Reducing the production of toxic Abeta peptides in Alzheimer's disease by mutating the APP cholesterol-binding site: a new therapeutic strategy?

通过突变 APP 胆固醇结合位点来减少阿尔茨海默病中有毒 Abeta 肽的产生：一种新的治疗策略？

• 批准号: MR/Y013859/1
• 负责人: Henrik Zetterberg
• 金额: $ 26.41万
• 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: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FY013859%2F1
• 关键词: Reducing; production; toxic; Abeta; peptides

Alzheimer's disease (AD) is the most common form of dementia in the elderly population and is characterized by two prominent neuropathological lesions: extracellular amyloid-beta (Abeta) containing plaques and intraneuronal fibrillary tangles comprised of aberrantly hyperphosphorylated tau protein. Current treatments targeting the amyloid pathology have had limited success so far. They aim at either reducing the production of Abeta peptides from the amyloid precursor protein or rely on immunotherapy (active or passive) to neutralize Abeta with antibodies. We previously found that by introducing a specific mutation in the cholesterol binding site of the amyloid precursor protein, we could generate short and non-toxic Abeta peptides. Here we will test i) if this specific mutation produces short and non-toxic Abeta peptides in human neuronal cells and in mouse models and, ii) when added on the top of a familial AD mutation, if it could prevent the production of toxic Abeta peptides due to AD mutation. In addition, we will develop new antibodies against these short Abeta peptides to measure their levels in biological fluids from elderly subjects with or without amyloid pathology in their brain. This project should provide data to consider early preventive treatments producing short and non-toxic Abeta peptides.

阿尔茨海默病（AD）是老年人群中最常见的痴呆形式，其特征在于两种显著的神经病理学病变：含有斑块的细胞外淀粉样蛋白-β（Abeta）和由异常过度磷酸化的tau蛋白组成的神经元内神经纤维缠结。目前针对淀粉样蛋白病理学的治疗迄今为止取得的成功有限。他们的目标是减少淀粉样前体蛋白产生的Abeta肽，或者依靠免疫疗法（主动或被动）用抗体中和Abeta。我们以前发现，通过在淀粉样前体蛋白的胆固醇结合位点引入特定突变，我们可以产生短而无毒的Abeta肽。在这里，我们将测试i）这种特定的突变是否在人类神经元细胞和小鼠模型中产生短而无毒的Abeta肽，以及ii）当添加到家族性AD突变的顶部时，它是否可以防止由于AD突变而产生有毒的Abeta肽。此外，我们将开发针对这些短Abeta肽的新抗体，以测量其在老年受试者的生物液体中的水平，无论他们的大脑中是否有淀粉样病变。该项目应提供数据，以考虑早期预防性治疗，产生短而无毒的Abeta肽。