Impact of apolipoprotein E isoforms on sporadic Alzheimer's disease:beyond the role of amyloid beta

The impact of apolipoprotein E(ApoE)isoforms on sporadic Alzheimer's disease has long been studied;however,the influences of apolipoprotein E gene(APOE)on healthy and pathological human brains are not fully understood.ApoE exists as three common isoforms(ApoE2,ApoE3,and ApoE4),which differ in two amino acid residues.Traditionally,ApoE binds cholesterol and phospholipids and ApoE isoforms display diffe rent affinities for their receptors,lipids transport and distribution in the brain and periphery.The role of ApoE in the human depends on ApoE isoforms,brain regions,aging,and neural injury.APOE E4 is the strongest genetic risk factor for sporadic Alzheimer's disease,considering its role in influencing amyloid-beta metabolism.The exact mechanisms by which APOE gene variants may increase or decrease Alzheimer's disease risk are not fully understood,but APOE was also known to affect directly and indirectly tau-mediated neurodegeneration,lipids metabolism,neurovascular unit,and microglial function.Consistent with the biological function of ApoE,ApoE4 isoform significantly alte red signaling pathways associated with cholesterol homeostasis,transport,and myelination.Also,the rare protective APOE variants confirm that ApoE plays an important role in Alzheimer's disease pathogenesis.The objectives of the present mini-review were to describe classical and new roles of various ApoE isoforms in Alzheimer's disease pathophysiology beyond the deposition of amyloid-beta and to establish a functional link between APOE,brain function,and memory,from a molecular to a clinical level.APOE genotype also exerted a heterogeneous effect on clinical Alzheimer's disease phenotype and its outcomes.Not only in learning and memory but also in neuro psychiatric symptoms that occur in a premorbid condition.Cla rifying the relationships between Alzheimer's disease-related pathology with neuropsychiatric symptoms,particularly suicidal ideation in Alzheimer's disease patients,may be useful for elucidating also the underlying pathophysiological process and its prognosis.Also,the effects of anti-amyloid-beta drugs,recently approved for the treatment of Alzheimer's disease,could be influenced by the APOE genotype.

Role of Microtubule-associated Protein Tau Phosphorylation in Alzheimer's Disease

As a major microtubule-associated protein, tau plays an important role in promoting microtubule assembly and stabilizing microtubules. In Alzheimer’s disease(AD) and other tauopathies, the abnormally hyperphosphorylated tau proteins are aggregated into paired helical filaments and accumulated in the neurons with the form of neurofibrillary tangles. An imbalanced regulation in protein kinases and protein phosphatases is the direct cause of tau hyperphosphorylation. Among various kinases and phosphatases, glycogen synthase kinase-3β(GSK-3β) and protein phosphatase 2A(PP2A) are the most implicated. Accumulation of the hyperphosphorylated tau induces synaptic toxicity and cognitive impairments. Here, we review the upstream factors or pathways that can regulate GSK-3β or PP2A activity mainly based on our recent findings. We will also discuss the mechanisms that may underlie tau-induced synaptic toxicity.

The effect of Anshen Dingzhi Fang on tau protein phosphorylation and DNF/TrkB signaling pathway in Alzheimer's disease rats

