and the polygonatum polysaccharide group were down-regulated,while the N-cadherin protein was up-regulated,with statistical difference(P<0.05).CONCLUSION Polygonatum polysaccharide can improve the learning and memory ability of zebrafish with Alzheimer disease by up regulating the protein level of N-cadherin and hindering P38 phosphorylation.

DL0410,a candidate for anti-Alzheimer disease with multiple targets in multiple pathways

OBJECTIVE To find a promising candidate for anti-Alzheimer disease(AD)with multiple targets in multiple pathways.METHODS A series of classifiers were constructed for predicting the active compounds against 51 key targets toward Alzheimer disease(AD)using the multitargetquantitative structure-activity relationships(mt-QSAR)method.While drug screening assays were established to evaluate the predicted active molecules.In addition,various cellular models and animal models related with AD were set up to further study the effects of the active compounds.RESULTS A system for the discovery of Multitarget-Directed Ligands against AD was set up and applied,the predicted active compounds were validated by the drug screening assays,and several active compounds with multiple targets were discovered.Among them,DL0410 exerted high activity on H3R,α7n ACh R,ACh E and ERα,also displayed the most significant effect in improving the ability of memory and learning in several AD animal models.The study on its action mechanisms showed that it′s effect may partially through increasing neurotransmitter,inhibiting oxidative emergency,inhibiting the expression of APP,and promoting long-term potentiation.Besides,DL0410 is of more safety than the first-line clinical medicines.CONCLUSION DL0410 is a promising candidate for further development for AD treatment.

Protective effects of resveratrol nanosuspensions loaded in situ hydrogel on Alzheimer disease model mice after intranasal administration

OBJECTIVE To evaluate the protective effects of resveratrol nanosuspensions loaded in situ hydrogel on Alzheimer disease model mice after intranasal administration. METHODS Resveratrol nanosuspensions were fabricated by antisolvent nano-precipitation method,and then dispersed into0.5% gellan gum to form resveratrol nanosuspenisons loaded ionic sensitive in situ hydrogel. The Alzheimer′s disease models were induced by lateral ventricle injection of Aβ_(25~35)and the protection and treatment effects of resveratrol nanosuspensions loaded in situ hydrogel on study and memory capability were performed after intranasal administration in water maze experiments. The analyses of the changes of cholinergic neurotransmitters in the brain were also determined according to the contents of acetylcholine(ACh),choline acetyltransferase(ChAT) and acetylcholinesterase(AChE). RESULTS Behavior assessment disclosed that in position navigation,escape latency test,each of experimental animals showed a decreased trend with swim training days increase,indicating that in the training process they had the ability of learning and memory in looking for the platform. Compared with the control group,average latency of model group significantly increased. While compared with the model group,treatment group′s average latency was significantly shorter. Space exploration experiment results showed that the times of model group across target quadrant of the platform is less than that of control group. But the crossing times of treatment group with resveratrol increased compared with the model group. As for the changes of cholinergic neurotransmitters,in AD mice brain ACh content decreased; the Ch AT activity decreased,while the activity of ACh E with the ability to hydrolysis acetylcholine increased. The administration of resveratrol can decrease the activity of ACh enzymes but increase Ch AT activity and the levels of acetylcholine. CONCLUSION Resveratrol nanosuspension loaded in situ gel can ameliorate the declining ability of learning and memory of AD model mice after intranasal administration. As a promising approach for the treatment of central nervous system(CNS) disease,intranasal administration route can effectively deliver to the brain and thus enhance the therapeutic effect.

Occurrence and influential factors of depression in patients with Alzheimer disease

BACKGROUND: The differential diagnosis between depressive pseudodementia and Alzheimer disease (AD) is a clinical problem, and it is more difficult to diagnose depression in AD. OBJECTIVE: To analyze the incidence and characters of depression in AD patients, and investigate the correlative factors. DESIGN: A randomized controlled study. SETTING: Beijing Geriatrics Hospital. PARTICIPANTS: From October 2005 to July 2006, 34 patients with probable AD were selected from the Department of Dementia, Beijing Geriatrics Hospital according to National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer Disease and Related Disorders Association (NINCDS-ADRDA) criteria for AD. There were 16 males and 18 females, aged 63-85 years. Meanwhile, 30 patients with other chronic neurological disorders (CND) were selected from our hospital as the CND control group, there were 16 males and 14 females, aged 55-85 years, including 18 cases of cerebrovascular sequela, 9 of Parkinson disease and 3 of migraineurs. Another 30 patients with chronic physical diseases (CPD) were enrolled as the CPD control group, there were 15 males and 15 females, aged 57-83 years, including 15 cases of chronic bronchitis, 8 of hypertension and 7 of diabetes mellitus. Besides, 30 physical examinees were enrolled as the healthy control group, including 15 males and 15 females, aged 55-80 years. All the subjects were informed and agreed with the detection. METHODS: ① All the subjects underwent the Hamilton rating scale for depression (HAMD) (24 items) assessment, and the total score < 8 points was regarded as no depression, 8-20 as mild depression, 20-35 as moderate depression, ≥ 35 as severe depression. ② All the AD patients were assessed with Cornell scale for depression in dementia (CSDD) (19 items), and the total score < 8 points was regarded as no depression, and ≥ 8 as depression. CSDD consisted of five subscales, including mood-related signs, behavioral disturbance, cyclic functions, ideational disturbance and physical signs, which were scored as 0-2 points respectively, and the abnormal rate of each factor was observed, the abnormal rate was the percentage of number of patients suffering from the symptoms in the subscales to the total number of patients. ③ The cognitive function of the AD patients was assessed with Mini-mental status examination (MMSE) (the total score ranged 0-30 points; ≤17 in illiterate, ≤ 20 in primary school and ≤ 24 in middle school and higher was regarded as cognitive deficit) and the daily living ability of the AD patients was assessed with ADL. MAIN OUTCOME MEASURES: ① HAMD scores in all the groups; ② CDSS scores and abnormal rate of factors in AD patients; ③ MMSE score and activity of daily life (ADL) score in AD patients; ④ Correlation between depression and correlative factors in AD patients. RESULTS: All the 124 subjects were involved in the analysis of results. ① The HAMD average score of the AD group was significantly higher than those of the CND, CPD and healthy control groups [(12.7±3.2), (5.5±2.5), (3.4±1.3), (2.6±1.7) points, P < 0.01]. ② In the AD group, the CDSS average score was (5.8±4.3) points, 41.2% (14/34) met the criteria for depression. The abnormal rates in order were 44% (15/34) for mood-related signs, 32% (11/34) for behavioral disturbance, 24% (8/34) for cyclic function, 12% (4/34) for ideational disturbance and 12% (4/34) for physical signs. ③ The factors of age, course, MMSE score and ADL score were finally excluded after a multiple regression (P > 0.05). There was a negative correlation between CSDD score and onset age (P < 0.05), sex was also obviously correlated with CSDD score (P < 0.05). CONCLUSION: The incidence of depression in AD is much higher with various manifestations. Female patients are the susc and earlier onset age is the risk factor for the presence of depression in AD.

