Localization of fibrillar polymorphs in human brain tissue
人脑组织中纤维状多晶型物的定位
基本信息
- 批准号:10043200
- 负责人:
- 金额:$ 43.18万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-09-01 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAgreementAlzheimer&aposs DiseaseAmyloidAnatomyAreaBrainBrain regionCryoelectron MicroscopyDataDepositionDiseaseDisease ProgressionEtiologyExhibitsFoundationsGoalsHeartHistologicHumanIn SituLengthLigand BindingLocationMapsMolecularMolecular ConformationMorphologyNeurofibrillary TanglesPathologicPatternPeptidesPlayPolymorphPositron-Emission TomographyProcessResolutionRoentgen RaysRoleSamplingSpatial DistributionStructural ModelsStructureTechniquesTestingTissuesVariantVisuospatialWorkamyloid structurebrain tissuedisease phenotypedisorder subtypeinsightinterestmillimetermolecular modelingmutantpreservationprion-likeprotein aggregationsolid state nuclear magnetic resonancespatial relationshiptau Proteinstau conformation
项目摘要
Localization of fibrillar polymorphs in human brain tissue
Summary
Fibrillar aggregates of A peptides and tau protein are defining features of Alzheimer's disease
(AD) but the role these structures play in the etiology of disease remains uncertain. High
resolution cryo-electron microscopy (cryo-EM) and solid-state NMR (ssNMR) have been used to
generate a host of molecular models of fibrillar polymorphs, some or all of which may be relevant
to disease. These structural models have provided the foundation for studies demonstrating an
association of specific polymorphs with different disease subtypes. Outstanding questions remain
as to the distribution of polymorphs between and within cases. The proposed work will apply, in
situ, a structural technique that has resolution higher than immunostaining; is very sensitive to
amyloid structure; can distinguish between fibrillar polymorphs; and keeps anatomical and spatial
relationships intact. Preliminary data show that it can probe both tangles and plaques in intact
unstained tissue. In agreement with other techniques, these data indicate that there are
polymorphs of A structure between and within cases. Analogous associations have yet to be
demonstrated for tau deposits, and those associations will be tested here. The central
hypothesis of the proposed work is that the spatial distribution of structural polymorphs
in brain tissue will provide important clues as to how fibrils contribute to disease. In the
proposed studies, X-ray microdiffraction (XMD) of histological sections of brain tissue will be used
to map the locations of fibrillar polymorphs of both A and tau, generating sub-cellular (~ 5
resolution maps of polymorph abundances across millimeter-scale regions of interest. Initial work
(Specific Aim 1) will map the distribution of A and tau polymorphs in human brain tissue in
sporadic AD cases, including samples from several brain regions. These results will be compared
(Specific Aim 2) to analogous results from (i) MAPT mutant cases, (ii) PS1 cases and to (iii) cases
of occipital predominant visuo-spatial AD. Comparison to MAPT mutants will demonstrate
whether tau fibrils with distinct molecular morphologies exhibit preservation of conformational
signatures during disease spread; comparison with PS1 cases will provide analogous information
for A fibrils; comparison with occipital predominant visuo-spatial AD will probe fibrillar
conformations and polymorph distributions in disease with distinctly different patterns of
progression. The results of these studies will provide a preliminary assessment of whether or not
different fibrillar polymorphs spread by a prion-like process during disease progression and
provide insights into the mechanisms by which different strains are associated with different
disease subtypes.
人脑组织中纤维状多型体的定位
总结
A β肽和tau蛋白的纤维状聚集体是阿尔茨海默病的定义特征
(AD)但这些结构在疾病病因学中的作用仍然不确定。高
分辨率低温电子显微镜(cryo-EM)和固态NMR(ssNMR)已被用于
产生大量的纤维状多晶型物的分子模型,其中一些或全部可能是相关的
疾病。这些结构模型为研究提供了基础
特定多态性与不同疾病亚型的关联。悬而未决的问题仍然存在
关于多晶型物在病例之间和病例内的分布。拟议的工作将适用于,在
原位,一种分辨率高于免疫染色的结构技术;对
淀粉样蛋白结构;可以区分纤维状多晶型物;并保持解剖和空间
关系完好无损。初步数据显示,它可以探测完整的缠结和斑块,
未染色的组织。与其他技术一致,这些数据表明,
A β结构的多晶型物在盒之间和盒内。类似的协会还没有
证明了tau沉积物,这些关联将在这里进行测试。中央
所提出的工作的假设是,结构多态性的空间分布
将为纤维如何导致疾病提供重要线索。在
在拟议的研究中,将使用脑组织组织切片的X射线显微衍射(XMD)
为了绘制A β和tau的纤维状多晶型物的位置,产生亚细胞(~ 5 μ g/ml)的
毫米级感兴趣区域的多晶型丰度分辨率图。初步工作
(具体目标1)将绘制人类脑组织中A β和tau多态性的分布,
散发性AD病例,包括来自几个脑区的样本。这些结果将被比较
(具体目的2)与(i)MAPT突变病例、(ii)PS1病例和(iii)病例的类似结果
枕叶主导型视觉空间AD与MAPT突变体的比较将证明
具有不同分子形态的tau原纤维是否表现出构象保留
疾病传播期间的特征;与PS1病例比较将提供类似信息
对于A纤维;与枕骨主要视觉空间AD的比较将探测纤维性
构象和多晶型分布的疾病具有明显不同的模式,
进展这些研究的结果将提供一个初步评估,
不同的纤维状多晶型物在疾病进展期间通过朊病毒样过程传播,
提供了对不同菌株与不同菌株相关的机制的见解,
疾病亚型。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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LEE MAKOWSKI其他文献
LEE MAKOWSKI的其他文献
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