荧光纳米金刚石揭示大脑相关遗传危险因子如何诱导神经元内运输障碍

Title: Fluorescentnanodiamond tracking reveals intraneuronal transport abnormalities induced bybrain-disease-related genetic risk factors.

Authors: Haziza etal.

Journal: NatNanotechnol. 2016 Nov 28.

Abstract

Brain diseasessuch as autism and Alzheimer's disease (each inflicting >1% of the worldpopulation) involve a large network of genes displaying subtle changes in theirexpression. Abnormalities in intraneuronal transport have been linked togenetic risk factors found in patients, suggesting the relevance of measuringthis key biological process. However, current techniques are not sensitiveenough to detect minor abnormalities. Here we report a sensitive method tomeasure the changes in intraneuronal transport induced by brain-disease-relatedgenetic risk factors using fluorescent nanodiamonds (FNDs). We show that thehigh brightness, photostability and absence of cytotoxicity allow FNDs to betracked inside the branches of dissociated neurons with a spatial resolution of12 nm and a temporal resolution of 50 ms. As proof of principle, we applied theFND tracking assay on two transgenic mouse lines that mimic the slight changesin protein concentration (～30%)found in the brains of patients. In both cases, we show that the FND assay issufficiently sensitive to detect these changes.

AQP4在血管周边间隙的定位和阿尔茨海默病患者的Aβ清除相关

Title: Associationof Perivascular Localization of Aquaporin-4 With Cognition and AlzheimerDisease in Aging Brains.

Authors: Zeppenfeldet al.

Journal: JAMANeurol. 2016 Nov 28.

Abstract

IMPORTANCE:

Cognitiveimpairment and dementia, including Alzheimer disease (AD), are common withinthe aging population, yet the factors that render the aging brain vulnerable tothese processes are unknown. Perivascular localization of aquaporin-4 (AQP4)facilitates the clearance of interstitial solutes, including amyloid-β, throughthe brain wide network of perivascular pathways termed the glymphatic system,which may be compromised in the aging brain.

OBJECTIVES:

To determinewhether alterations in AQP4 expression or loss of perivascular AQP4localization are features of the aging human brain and to define theirassociation with AD pathology.

DESIGN, SETTING,AND PARTICIPANTS:

Expression of AQP4was analyzed in postmortem frontal cortex of cognitively healthy andhistopathologically confirmed individuals with AD by Western blot orimmunofluorescence for AQP4, amyloid-β 1-42, and glial fibrillary acidicprotein. Postmortem tissue and clinical data were provided by the Oregon Healthand Science University Layton Aging and Alzheimer Disease Center and OregonBrain Bank. Postmortem tissue from 79 individuals was evaluated, includingcognitively intact "young" individuals aged younger than 60 years(range, 33-57 years), cognitively intact "aged" individuals agedolder than 60 years (range, 61-96 years) with no known neurological disease,and individuals older than 60 years (range, 61-105 years) of age with aclinical history of AD confirmed by histopathological evaluation. Forty-eightpatient samples (10 young, 20 aged, and 18 with AD) underwent histologicalanalysis. Sixty patient samples underwent Western blot analysis (15 young, 24aged, and 21 with AD).

MAIN OUTCOMES ANDMEASURES:

Expression of AQP4protein, AQP4 immunoreactivity, and perivascular AQP4 localization in thefrontal cortex were evaluated.

RESULTS:

Expression of AQP4was associated with advancing age among all individuals (R2 = 0.17; P = .003).Perivascular AQP4 localization was significantly associated with AD statusindependent of age (OR, 11.7 per 10% increase in localization; z = -2.89;P = .004) and was preserved among eldest individuals older than 85 years of agewho remained cognitively intact. Whencontrolling for age, loss of perivascular AQP4 localization was associated withincreased amyloid-β burden (R2 = 0.15; P = .003) and increasing Braak stage(R2 = 0.14; P = .006).

CONCLUSIONS ANDRELEVANCE:

In this study,altered AQP4 expression was associated with aging brains. Loss of perivascularAQP4 localization may be a factor that renders the aging brain vulnerable tothe misaggregation of proteins, such as amyloid-β, in neurodegenerativeconditions such as AD.

综合护理和居家职业治疗无法延缓AD的生活功能下降

TargetingFunctional Decline in Alzheimer Disease: A Randomized Trial.

Authors: Callahanet al.

