Are mechanisms leading to FAD, SAD and age-associated cognitive decline similar?
导致 FAD、SAD 和与年龄相关的认知能力下降的机制是否相似?
基本信息
- 批准号:10792026
- 负责人:
- 金额:$ 179.27万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-08-01 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Abstract
Alzheimer’s Disease (AD) is the most common cause of ageing-dependent dementia in the
world and is associated with cerebral amyloid plaques, mostly composed of Aβ peptides. These
peptides are produced by a double cleavage of the amyloid precursor protein (APP). BACE1
cleavage produces the C-terminal fragment, β-CTF, which is then processed into several Aβ
isoforms by γ-secretase. Genetic data suggest that regulation of APP processing contributes to
AD. In addition, a polymorfism of APP that reduces processing of APP by BACE1 protects from
sporadic AD and from normal aging-dependent cognitive decline. Thus, the human genetic
evidence indicates that APP and APP processing are important for normal cognitive functions.
To gain insights into the pathogenic mechanisms of AD and the mechanisms by which the
protective mutation protects humans from AD and normal aging-dependent cognitive decline,
we introduced a familial APP mutation (the Swedish K670N/M671L mutation, Apps rats), the
protective APP mutation (Appp rats) and a familial PSEN1 mutation (L435F, Psen1LF rats) into
the genomic App and Psen1 rat loci, respectively. Rat and human APP differ by 3 amino-acids
in the Aβ region: given that aggregated forms of Aβ are considered by most the main
pathogenic factor in AD, and given that human Aβ may have higher propensity than rodent Aβ
to form yet-to-be-identified toxic forms of Aβ, together with the Swedish mutations we
introduced mutations to “humanize” the rat Aβ sequence. As controls, we produced rats
carrying only the humanized Aβ sequence (Apph rats). We choose a knock in (KI) approach
rather than the more common transgenic overexpression approach because KI models make
no preconceived assumption about pathogenic mechanisms, except the unbiased genetic one.
In contrast, transgenic models, which produce high levels of Aβ and can readily deposit
amyloid plaques, are based on the hypothesis that plaques and/or other forms of toxic Abβ have
a central pathogenic role. We propose to dissect protective mechanisms triggered by the rare
protective APP variant using these KI rat models. We will study the impact of Appp on the
pathological processes triggered by the Apps and Psen1LF FAD mutations and on normal aging-
dependent cognitive decline. We will analyze APP processing, brain pathology, neuro-
inflammation and neurodegeneration, synaptic transmission/plasticity, learning & memory.
Dissecting protective pathways set off by the Appp variant may pave the way to therapeutic
approaches that can prevent dementia as well as “normal” cognitive decline mimicking the
mechanisms triggered by the protective APP variant.
摘要
阿尔茨海默病(AD)是老年痴呆症的最常见原因,
与脑淀粉样斑块有关,主要由Aβ肽组成。这些
肽是通过淀粉样前体蛋白(APP)的双切割产生的。BACE1
切割产生C-末端片段β-CTF,然后加工成几个Aβ
通过γ-β分泌酶的同种型。遗传数据表明,APP加工的调节有助于
AD.此外,APP的多晶型减少了BACE 1对APP的加工,
散发性AD和来自正常老化的依赖性认知衰退。因此,人类基因
有证据表明APP和APP加工对于正常的认知功能是重要的。
为了深入了解AD的致病机制以及AD的发病机制,
保护性突变保护人类免受AD和正常衰老--阿尔茨海默病依赖性认知衰退,
我们引入了一种家族性APP突变(瑞典K670 N/M671 L突变,Apps大鼠),
保护性APP突变(Appp大鼠)和家族性PSEN 1突变(L435 F,Psen 1 LF大鼠),
基因组App和Psen 1大鼠基因座。大鼠和人APP相差3个氨基酸
在Aβ区域:鉴于大多数主要研究者认为Aβ的聚集形式
AD中的致病因子,并且考虑到人Aβ可能比啮齿动物Aβ具有更高的倾向
形成尚未确定的Aβ毒性形式,与瑞典突变一起,我们
引入突变以“人源化”大鼠Aβ序列。作为对照组,
仅携带人源化Aβ序列(Apph大鼠)。我们选择敲入(KI)方法
而不是更常见的转基因过表达方法,因为KI模型使
没有关于致病机制的先入为主的假设,除了无偏见的遗传。
相反,转基因模型产生高水平的Aβ,并且容易存款,
淀粉样蛋白斑块,是基于这样的假设,即斑块和/或其他形式的有毒Abβ具有
一个重要的致病作用。我们建议剖析由罕见的
保护性APP变体使用这些KI大鼠模型。我们将研究Appp对
由Apps和Psen 1 LF FAD突变触发的病理过程和正常衰老-
依赖性认知衰退我们将分析APP处理,大脑病理学,神经学
炎症和神经变性,突触传递/可塑性,学习和记忆。
解剖由Appp变异体引发的保护性通路可能为治疗铺平道路。
这种方法可以预防痴呆症以及模仿老年痴呆症的“正常”认知能力下降。
由保护性APP变体触发的机制。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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LUCIANO D'ADAMIO其他文献
LUCIANO D'ADAMIO的其他文献
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Studies of dementia pathogenesis in genetically faithful rat models of Familal Alzheimer disease
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