Objective:To observe the effect of Anshen Dingzhi Decoction on tau phosphorylation in hippocampus of Alzheimer's disease rat model and its related mechanism.Methods:SD rats were randomly divided into control group,model group,Anshen Dingzhi Decoction(low,medium and high dose group)and Dopazide group.Except for the control group,the rats in the other groups were injected with streptozotocin into the lateral ventricle to replicate the model of Alzheimer's disease and then given corresponding drugs for 2 weeks.orris water maze test was used to detect learning and memory ability of rats,HE staining was used to detect hippocampal histological morphology,Western-blot was used to detect tau phosphorylation level and expression abundance of BDNF and TrkB protein in hippocampal tissue of rats.Results:The escape latency of the model group was significantly increased,the number of crossing platforms and effective residence time were significantly reduced,the phosphorylation level of tau protein was significantly increased,and the phosphorylation levels of BDNF and TrkB protein were significantly decreased when compared with the control group,the difference has statistically significant(P<0.05).Anshen Dingzhi Fang could significantly reduce the escape latency of AD rats,increase the number of crossing platforms and effective residence time,inhibit the phosphorylation of tau protein,and up-regulate the phosphorylation of BDNF and TrkB protein,the difference was statistically significant when compared with the model group(P<0.05).Conclusion:Anshen Dingzhi Fang can inhibit the phosphorylation of tau protein by activating BDNF/TrkB signaling pathway and promote the learning and memory ability of AD rats.

Mesenchymal stem cell-and extracellular vesicle-based therapies for Alzheimer's disease:progress,advantages,and challenges

Alzheimer's disease is a severe, highly disabling neurodegenerative disease, clinically characterized by a progressive decline in cognitive functions, and is the most common form of dementia in the elderly. For decades, the search for disease-modifying therapies has focused on the two main Alzheimer's disease histopathological hallmarks, seeking to prevent, mitigate, or clear the formation of extracellular aggregates of β-amyloid peptide and intracellular neurofibrillary tangles of tau protein, although without clinical success. Mesenchymal stem cell-based therapy has emerged as a promising alternative for the treatment of Alzheimer's disease, especially because it also targets other crucial players in the pathogenesis of the disease, such as neuroinflammation, synaptic dysfunction/loss, oxidative stress, and impaired neurogenesis. Herein, we review current knowledge of the therapeutic potential of mesenchymal stem cells and their extracellular vesicles for Alzheimer's disease, discussing the most recent findings in both preclinical and clinical trials as well as how advanced technologies have helped to overcome some limitations and contributed to stimulate the development of more effective treatments.

Searching for new drugs to treat Alzheimer’s disease dementia through multiple pathways

Dementia is a group of diseases,including Alzheimer's disease(AD),vascular dementia,Lewy body dementia,frontotemporal dementia,Parkinson's disease dementia,metabolic dementia and toxic dementia.The treatment of dementia mainly includes symptomatic treatment by controlling the primary disease and accompanying symptoms,nutritional support therapy for repairing nerve cells,psychological auxiliary treatment,and treatment that improves cognitive function through drugs.Among them,drug therapy to improve cognitive function is important.This review focuses on introducing and commenting on some recent progress in exploring drugs to improve cognitive function,especially the new progress in drug treatment for AD.We mainly discuss the opportunities and challenges in finding and developing new therapeutic drugs from the aspects of acetylcholinesterase,N-methyl-D-aspartate glutamate receptor,amyloid protein,tau protein and chronic immune inflammation.

Emerging blood exosome-based biomarkers for preclinical and clinical Alzheimer's disease:a meta-analysis and systematic review

