新技术有助于开发Aβ42聚集抑制剂

Title: Systematicdevelopment of small molecules to inhibit specific microscopic steps of Aβ42aggregation in Alzheimer's disease.

Author information:Habchi J et al.

Journal: Proc NatlAcad Sci U S A. 2016 Dec 23.

Abstract

The aggregation ofthe 42-residue form of the amyloid-β peptide (Aβ42) is a pivotal event inAlzheimer's disease (AD). The use ofchemical kinetics has recently enabled highly accurate quantifications ofthe effects of small molecules on specific microscopic steps in Aβ42aggregation. Here, we exploit this approach to develop a rational drugdiscovery strategy against Aβ42 aggregation that uses as a read-out the changesin the nucleation and elongation rateconstants caused by candidate small molecules. We thus identify a pool ofcompounds that target specific microscopic steps in Aβ42 aggregation. We thentest further these small molecules in human cerebrospinal fluid and in aCaenorhabditis elegans model of AD. Our results show that this strategyrepresents a powerful approach to identify systematically small molecule leadcompounds, thus offering an appealing opportunity to reduce the attritionproblem in drug discovery.

血液检测PrPSc可以100%的敏感性诊断CJD

Title: Detectionof prions in blood from patients with variant Creutzfeldt-Jakob disease.

Author information:Concha-Marambio et al.

Journal: SciTransl Med. 2016 Dec 21;8(370):370ra183.

Abstract

Human priondiseases are infectious and invariably fatal neurodegenerative diseases. Theyinclude sporadic Creutzfeldt-Jakob disease (sCJD), the most common form, andvariant CJD (vCJD), which is caused by interspecies transmission of prions fromcattle infected by bovine spongiform encephalopathy. Development of abiochemical assay for the sensitive, specific, early, and noninvasive detectionof prions (PrPSc) in the blood of patients affected by prion disease is a topmedical priority to increase the safety of the blood supply. vCJD has alreadybeen transmitted from human to human by blood transfusion, and the number ofasymptomatic carriers of vCJD in the U.K. alone is estimated to be 1 in 2000people. We used the protein misfoldingcyclic amplification (PMCA) technique to analyze blood samples from 14cases of vCJD and 153 controls, including patients affected by sCJD and otherneurodegenerative or neurological disorders as well as healthy subjects. Ourresults showed that PrPSc could bedetected with 100% sensitivity and specificity in blood samples from vCJDpatients. Detection was possible in any of the blood fractions analyzed andcould be done with as little as a few microlitersof sample volume. The PrPSc concentration in blood was estimated to be ~0.5 pg/ml. Our findings suggest thatPMCA may be useful for premortem noninvasive diagnosis of vCJD and to identifyprion contamination of the blood supply. Further studies are needed to fullyvalidate the technology.

IL-2可以减轻AD的淀粉样蛋白病理改变、突触损害和记忆障碍

Title: Interleukin-2improves amyloid pathology, synaptic failure and memory in Alzheimer's diseasemice.

Author information:Alves S et al.

Journal: Brain.2016 Dec 20. pii: aww330.

Abstract

Interleukin-2(IL-2)-deficient mice have cytoarchitectural hippocampal modifications andimpaired learning and memory ability reminiscent of Alzheimer's disease. IL-2stimulates regulatory T cells whose role is to control inflammation. Asneuroinflammation contributes to neurodegeneration, we investigated IL-2 inAlzheimer's disease. Therefore, we investigated IL-2 levels in hippocampalbiopsies of patients with Alzheimer's disease relative to age-matched controlindividuals. We then treated APP/PS1ΔE9 mice having established Alzheimer'sdisease with IL-2 for 5 months using single administration of an AAV-IL-2vector. We first found decreased IL-2 levels in hippocampal biopsies ofpatients with Alzheimer's disease. In mice, IL-2-induced systemic and brainregulatory T cells expansion and activation. In the hippocampus, IL-2 induced astrocytic activation andrecruitment of astrocytes around amyloid plaques, decreased amyloid-β42/40ratio and amyloid plaque load, improved synaptic plasticity and significantlyrescued spine density. Of note, this tissue remodelling was associated withrecovery of memory deficits, as assessed in the Morris water maze task.Altogether, our data strongly suggest that IL-2 can alleviate Alzheimer'sdisease hallmarks in APP/PS1ΔE9 mice with established pathology. Therefore,this should prompt the investigation of low-dose IL-2 in Alzheimer's diseaseand other neuroinflammatory/neurodegenerative disorders.

临床前AD具有显著的神经解剖学异质性

Title: Heterogeneityof neuroanatomical patterns in prodromal Alzheimer's disease: links tocognition, progression and biomarkers.