Journal: AnnIntern Med. 2016 Nov 22.

Abstract

BACKGROUND:

Alzheimer diseaseresults in progressive functional decline, leading to loss of independence.

OBJECTIVE:

To determinewhether collaborative care plus 2 years of home-based occupational therapydelays functional decline.

DESIGN:

Randomized,controlled clinical trial. (ClinicalTrial.gov: NCT01314950).

SETTING:

Urban publichealth system.

PATIENTS:

180community-dwelling participants with Alzheimer disease and their informalcaregivers.

INTERVENTION:

All participantsreceived collaborative care for dementia. Patients in the intervention groupalso received in-home occupational therapy delivered in 24 sessions over 2years.

MEASUREMENTS:

The primaryoutcome measure was the Alzheimer's Disease Cooperative Study Group Activitiesof Daily Living Scale (ADCS ADL);performance-based measures included the Short Physical Performance Battery (SPPB) and Short Portable SarcopeniaMeasure (SPSM).

RESULTS:

At baseline,clinical characteristics did not differ significantly between groups; the meanMini-Mental State Examination score for both groups was 19 (SD, 7). Theintervention group received a median of 18 home visits from the studyoccupational therapists. In both groups, ADCS ADL scores declined over 24months. At the primary end point of 24 months, ADCS ADL scores did not differbetween groups (mean difference, 2.34 [95% CI, -5.27 to 9.96]). We also couldnot definitively demonstrate between-group differences in mean SPPB or SPSM values.

LIMITATION:

The results ofthis trial are indeterminate and do not rule out potential clinically importanteffects of the intervention.

CONCLUSION:

We could notdefinitively demonstrate whether the addition of 2 years of in-homeoccupational therapy to a collaborative care management model slowed the rateof functional decline among persons with Alzheimer disease. This trialunderscores the burden undertaken by caregivers as they provide care for familymembers with Alzheimer disease and the difficulty in slowing functionaldecline.

荟萃分析揭示尚无足够证据支持视网膜Aβ的检测用于阿尔茨海默病的诊断

Title: AmyloidPlaques in Retina for Diagnosis in Alzheimer's Patients: a Meta-Analysis.

Authors: Jiang J,Wang H, Li W, Cao X, Li C.

Journal: FrontAging Neurosci. 2016 Nov 10;8:267.

Abstract

Background: Detectionof retinal β-amyloid (Aβ) peptide accumulation is a novel diagnostic method forAlzheimer's disease (AD), but there is, as yet, no conclusive evidence of itsaccuracy. Aim: To identify thediagnostic accuracy of pathological retinal Aβdetection for AD by a meta-analytic approach. Methods: Electronic and referencesearches were conducted to identify studies related to the diagnostic effectsof retinal Aβ detection in AD that met pre-defined inclusion criteria. TheQUADAS-2 tool was employed to assess the risk of bias, and Review Manager plusthe Open Meta-Analyst were used to perform the data analysis. Results: From 493 unduplicated reports,five studies with small sample sizeswere included in this review. Six staining methods were employed. Theeligible studies showed extremely broad ranges of sensitivity (0-1.00) andspecificity (0.50-1.00) with substantial heterogeneity. The estimates of positive likelihood ratio (PLR), negative likelihoodratio (NLR), diagnostic odds ratio (DOR) were also extremely varied (from 0.71to 11.57 for PLR, from 0.04 to 1.11 for NLR, and from 0.69 to 297.00 for DOR).Conclusions: The limited number of eligible studies and their methodologicalheterogeneity make it impossible to come to a conclusion whether pathologicalretinal Aβ detection is an effective diagnostic tool for AD. More studies,especially large surveys investigating retina Aβ load with quantitative methodsamong consecutive or random samples, are needed to determine the accuracy of Aβdetection for diagnosing AD.

RCT揭示阿尔茨海默病患者补充益生菌有助于改善认知功能和代谢状态

Title：Effectof Probiotic Supplementation on Cognitive Function and Metabolic Status inAlzheimer's Disease: A Randomized, Double-Blind and Controlled Trial.

Authors：Akbariet al.

Journal: FrontAging Neurosci. 2016 Nov 10;8:256.

