Biochemical and Immunohistochemical Analysis of FTDs

额颞叶痴呆（Frontotemporal dementia，FTD）是一组异质性的散发性和家族性神经退行性疾病。大约一半的FTD患者在神经元和神经胶质中出现大量tau病变。这组FTD的家族对应物被称为与17号染色体相关的额颞叶痴呆伴帕金森综合征（FTDP-17），其包括具有类似于散发性疾病的表型的患者，如进行性核上性麻痹（PSP）、皮克病（PiD）、皮质基底变性（CBD）和嗜银颗粒病（AGD）。与以显著tau病理为特征的FTD相反，其余FTD患者的大脑缺乏独特的神经病理学病变，称为痴呆 缺乏独特的组织病理学（DLDH）或显示泛素阳性，但tau和α-突触核蛋白（α-syn）阴性内含物，伴或不伴运动神经元疾病（FTD-MND）。为了阐明FTDs潜在机制之间的相似性和差异，项目3的目标是使用生物化学，免疫组织化学和超微结构方法表征FTDs的神经病理学，特别强调测试辅助因子（如α-syn，硫酸乙酰肝素或氧化剂）在调节tau病理学（包括tau病变的同种型组成）中发挥不同作用的假设。其他研究将确定氨基或羧基末端截短的tau片段是否作为“种子”来促进tau融合。最后，为了进一步 为了研究不同FTDs的病因和发病机制，项目3还将通过分离泛素阳性、tau和α-syn阴性包涵体并确定这些包涵体的蛋白质构建块来检查FTD-MND。项目3中提出的研究的成功完成将解决FTDs的基本疾病机制，与该项目资助的其他项目的研究进展相结合，将加速为不同FTDs患者找到更好的治疗干预措施的努力。

Frontotemporal dementia (FTD) is a group of heterogeneous sporadic and familial neurodegenerative disorders. Approximately half of the patients with FTD develop abundant tau pathologies in neurons and glia. The familial counterpart of this group of FTDs is known as frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) which includes patients with phenotypes similar to sporadic disorders like progressive supranuclear palsy (PSP), Pick's disease (PiD), cortical basal degeneration (CBD), and argyrophilic grains disease (AGD). In contrast to FTD characterized by prominent tau pathologies, the brains of the remaining FTD patients either lack distinctive neuropathological lesions, referred to as dementia lacking distinctive histopathology (DLDH) or show ubiquitin-positive, but tau and alpha-synuclein (alpha-syn) negative inclusions with or without motor neuron disease (FTD-MND). To clarify similarities and differences among mechanisms underlying FTDs, the goals of Project 3 are to characterize the neuropathology of FTDs using biochemical, immunohistochemical and ultrastructural methods with specific emphasis on testing the hypothesis that cofactors such as alpha-syn, heparan sulfate, or oxidants play distinct roles in regulating tau pathologies including the isoform composition of tau lesions. Other studies will determine if amino or carboxy-terminal truncated tau fragments serve as "seeds" to facilitate tau fibrillization. Finally, to further investigate the etiology and pathogenesis of distinct FTDs, Project 3 also will examine FTD-MND by isolating the ubiquitin-positive, tau and alpha-syn negative inclusions and determining the protein building blocks of these inclusions. Successful completion of the studies proposed in Project 3 will address fundamental disease mechanisms of FTDs, which, in conjunction with research advances from other projects in this Program Project Grant will accelerate efforts to find better therapeutic interventions for patients with diverse FTDs.