Neuropathological and amyloid peptide differences between DS and familial AD with duplications and missense mutations in APP gene

DS 和家族性 AD 之间的神经病理学和淀粉样肽差异（APP 基因重复和错义突变）

• 批准号: MR/S005145/1
• 负责人: Henrik Zetterberg
• 金额: $ 33.73万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS005145%2F1
• 关键词: Neuropathological; amyloid; peptide; differences; between

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the presence of amyloid plaques mainly constituted of extracellular amyloid beta peptides (Abeta) deposits in brain parenchyma and intraneuronal neurofibrillary tangles consisting of hyperphosphorylated tau protein. Additionally Abeta can be found deposited in blood vessel walls as cerebral amyloid angiopathy (CAA), a major cause of intracerebral hemorrhage. While the presence of amyloid plaques in postmortem brains is common to all AD cases including sporadic, familial and Down syndrome (DS, trisomy of chromosome 21, with overdose of the Amyloid Precursor Protein (APP) gene on Hsa21), CAA is a more prominent phenotype in familial cases with either APP duplication or certain (but not all) point mutations. The nature and mechanisms underlying these pathological and clinical differences between APP causes of AD remain unclear. We propose a unique study specifically focusing on rare and poorly studied patient groups focusing on rare and poorly studied, but potentially very informative patient groups - those with APP mutations and duplications and DS - to elucidate differences that may provide important clues for treatment. We plan to investigate the diversity of clinical and neuropathological phenotypes associated with the diversity of alterations in the APP gene by studying endo-lysosomal alterations and Abeta species neuropathological differences in human cases, novel mouse models, and in several cell types derived from iPSC lines reproducing various diseases to unravel pathophysiological mechanisms involved in specific Abeta deposition.

阿尔茨海默病（AD）是一种神经退行性疾病，其特征在于存在主要由脑实质中的细胞外淀粉样β肽（Abeta）沉积物组成的淀粉样斑块和由过度磷酸化的tau蛋白组成的神经元内神经元缠结。此外，可以发现Abeta作为脑淀粉样血管病（CAA）沉积在血管壁中，这是脑出血的主要原因。虽然淀粉样蛋白斑块在尸检脑中的存在在所有AD病例中是常见的，包括散发性、家族性和唐氏综合征（DS，21号染色体三体，Hsa 21上淀粉样蛋白前体蛋白（APP）基因过量），但CAA在具有APP复制或某些（但不是全部）点突变的家族性病例中是更突出的表型。这些病理和临床差异的APP AD原因的本质和机制仍不清楚。我们提出了一项独特的研究，专门关注罕见和研究不足的患者群体，重点关注罕见和研究不足，但可能非常有用的患者群体-APP突变和重复和DS -阐明差异，可能提供重要的治疗线索。我们计划通过研究人类病例、新型小鼠模型和源自再现各种疾病的iPSC系的几种细胞类型中的内溶酶体改变和Abeta物种神经病理学差异，来研究与APP基因改变的多样性相关的临床和神经病理学表型的多样性，以解开特定Abeta沉积所涉及的病理生理学机制。

项目成果

Susceptibility to COVID-19 Diagnosis in People with Down Syndrome Compared to the General Population: Matched-Cohort Study Using Primary Care Electronic Records in the UK.

唐氏综合症患者与普通人群相比对 COVID-19 诊断的易感性：使用英国初级保健电子记录的匹配队列研究。

• DOI: 10.1007/s11606-022-07420-9
• 发表时间: 2022-06
• 期刊: Journal of general internal medicine
• 影响因子: 5.7
• 作者: Baksh RA;Strydom A;Pape SE;Chan LF;Gulliford MC
• 通讯作者: Gulliford MC

Endosomal structure and APP biology are not altered in a preclinical mouse cellular model of Down syndrome.

• DOI: 10.1371/journal.pone.0262558
• 发表时间: 2022
• 期刊: PloS one
• 影响因子: 3.7

Using mouse models to understand Alzheimer's disease mechanisms in the context of trisomy of chromosome 21.

• DOI: 10.1016/bs.pbr.2019.10.004
• 发表时间: 2020
• 期刊: Progress in brain research
• 作者: Claudia Cannavo;Justin L. Tosh;E. Fisher;F. Wiseman

Multiple morbidity across the lifespan in people with Down syndrome or intellectual disabilities: a population-based cohort study using electronic health records

• DOI: 10.1016/s2468-2667(23)00057-9
• 发表时间: 2023-05-25
• 期刊: LANCET PUBLIC HEALTH
• 影响因子: 50
• 作者: Baksh, R. Asaad;Pape, Sarah E.;Strydom, Andre
• 通讯作者: Strydom, Andre

Understanding inequalities in COVID-19 outcomes following hospital admission for people with intellectual disability compared to the general population: a matched cohort study in the UK.

• DOI: 10.1136/bmjopen-2021-052482
• 发表时间: 2021-10-04
• 期刊: BMJ open
• 影响因子: 2.9
• 作者: Baksh RA;Pape SE;Smith J;Strydom A
• 通讯作者: Strydom A