Blood exosomes,which are extracellular vesicles secreted by living cells into the circulating blood,are regarded as a relatively noninvasive novel tool for monitoring brain physiology and disease states.An increasing number of blood cargo-loaded exosomes are emerging as potential biomarkers for preclinical and clinical Alzheimer's disease.Therefo re,we conducted a meta-analysis and systematic review of molecular biomarkers derived from blood exosomes to comprehensively analyze their diagnostic performance in preclinical Alzheimer's disease,mild cognitive impairment,and Alzheimer's disease.We performed a literature search in PubMed,Web of Science,Embase,and Cochrane Library from their inception to August 15,2020.The research subjects mainly included Alzheimer's disease,mild cognitive impairment,and preclinical Alzheimer's disease.We identified 34 observational studies,of which 15 were included in the quantitative analysis(Newcastle-Ottawa Scale score 5.87 points)and 19 were used in the qualitative analysis.The meta-analysis results showed that core biomarkers including Aβ_(1-42),P-T181-tau,P-S396-tau,and T-tau were increased in blood neuro nderived exosomes of preclinical Alzheimer's disease,mild cognitive impairment,and Alzheimer's disease patients.M olecules related to additional risk facto rs that are involved in neuroinflammation(C1q),metabolism disorder(P-S312-IRS-1),neurotrophic deficiency(HGF),vascular injury(VEGF-D),and autophagy-lysosomal system dysfunction(cathepsin D)were also increased.At the gene level,the differential expression of transc ription-related factors(REST)and microRNAs(miR-132)also affects RNA splicing,transport,and translation.These pathological changes contribute to neural loss and synaptic dysfunction.The data confirm that the above-mentioned core molecules and additional ris k-related factors in blood exosomes can serve as candidate biomarkers for preclinical and clinical Alzheimer's disease.These findings support further development of exosome biomarkers for a clinical blood test for Alzheimer's disease.This meta-analysis was registered at the International Prospective Register of Systematic Reviews(Registration No.CRD4200173498,28/04/2020).

Death-associated protein kinase 1 is associated with cognitive dysfunction in major depressive disorder

We previously showed that death-associated protein kinase 1(DAPK1)expression is increased in hippocampal tissue in a mouse model of major depressive disorde and is related to cognitive dysfunction in Alzheimer's disease.In addition,depression is a risk factor for developing Alzheimer's disease,as well as an early clinical manifestation of Alzheimer's disease.Meanwhile,cognitive dysfunction is a distinctive feature of major depressive disorder.Therefore,DAPK1 may be related to cognitive dysfunction in major depressive disorder.In this study,we established a mouse model of major depressive disorder by housing mice individually and exposing them to chronic,mild,unpredictable stressors.We found that DAPK1 and tau protein levels were increased in the hippocampal CA3 area,and tau was hyperphosphorylated at Thr231,Ser262,and Ser396 in these mice.Furthermore,DAPK1 shifted from axonal expression to overexpression on the cell membrane.Exercise and treatment with the antidepressant drug citalopram decreased DAPK1 expression and tau protein phosphorylation in hippocampal tissue and improved both depressive symptoms and cognitive dysfunction.These results indicate that DAPK1 may be a potential reason and therapeutic target of cognitive dysfunction in major depressive disorder.

INHIBITION OF MELATONIN BIOSYNTHESIS ACTIVATES PROTEIN KINASE A AND INDUCES ALZHEIMER-LIKE TAU HYPERPHOSPHORYLATION IN RATS

Objective To investigate effect of inhibiting melatonin biosynthesis on activities of protein kinase A (PKA), glycogen synthase kinase-3 (GSK-3) and tau phosphorylation at PS214 and M4 epitopes using haloperidol, a specific inhibitor of 5-hydroxyindole-O-methyltransferase. Methods Brain ventricular and intraperitoneal injections were used for haloperidol administration, Western blots for tau phosphorylation, 32P-labeling for PKA and GSK-3 activity, and high performance liquid chromatograph for detection of serum melatonin levels. Results Haloperidol injection through the lateral ventricle and intraperitoneal reinforcement significantly stimulated PKA activity with a concurrent hyperphosphorylation of tau at M4 (Thr231/Ser235) and PS214 (Ser214) sites. Prior treatment of the rats using melatonin supplement for one week and reinforcement during the haloperidol administration arrested PKA activity and attenuated tau hyperphosphorylation. GSK-3 activity showed no obvious change after haloperidol injection, however, melatonin supplements and reinforcements during haloperidol infusion inactivated basal activity of GSK-3. Conclusion Decreased melatonin may be involved in Alzheimer-like tau hyperphosphorylation, and overactivation of PKA may play a crucial role in this process.