Author information:Dong et al.

Journal: Brain.2016 Dec 20. pii: aww319.

Abstract

Individuals withmild cognitive impairment and Alzheimer's disease clinical diagnoses candisplay significant phenotypic heterogeneity. This variability likely reflectsunderlying genetic, environmental and neuropathological differences.Characterizing this heterogeneity is important for precision diagnostics,personalized predictions, and recruitment of relatively homogeneous sets ofpatients into clinical trials. In this study, we apply state-of-the-artsemi-supervised machine learning methods to the Alzheimer's diseaseNeuroimaging cohort (ADNI) to elucidate the heterogeneity of neuroanatomicaldifferences between subjects with mild cognitive impairment (n = 530) andAlzheimer's disease (n = 314) and cognitively normal individuals (n = 399),thereby adding to an increasing literature aiming to establish neuroanatomicaland neuropathological (e.g. amyloid and tau deposition) dimensions inAlzheimer's disease and its prodromal stages. These dimensional approaches aimto provide surrogate measures of heterogeneous underlying pathologic processesleading to cognitive impairment. We relate these neuroimaging patterns tocerebrospinal fluid biomarkers, white matter hyperintensities, cognitive andclinical measures, and longitudinal trajectories. We identified four suchatrophy patterns: (i) individuals with largely normal neuroanatomical profiles,who also turned out to have the least abnormal cognitive and cerebrospinalfluid biomarker profiles and the slowest clinical progression during follow-up;(ii) individuals with classical Alzheimer's disease neuroanatomical, cognitive,cerebrospinal fluid biomarkers and clinical profile, who presented the fastestclinical progression; (iii) individuals with a diffuse pattern of atrophy withrelatively less pronounced involvement of the medial temporal lobe, abnormalcerebrospinal fluid amyloid-β1-42 values, and proportionally greater executiveimpairment; and (iv) individuals withnotably focal involvement of the medial temporal lobe and a slow steadyprogression, likely representing in early Alzheimer's disease stages. Thesefour atrophy patterns effectively define a 4-dimensional categorization ofneuroanatomical alterations in mild cognitive impairment and Alzheimer'sdisease that can complement existing dimensional approaches for stagingAlzheimer's disease using a variety of biomarkers, which offer the potentialfor enabling precision diagnostics and prognostics, as well as targeted patientrecruitment of relatively homogeneous subgroups of subjects for clinicaltrials.

AV-1451不能用于非AD tau蛋白病变的神经影像学分析

Title: Pathologiccorrelations of [F-18]-AV-1451 imaging in non-Alzheimer tauopathies.

Author information:Marquié et al.

Journal：AnnNeurol. 2016 Dec 20.

Abstract

OBJECTIVE:

Recent studieshave shown that PET tracer AV-1451 exhibits high binding affinity for pairedhelical filament (PHF)-tau pathology in Alzheimer's brains. However, theability of this ligand to bind to tau lesions in other tauopathies remainscontroversial. Our goal was to examine the correlation of in vivo andpostmortem AV-1451 binding patterns in three autopsy-confirmed non-Alzheimertauopathy cases.

METHODS:

We quantified invivo retention of [F-18]-AV-1451 and performed autoradiography, [H-3]-AV-1451binding assays and quantitative tau measurements in postmortem brain samplesfrom two Progressive Supranuclear Palsy (PSP) cases and a MAPT P301L mutationcarrier. They all underwent [F-18]-AV-1451 PET imaging prior to death.

RESULTS:

The three subjectsexhibited [F-18]-AV-1451 in vivo retention predominantly in basal ganglia andmidbrain. Neuropathologic examination confirmed the PSP diagnosis in the firsttwo subjects; the MAPT P301L mutation carrier had an atypical tauopathycharacterized by grain-like tau-containing neurites in grey and white matterwith heaviest burden in basal ganglia. In all three cases, autoradiography failedto show detectable [F-18]-AV-1451 binding in multiple brain regions examinedwith the exception of entorhinal cortex (reflecting incidental age-relatedneurofibrillary tangles) and neuromelanin-containingneurons in the substantia nigra (off-target binding). The lack of aconsistent significant correlation between in vivo [F-18]-AV-1541 retention andpostmortem in vitro binding and tau measures in these cases suggests that thisligand has low affinity for tau lesions primarily made of straight tau filaments.

INTERPRETATION:

AV-1451 may have limited utility for in vivo selectiveand reliable detection of tau aggregates in these non-Alzheimer tauopathies. Thisarticle is protected by copyright. All rights reserved.