Abstract

Alzheimer'sdisease (AD) is associated with severe cognitive impairments as well as somemetabolic defects. Scant studies in animal models indicate a link betweenprobiotics and cognitive function. This randomized, double-blind, andcontrolled clinical trial was conducted among 60 AD patients to assess the effects of probiotic supplementation oncognitive function and metabolic status. The patients were randomly dividedinto two groups (n = 30 in each group) treating with either milk (controlgroup) or a mixture of probiotics(probiotic group). The probiotic supplemented group took 200 ml/dayprobiotic milk containing Lactobacillusacidophilus, Lactobacillus casei, Bifidobacterium bifidum, and Lactobacillusfermentum (2 × 109 CFU/g for each) for 12 weeks. Mini-mental stateexamination (MMSE) score was recorded in all subjects before and after thetreatment. Pre- and post-treatment fasting blood samples were obtained todetermine the related markers. After 12weeks intervention, compared with the control group (-5.03% ± 3.00), theprobiotic treated (+27.90% ± 8.07) patients showed a significant improvement inthe MMSE score (P <0.001). In addition, changes in plasmamalondialdehyde (-22.01% ± 4.84 vs. +2.67% ± 3.86 μmol/L, P <0.001), serumhigh-sensitivity C-reactive protein (-17.61% ± 3.70 vs. +45.26% ± 3.50 μg/mL, P<0.001), homeostasis model of assessment-estimated insulin resistance(+28.84% ± 13.34 vs. +76.95% ± 24.60, P = 0.002), Beta cell function (+3.45% ±10.91 vs. +75.62% ± 23.18, P = 0.001), serum triglycerides (-20.29% ± 4.49 vs.-0.16% ± 5.24 mg/dL, P = 0.003), and quantitative insulin sensitivity checkindex (-1.83 ± 1.26 vs. -4.66 ± 1.70, P = 0.006) in the probiotic group weresignificantly varied compared to the control group. We found that the probiotictreatment had no considerable effect on other biomarkers of oxidative stressand inflammation, fasting plasma glucose, and other lipid profiles. Overall, the current study demonstratedthat probiotic consumption for 12 weeks positively affects cognitive functionand some metabolic statuses in the AD patients.

BACE1干扰通过修复磷脂酰乙醇胺代谢异常进而促进AD模型小鼠的记忆损害

Title：BACE1RNAi Restores the Composition of Phosphatidylethanolamine-Derivates Related toMemory Improvement in Aged 3xTg-AD Mice.

Authors: Villamil-Ortizet al.

Journal：FrontCell Neurosci. 2016 Nov 11;10:260.

Abstract

β-amyloid (Aβ) isproduced by the β-secretase 1 (BACE1)-mediated enzymatic cleavage of theamyloid precursor protein through the amyloidogenic pathway, making BACE1 atherapeutic target against Alzheimer's disease (AD). Alterations in lipidmetabolism are a risk factor for AD by an unknown mechanism. The objective ofthis study was to determine the effect of RNA interference against BACE1 (shBACEmiR)on the phospholipid profile in hippocampal CA1 area in aged 3xTg-AD mice after6 and 12 months of treatment compared to aged PS1KI mice. The shBACEmiRtreatment induced cognitive function recovery and restored mainly the fattyacid composition of lysophosphatidylethanolamine andetherphosphatidylethanolamine, reduced the cPLA2's phosphorylation,down-regulated the levels of arachidonic acid and COX2 in the hippocampi of3xTg-AD mice. Together, our findings suggest, for the first time, that BACE1silencing restores phospholipids composition which could favor the recovery ofcellular homeostasis and cognitive function in the hippocampus of tripletransgenic AD mice.

综述：纳米技术依赖的药物运输系统在AD中的应用

Title: Nanotechnology-baseddrug delivery systems for Alzheimer's disease management: Technical,industrial, and clinical challenges.

Authors: Wen et al.

Journal: J ControlRelease. 2016 Nov 23.