THE PROTECTIVE EFFECTS OF THE TOTAL SAPONIN OF DIPSACUS ASPEROIDES ON THE APOPTOSIS OF HIPPOCAMPAL NEURONS INDUCED BY β-AMYLOID PROTEIN

Objective To investigate the effects of the total saponin of Dipsacus asperoides (tSDA) and ginsenoside Rb1 (GRb1) on the apoptosis of primary cultured hippocampal neurons induced by β-amyloid protein (Aβ). Methods Primary cultured hippocampal neurons, the cultures were pretreated with tSDA and GRb1 on 10d for 24 hours respectively. Then the cultures were treated with 35 μmol·L -1 Aβ25-35 for 24 hours, observed the changing of survival rate of neurons and the apoptosis of neurons with biochemical analysis combining immunofluorescent cytochemical double-staining technique. Results Hippocampal neurons were treated with 35 μmol·L -1 Aβ for 24 hours, and survival rate of neurons downed to 52.6%. When neurons were pretreated by tSDA and GRb1, survival rate of neurons increased 11% to 15%. The findings of immunofluorescent cytochemical double-staining indicated that apoptotic neurons were obviously more than that of the blank group, reaching 43.9%.When neurons were pretreated by tSDA and GRb1, apoptotic neurons were downed to 16.6%, 10.8% respectively. Conclusion tSDA had the same effects as GRb1, protecting the neurons, antagonizing neurotoxicity of Aβ, increasing survival rate of neurons, and reducing apoptotic neurons induced by Aβ.

The β-amyloid protein induces S100β expression in rat hippocampus through a mechanism that involves IL-1

Objective To explore the effect of β-amyloid protein (Aβ) on S100β expression in rat hippocampus and its mechanisms. Methods At 7 days after bilateral stereotaxis injection of different dose of fibrillar Aβ 25-35 and interluekin-1 receptor antagonist (IL-1ra) into the rat CA1 region, the learning and memory abilities of rats were tested with passive avoidance task. Amyloid deposition was detected by using Congo red staining technique. Nissl staining and immunohistochemical techniques were used to analyze the number of neurons, and GFAP and the S100β expression in hippocampal CA1 region , respectively. Results After fibrillar Aβ injection, the step-through latency of rats was significantly shortened compared to that of the control group. The GFAP positive astrocytes were found surrounding amyloid deposition. Neuronal loss occurred in the pyramidal cell layer of CA1 region. The number of S100β positive cells in Aβ-treated group was significantly increased compared with that in the control group. After IL-1ra injection, the number of S100β positive cells was significantly decreased. Conclusion Intrahippocampal injection of Aβ 25-35 could cause similar pathologic changes of Alzheimer’s disease. Aβ 25-35 was capable of up-regulating S100β expression in a dose-dependent manner. The injection of IL-1ra could attenuate the effect of Aβ on S100β expression.

Overinhibition of Mitogen-Activated Protein Kinase Inducing Tau Hyperphosphorylation

To reveal the relationship between mitogen-acti-vated protein kinase (MAPK)and tau phosphorylation, we used different concentration of PD98059, an inhibitor of MEK (MAPKkinase), to treat mice neuroblastma (N2a) cell line for 6 h. It showed that theactivity of MAPKdecreased in a dose-dependent manner. But Western blot and immunofluo-rescence revealed that justwhen the cells were treated with 16 mu mol/L PD98059, tau was hyperphosphorylated at Ser396/ 404 andSerl99/202 sites. We obtained the conclusion that overinhibited MAPK induced tauhyperphosphorylation at Ser396/404 and Serl99/202 sites.