TREM2突变在不同疾病中具有不同的结构和功能机制

Title: Neurodegenerativedisease mutations in TREM2 reveal a functional surface and distinctloss-of-function mechanisms.

Author information:Kober et al.

Journal: Elife.2016 Dec 20;5. pii: e20391.

Abstract

Genetic variationsin the myeloid immune receptor TREM2 are linked to several neurodegenerativediseases. To determine how TREM2 variants contribute to these diseases, weperformed structural and functional studies of wild-type and variant proteins.Our 3.1 Å TREM2 crystal structure revealed that mutations found in Nasu-Hakoladisease are buried whereas Alzheimer's disease risk variants are found on thesurface, suggesting that these mutations have distinct effects on TREM2function. Biophysical and cellular methods indicate that Nasu-Hakola mutationsimpact protein stability and decrease folded TREM2 surface expression, whereasAlzheimer's risk variants impact binding to a TREM2 ligand. Additionally, theAlzheimer's risk variants appear to epitope map a functional surface on TREM2that is unique within the larger TREM family. These findings provide a guide tostructural and functional differences among genetic variants of TREM2,indicating that therapies targeting theTREM2 pathway should be tailored to these genetic and functional differenceswith patient-specific medicine approaches for neurodegenerative disorders.

腺苷酸环化酶激活肽有助于治疗脊肌萎缩症

Title: Adenylylcyclase activating polypeptide reduces phosphorylation and toxicity of thepolyglutamine-expanded androgen receptor in spinobulbar muscular atrophy.

Author information:Polanco et al.

Journal: SciTransl Med. 2016 Dec 21;8(370):370ra181.

Abstract

Spinobulbarmuscular atrophy (SBMA) is an X-linked neuromuscular disease caused bypolyglutamine (polyQ) expansion in the androgen receptor (AR) gene. SBMAbelongs to the family of polyQ diseases, which are fatal neurodegenerativedisorders mainly caused by protein-mediated toxic gain-of-function mechanisms andcharacterized by deposition of misfolded proteins in the form of aggregates.The neurotoxicity of the polyQ proteins can be modified by phosphorylation atspecific sites, thereby providing the rationale for the development ofdisease-specific treatments. We sought to identify signaling pathways thatmodulate polyQ-AR phosphorylation for therapy development. We report thatcyclin-dependent kinase 2 (CDK2) phosphorylates polyQ-AR specifically at Ser96Phosphorylation of polyQ-AR by CDK2 increased protein stabilization andtoxicity and is negatively regulated by the adenylyl cyclase (AC)/proteinkinase A (PKA) signaling pathway. To translate these findings into therapy, wedeveloped an analog of pituitaryadenylyl cyclase activating polypeptide (PACAP), a potent activator of theAC/PKA pathway. Chronic intranasal administration of the PACAP analog toknock-in SBMA mice reduced Ser96 phosphorylation, promoted polyQ-ARdegradation, and ameliorated disease outcome. These results provide proof ofprinciple that noninvasive therapy based on the use of PACAP analogs is atherapeutic option for SBMA.

尿嘧啶核苷可以用于治疗CAD突变的癫痫脑病

Title: CADmutations and uridine-responsive epileptic encephalopathy.

Author information:Koch et al.

Journal: Brain.2016 Dec 21.

Abstract

Unexplained globaldevelopmental delay and epilepsy in childhood pose a major socioeconomicburden. Progress in defining the molecular bases does not often translate intoeffective treatment. Notable exceptions include certain inborn errors ofmetabolism amenable to dietary intervention. CAD encodes a multifunctionalenzyme involved in de novo pyrimidine biosynthesis. Alternatively, pyrimidinescan be recycled from uridine. Exome sequencing in three families identifiedbiallelic CAD mutations in four children with global developmental delay,epileptic encephalopathy, and anaemia with anisopoikilocytosis. Two died aged 4and 5 years after a neurodegenerative disease course. Supplementation of thetwo surviving children with oral uridine led to immediate cessation of seizuresin both. A 4-year-old female, previously in a minimally conscious state, beganto communicate and walk with assistance after 9 weeks of treatment. A3-year-old female likewise showed developmental progress. Blood smearsnormalized and anaemia resolved. We establish CAD as a gene confidentlyimplicated in this neurometabolic disorder, characterized by co-occurrence ofglobal developmental delay, dyserythropoietic anaemia and seizures. While thenatural disease course can be lethal in early childhood, our findings supportthe efficacy of uridine supplementation, rendering CAD deficiency a treatableneurometabolic disorder and therefore a potential condition for future(genetic) newborn screening.

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