Abstract

Alzheimer'sdisease (AD) is a neurodegenerative disease with high prevalence in the rapidlygrowing elderly population in the developing world. The currently FDA approveddrugs for the management of symptomatology of AD are marketed mainly asconventional oral medications. Due to their gastrointestinal side effects andlack of brain targeting, these drugs and dosage regiments hinder patientcompliance and lead to treatment discontinuation. Nanotechnology-based drugdelivery systems (NTDDS) administered by different routes can be considered aspromising tools to improve patient compliance and achieve better therapeutic outcomes.Despite extensive research, literature screening revealed that clinicalactivities involving NTDDS application in research for AD are lagging comparedto NTDDS for other diseases such as cancers. The industrial perspectives,processability, and cost/benefit ratio of using NTDDS for AD treatment areusually overlooked. Moreover, active and passive immunization against AD are byfar the mostly studied alternative AD therapies because conventional oral drugtherapy is not yielding satisfactorily results. NTDDS of approved drugs appear promising to transform this researchfrom 'paper to clinic' and raise hope for AD sufferers and their caretakers.This review summarizes the recent studies conducted on NTDDS for AD treatment,with a primary focus on the industrial perspectives and processability.Additionally, it highlights the ongoing clinical trials for AD management.

Science发表综述阐述生物节律、睡眠和神经变性之间的关系

Title: Mechanismslinking circadian clocks, sleep, and neurodegeneration.

Authors: MusiekES, Holtzman DM.

Journal: Science.2016 Nov 25;354(6315):1004-1008.

Abstract

Disruptions ofnormal circadian rhythms and sleep cycles are consequences of aging and canprofoundly affect health. Accumulating evidence indicates that circadian andsleep disturbances, which have long been considered symptoms of manyneurodegenerative conditions, may actually drive pathogenesis early in thecourse of these diseases. In this Review, we explore potential cellular andmolecular mechanisms linking circadian dysfunction and sleep loss toneurodegenerative diseases, with a focus on Alzheimer's disease. We examine theinterplay between central and peripheral circadian rhythms, circadian clockgene function, and sleep in maintaining brain homeostasis, and discusstherapeutic implications. The circadian clock and sleep can influence a numberof key processes involved in neurodegeneration, suggesting that these systemsmight be manipulated to promote healthy brain aging.

使用3D纤维束局部和全脑成像分析AD患者白质完整性损害

Title: 3Dtract-specific local and global analysis of white matter integrity inAlzheimer's disease.

Authors: Jin etal. Alzheimer's Disease Neuroimaging Initiative.

Journal; Hum BrainMapp. 2016 Nov 24.

Abstract

Alzheimer'sdisease (AD) is a chronic neurodegenerative disease characterized by progressivedecline in memory and other aspects of cognitive function. Diffusion-weightedimaging (DWI) offers a non-invasive approach to delineate the effects of AD onwhite matter (WM) integrity. Previous studies calculated either some summarystatistics over regions of interest (ROI analysis) or some statistics alongmean skeleton lines (Tract Based Spatial Statistic [TBSS]), so they cannotquantify subtle local WM alterations along major tracts. Here, a comprehensiveWM analysis framework to map disease effects on 3D tracts both locally andglobally, based on a study of 200 subjects: 49 healthy elderly normal controls,110 with mild cognitive impairment, and 41 AD patients has been presented. 18major WM tracts were extracted with our automated clustering algorithm-autoMATE(automated Multi-Atlas Tract Extraction); we then extracted multipleDWI-derived parameters of WM integrity along the WM tracts across all subjects.A novel statistical functional analysismethod-FADTTS (Functional Analysis for Diffusion Tensor Tract Statistics) wasapplied to quantify degenerative patterns along WM tracts across differentstages of AD. Gradually increasing WM alterations were found in all tractsin successive stages of AD. Among all 18 WM tracts, the fornix was most adversely affected. Among all the parameters, mean diffusivity (MD) was the mostsensitive to WM alterations in AD. This study provides a systematicworkflow to examine WM integrity across automatically computed 3D tracts in ADand may be useful in studying other neurological and psychiatric disorders.

通过小片肽段阻断EphB2和ADDLs之间的相互作用可以显著的改善AD小鼠模型的突触可塑性损害和记忆缺陷

Title: Blockingthe Interaction between EphB2 and ADDLs by a Small Peptide Rescues ImpairedSynaptic Plasticity and Memory Deficits in a Mouse Model of Alzheimer'sDisease.

Authors: Shi etal.

Journal: JNeurosci. 2016 Nov 23;36(47):11959-11973.