Therapeutic Mechanism of Kai Xin San on Alzheimer's Disease Based on Network Pharmacology and Experimental Validation

Objective: To explore the specific pharmacological molecular mechanisms of Kai Xin San(KXS)on treating Alzheimer’s disease(AD) based on network pharmacology and experimental validation. Methods:The chemical compounds of KXS and their corresponding targets were screened using the Encyclopedia of Traditional Chinese Medicine(ETCM) database. AD-related target proteins were obtained from MalaCards database and DisGeNET databases. Key compounds and targets were identified from the compound-targetdisease network and protein-protein interaction(PPI) network analysis. Functional enrichment analysis predicted the potential key signaling pathways involved in the treatment of AD with KXS. The binding affinities between key ingredients and targets were further verified using molecular docking. Finally, the predicted key signaling pathway was validated experimentally. Positioning navigation and space search experiments were conducted to evaluate the cognitive improvement effect of KXS on AD rats. Western blot was used to further examine and investigate the expression of the key target proteins related to the predicted pathway. Results: In total, 38active compounds and 469 corresponding targets of KXS were screened, and 264 target proteins associated with AD were identified. The compound-target-disease and PPI networks identified key active ingredients and protein targets. Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway analysis suggested a potential effect of KXS in the treatment of AD via the amyloid beta(Aβ)-glycogen synthase kinase-3 beta(GSK3β)-Tau pathway. Molecular docking revealed a high binding affinity between the key ingredients and targets. In vivo,KXS treatment significantly improved cognitive deficits in AD rats induced by Aβ1-42, decreased the levels of Aβ, p-GSK3β, p-Tau and cyclin-dependent kinase 5, and increased the expressions of protein phosphatase 1alpha(PP1A) and PP2A(P<0.05 or P<0.01). Conclusion: KXS exerted neuroprotective effects by regulating the Aβ-GSK3β-Tau signaling pathway, which provides novel insights into the therapeutic mechanism of KXS and a feasible pharmacological strategy for the treatment of AD.

Effects of TYROBP Deficiency on Neuroinflammation of a Alzheimer’s Disease Mouse Model Carrying a PSEN1 p.G378E Mutation

Objective To study the effects of TYRO protein kinase-binding protein(TYROBP)deficiency on learning behavior,glia activation and pro-inflammatory cycokines,and Tau phosphorylation of a new Alzheimer’s disease(AD)mouse model carrying a PSEN1 p.G378E mutation.Methods A new AD mouse model carrying PSEN1 p.G378E mutation was built based on our previously found AD family which might be ascribed to the PSEN1 mutation,and then crossed with TYROBP deficient mice to produce the heterozygous hybrid mice(PSEN1^(G378E)/WT;Tyrobp^(+/-))and the homozygous hybrid mice(PSEN1^(G378E/G378E);Tyrobp^(-/-)).Water maze test was used to detect spatial learning and memory ability of mice.After the mice were sacrificed,the hippocampus was excised for further analysis.Immunofluorescence was used to identify the cell that expresses TYROBP and the number of microglia and astrocyte.Western blot was used to detect the expression levels of Tau and phosphorylated Tau(p-Tau),and ELISA to measure the levels of pro-inflammatory cytokines.Results Our results showed that TYROBP specifically expressed in the microglia of mouse hippocampus.Absence of TYROBP in PSEN1^(G378E) mutation mouse model prevented the deterioration of learning behavior,decreased the numbers of microglia and astrocytes,and the levels of interleukin-6,interleukin-1βand tumor necrosis factor-αin the hippocampus(all P<0.05).The ratios of AT8/Tau5,PHF1/Tau5,pT181/Tau5,pT231/Tau5 and p-ERK/ERK were all higher in homozygous hybrid mice(PSEN1^(G378E/G378E);Tyrobp^(-/-) mice)compared with PSEN1^(G378E/G378E) mice(all P<0.05).Conclusions TYROBP deficiency might play a protective role in the modulation of neuroinflammation of AD.However,the relationship between neuroinflammation processes involving microglia and astrocyte activation,and release of pro-inflammatory cytokines,and p-Tau pathology needs further study.