Effect of rhynchophylline on behavior of zebrafish with Alzheimer disease

OBJECTIVE To investigate the effect of rhynchophylline on behavior of zebrafish with Alzheimer disease induced by AlCl3.METH⁃ODS Take a video of the zebrafish before train⁃ing,which is convenient for judging whether the zebrafish has been trained successfully.Then,the zebrafish were trained for 7 d.The 60 zebraf⁃ish that were successfully trained were randomly divided into 6 groups:normal group,model group,positive group,low-dose rhynchophylline group,middle-dose group,and high-dose group.The normal group was video-recorded,while the model group,positive group,low-dose group,middle-dose group,and high-dose group were given AlCl3 for modeling.After that,the model group was videotaped,and the other groups were given drug intervention.Both the positive group and the rhynchophylline administration group were administered for 6 d,and finally all the administration groups were videotaped.After all the video is finished,the behavioral analysis software smart 3.0 was used for behavioral anal⁃ysis,and conclusions are drawn by analyzing the data.RESULTS The data of the 6 groups of zebrafish staying in the red short arm area were used for comparative analysis:there was a signif⁃icant difference between the normal group and the model group(P<0.05),the model group and the positive group,and the middle-dose group of rhynchophylline There are significant differences in the high-dose group(P<0.05).Comparative analysis with the data of the percentage of zebraf⁃ish in the red short arm area of the 6 groups:the normal group and the model group are signifi⁃cantly different(P<0.05),There were significant differences between the model group and posi⁃tive group,the dose of the rhynchophylline administration group high-dose group and the middle-dose group(P<0.05).Comparing the data of the swimming distance of the 6 groups of zebrafish in the red short arm area:the normal group and the model group are not significantly different(P>0.05),while the model group is only significantly different from the high-dose group(P<0.05).However,the comparison of the percentage of zebrafish swimming distance in the red short arm area of the 6 groups of data:the normal group and the model group are signifi⁃cantly different(P<0.05),the model group and the positive group,and the rhynchophylline administration group There were significant differ⁃ences between the dose group and the high-dose group(P<0.05).CONCLUSION Rhynchophyl⁃line can improve the behavior of zebrafish with Alzheimer disease.

Effect of rhynchophylline on p38MAPK/N-cadherin in zebrafish with Alzheimer disease

OBJECTIVE To investigate the effect of rhynchophylline on zebrafish with Alzheimer disease induced by AlCl3.METHODS Zebrafish were trained in T maze for 7 d.60 zebrafish were selected and divided into 6 groups:blank group,model group,positive group,low-dose group,medium-dose group and high-dose group,with 10 in each group.Feeding zebrafish adaptively for 2 d,starting training on the third day,and recording its movement track;Except the blank group,the other five groups were modeled and their motion trajectories were recorded.After modeling,the drug group was giv⁃en rhynchophylline,while the positive group was given huperzine A,and the movement track was recorded.The recorded movement track was analyzed by behavioral record analysis software smart 3.0.The expression levels of P38,p-P38 protein and N-cadherin protein in zebrafish brain tissue were detected by Western blotting.RESULTS The data of time spent in the green short arm area of six groups of zebrafish were compared and analyzed:there was significant dif⁃ference between blank group and model group(P<0.05),and there was significant difference between model group and positive group,low dose group,middle dose group and high dose group(P<0.05).Comparative analysis of the time percentage of zebrafish in the green arm area of six groups:there was significant differ⁃ence between the blank group and the model group(P<0.05),and there was significant differ⁃ence between the model group and the positive group,the rhynchophylline administration group,low dose group,middle dose group and high dose group(P<0.05).The protein was detected by Western blotting.Compared with the model group,the expression level of N-cadherin protein was up-regulated(P<0.05).Compared with the model group,the expression levels of p-P38 pro⁃tein in blank group,positive group and rhyncho⁃phylline administration group were down-regulat⁃ed(P<0.05).CONCLUSION Uncaria rhyncho⁃phylline can down-regulate the ratio of p-P38/P38 and up-regulate N-cadherin,thus improving the learning and memory ability of zebrafish with Alzheimer disease.