Abstract

Soluble amyloid-β(Aβ) oligomers, also known as Aβ-derived diffusible ligands (ADDLs), arethought to be the key pathogenic factor in Alzheimer's disease (AD), but thereis still no effective treatment for preventing or reversing the progression ofthe disease. Targeting NMDA receptor trafficking and regulation is a newstrategy for early treatment of AD. Aβ oligomers have been found to bind to thefibronectin (FN) type III repeat domain of EphB2 to trigger EphB2 degradation,thereby impairing the normal functioning of NMDA receptors and resulting incognitive deficits. Here, we identified for the first time the interactionsites of the EphB2 FN domain with ADDLs by applying the peptide array method todesign and synthesize four candidate peptides (Pep21, Pep25, Pep32, and Pep63)that might be able to block the EphB2-ADDL interaction. Among them, Pep63 wasfound to be the most effective at inhibiting the binding between EphB2 andADDLs. We found that Pep63 not only rescued the ADDL-induced depletion ofEphB2- and GluN2B-containing NMDA receptors from the neuronal surface incultured hippocampal neurons, but also improved impaired memory deficits inAPPswe/PS1dE9 (APP/PS1) transgenic mice and the phosphorylation and surfaceexpression of GluN2B-containing NMDA receptors in cultures. Together, theseresults suggest that blocking the EphB2-ADDL interaction by small interferingpeptides may be a promising strategy for AD treatment.

SIGNIFICANCESTATEMENT:

Alzheimer'sdisease (AD) is an age-dependent neurodegenerative disorder and amyloidβ-derived diffusible ligands (ADDLs) play a key role in triggering the earlycognitive deficits that constitute AD. ADDLs may bind EphB2 and alter NMDAreceptor trafficking and synaptic plasticity. Here, we identified theinteraction sites of the EphB2 FN domain with ADDLs for the first time todevelop a small (10 aa) peptide (Pep63) capable of blocking the EphB2-ADDLinteraction. We found that Pep63 not only rescued the ADDL-induced depletion ofEphB2 and GluN2B-containing NMDA receptors from the neuronal surface incultured hippocampal neurons, but also improved impaired memory deficits inAPPswe/PS1dE9 (APP/PS1) transgenic mice. Our results suggest that blocking theEphB2-ADDL interaction with Pep63 may be a promising strategy for AD treatment.

贮存操作钙离子通道复合体可能是AD的潜在治疗靶点

Title: Store-OperatedCalcium Channel Complex in Postsynaptic Spines: A New Therapeutic Target forAlzheimer's Disease Treatment.

Authors: Zhang etal.

Journal: JNeurosci. 2016 Nov 23;36(47):11837-11850.

Abstract

Mushroom dendriticspine structures are essential for memory storage and the loss of mushroomspines may explain memory defects in aging and Alzheimer's disease (AD). Thestability of mushroom spines depends on stromal interaction molecule 2(STIM2)-mediated neuronal-store-operated Ca2+ influx (nSOC) pathway, which iscompromised in AD mouse models, in aging neurons, and in sporadic AD patients.Here, we demonstrate that the Transient Receptor Potential Canonical 6 (TRPC6)and Orai2 channels form a STIM2-regulated nSOC Ca2+ channel complex inhippocampal mushroom spines. We further demonstrate that a known TRPC6activator, hyperforin, and a novel nSOC positive modulator, NSN21778 (NSN), canstimulate activity of nSOC pathway in the spines and rescue mushroom spine lossin both presenilin and APP knock-in mouse models of AD. We further show thatNSN rescues hippocampal long-term potentiation impairment in APP knock-in mousemodel. We conclude that the STIM2-regulated TRPC6/Orai2 nSOC channel complex indendritic mushroom spines is a new therapeutic target for the treatment ofmemory loss in aging and AD and that NSN is a potential candidate molecule fortherapeutic intervention in brain aging and AD.

SIGNIFICANCESTATEMENT:

Mushroom dendriticspine structures are essential for memory storage and the loss of mushroomspines may explain memory defects in Alzheimer's disease (AD). This studydemonstrated that Transient Receptor Potential Canonical 6 (TRPC6) and Orai2form stromal interaction molecule 2 (STIM2)-regulated neuronal-store-operatedCa2+ influx (nSOC) channel complex in hippocampal synapse and the resultingCa2+ influx is critical for long-term maintenance of mushroom spines inhippocampal neurons. A novel nSOC-positive modulator, NSN21778 (NSN), rescuesmushroom spine loss and synaptic plasticity impairment in AD mice models. TheTRPC6/Orai2 nSOC channel complex is a new therapeutic target and NSN is a potentialcandidate molecule for therapeutic intervention in brain aging and AD.