Computational Assessment and Pharmacological Property Breakdown of Eight Patented and Candidate Drugs against Four Intended Targets in Alzheimer’s Disease

Alzheimer’s Disease (AD) is the most prevalent age-related dementia. AD can be caused by abnormal processing of amyloid precursor protein (APP) or by oxidative stress or may be due to the actions of kinases or the degeneration and loss of functions of neurons in the brain. Although various treatments have already gained success in the in vitro studies, however, till now not a single satisfactory drug has been proven that can cure this disease permanently till now. In this study, the best possible drug has been determined from a group of drug molecules using methods of molecular docking. Molecular docking is a computational approach which helps to determine the best molecule from a group of molecules which may bind with the highest affinity with the intended target by mimicking the original biological environment in a computer. The tested drug molecules in this experiment are the disease modifying agents, capable of inhibiting a particular protein involving in the AD pathway. Eight drug molecules (ligands)-memantine (-4.075 Kcal/mol), hymenialdisine (-8.079 Kcal/mol), tideglusib (-6.445 Kcal/mol), kenpaullone (-7.545 Kcal/mol), dihydrospiro[dibenzo[a,d][7]annulene-5,4’-imidazol] (-4.742 Kcal/mol), harmine (-7.57 Kcal/mol), harmol (-6.583 Kcal/mol) and 1-Methyl-4-Phenylpyridinium (-5.214 Kcal/mol), have been docked successfully against four targets (proteins)-N-Methyl-D-Aspartate Receptor (NMDAR), glycogen synthase kinase-3β (GSK-3β), beta-secretase (β-secretase) and dual specificity tyrosine (Y)-phosphorylation-regulated kinase 1A (DYR-K1A) in this experiment which are intended targets in current AD treatment approaches. Investigation of docking results, druglikeness properties and ADME/T testing results suggest that the best findings of this experiment are memantine, hymenialdisine, dihydrospiro[dibenzo[a,d][7]annulene-5,4’-imi- dazol] and harmol, that could be the best possible drugs for the treatment of AD.

The Beneficial Effect of Enriched Environment on Pathogenesis of Alzheimer’s Disease

Alzheimer’s disease (AD) is a common neurodegenerative disease, its main clinical symptoms are the progressive decline of cognitive and memory functions. Enriched Environment (EE) achieves the goal of improving brain cognitive reserve by enhancing the multi-directional stimulation on movement, sensory and cognitive systems of animals. And EE can regulate the levels of various trophic factors in the brain, promote synaptic regeneration and enhance neural plasticity to reduce the loss of neurons induced by inflammation. At present, there is still no effective treatment for AD and the clinical intervention drug is expensive. So it is essential to actively explore non-drug treatment. This review will explain the effects of EE on learning ability, memory ability and mental behavior in AD, and provide a new direction for the treatment and rehabilitation of AD.

Terahertz Irradiation Improves Cognitive Impairments and Attenuates Alzheimer’s Neuropathology in the APP^(SWE)/PS1^(DE9) Mouse:A Novel Therapeutic Intervention for Alzheimer’s Disease

Alzheimer's disease(AD)is a progressive neurodegenerative disease characterized by the deposition of amyloid-β(Aβ),neurofibrillary tangles,neuroinflammation,and neurodegeneration in the brain.In recent years,considering the unsatisfied benefits of pharmacological therapies,non-pharmacological therapy has become a research hotspot for AD intervention.Terahertz(THz)waves with a range between microwave and infrared regions in the electromagnetic spectrum and high permeability to a wide range of materials have great potential in the bioengineering field.However,its biological impacts on the central nervous system,under either physiological or pathological conditions,are poorly investigated.In this study,we first measured the 0.14 THz waves penetration across the skull of a C57BL/6 mouse and found the percentage of THz penetration to be~70%,guaranteeing that THz waves can reach the relevant brain regions.We then exposed the APPSWE/PS1DE9 mouse model of AD to repeated low-frequency THz waves on the head.We demonstrated that THz waves treatment significantly improved the cognitive impairment and alleviated AD neuropathology including Aβdeposition and tau hyperphosphorylation in the AD mice.Moreover,THz waves treatment effectively attenuated mitochondrial impairment,neuroinflammation,and neuronal loss in the AD mouse brain.Our findings reveal previously unappreciated beneficial effects of THz waves treatment in AD and suggest that THz waves may have the potential to be used as a novel therapeutic intervention for this devastating disease.

正常人群脑脊液Tau蛋白含量的定量分析

目的 :探讨正常人群脑脊液 ( CSF) Tau蛋白含量的分布范围 ,为阿尔茨海默病 ( AD)的相关研究奠定基础。方法 :采用双抗体夹心式 ELISA技术 ,对 2 0例正常对照 ( NC)组及 2 0例非 AD神经系统疾病 ( ND)组 CSF- Tau蛋白含量进行检测及统计分析。结果 :CSF- Tau蛋白含量 NC组与ND组间比较、男女性别间比较、CSF蛋白正常组和增高组间比较差异均无显著性。以年龄因素作直线相关分析 ,NC组 r=0 .5 3( P<0 .0 5 ) ,呈正相关。结论 :正常人群 CSF- Tau蛋白含量为( 1 2 5 .88± 45 .62 ) ng· L-1,并随着年龄的增长有缓慢增高的趋势 ,但与性别及 CSF蛋白总量无关。

脑脊液Tau蛋白测定在老年性痴呆诊断中的意义

目的探讨阿尔茨海默病(AD)患者脑脊液Tau蛋白含量变化的临床意义。方法采用夹心酶联免疫吸附法(ELISA)测定了18例AD、16例多发性梗死性痴呆(MID)、19例其他神经系统疾病患者脑脊液中Tau蛋白含量。结果脑脊液中Tau蛋白含量,3组间差异有非常显著意义(P<0.01);AD组与MID组间及AD组与对照组间差异均有非常显著意义(分别为P<0.01和P<0.01);MID组和对照组间差异无显著意义(P>0.05)。AD组患者脑脊液中Tau蛋白含量随年龄有增高趋势,但统计学检验与年龄无相关关系(P>0.05)。轻、中、重度痴呆患者间的差异无显著性(P>0.05)。结论脑脊液Tau蛋白的升高有助于AD的诊断和鉴别诊断。

Kallikrein-related peptidases 6 and 10 are elevated in cerebrospinal fluid of patients with Alzheimer’s disease and associated with CSF-TAU and FDG-PET

Background:Alterations in the expression of human kallikrein-related peptidases(KLKs)have been described in patients with Alzheimer’s disease(AD).We elucidated the suitability of KLK6,KLK8 and KLK10 to distinguish AD from NC and explored associations with established AD biomarkers.Methods:KLK levels in cerebrospinal fluid(CSF),as determined by ELISA,were compared between 32 AD patients stratified to A/T/(N)system with evidence for amyloid pathology and of 23 normal controls with normal AD biomarkers.Associations between KLK levels and clinical severity,CSF and positron emission tomography(PET)based AD biomarkers were tested for.Results:Levels of KLK6 and KLK10 were significantly increased in AD.KLK6 differed significantly between AD A+/T+/N+and AD A+/T−/N+or NC with an AUC of 0.922.CSF pTau and tTau levels were significantly associated with KLK6 in AD.Conclusions:KLK6 deserves further investigations as a potential biomarker of Tau pathology in AD.

Development in the research of molecular mechanism of Alzheimer's disease

Alzheimer’s disease (AD) is a kind of central nervous system disease. The cause of AD is unclear. It is found that the remarkable histopathological characters of AD are senile plaques and neurofibrillary tangles.β-amyloid plays an important role in the formation of senile plaques and the abnormal phosphorylation of Tau protein is the main reason of neurofibrillary tangles. Apolipoprotein E is correlated to AD’s access, and the third pathological characterAMY plaque perhaps represents a new cause of AD. Presenlin and proteinaceous infectious particles are also related with AD. A summary of molecular mechanism for AD and the development of research is presented.