Temporal and spatial aspects of amyloidogenesis in sporadic Alzheimer disease

散发性阿尔茨海默病淀粉样蛋白生成的时间和空间方面

基本信息

批准号：
10630162
负责人：
MALCOLM A LEISSRING
金额：
$ 62.62万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10630162
关键词：
ABCB1 gene Abeta clearance Abeta synthesis Address Age Aging Alzheimer like pathology Alzheimer&apos s Disease Alzheimer&apos s disease risk Amyloid Amyloid beta-Protein Animal Model Animals Aspartic Endopeptidases Basic Science Blood - brain barrier anatomy Brain Cathepsins Cells Cerebrum Chronic Clinical Clinical Trials DNA Sequence Alteration Data Defect Deposition Development Diffuse Disease Down-Regulation Early Diagnosis Elderly Environment Etiology Exploratory/Developmental Grant for Diagnostic Cancer Imaging Genetic Goals Grant Human Impairment Innovative Therapy Knock-in Mouse Lead Life Link Memory Loss Methods Modeling Mus Mutation Neprilysin Nerve Degeneration Neuronal Dysfunction Neurons Pathogenesis Pathologic Pathology Peptide Hydrolases Proteins Publishing Risk Factors Role Senile Plaques Stress Study models Symptoms Tariquidar Testing Time Traumatic Brain Injury Twin Multiple Birth Work abeta deposition age related aged amyloidogenesis effective therapy empowerment experimental study extracellular familial Alzheimer disease human old age (65+)improved inhibitor innovation insight interest mouse model normal aging novel poor sleep promoter therapeutically effective

项目摘要

PROJECT SUMMARY/ABSTRACT Rare forms of familial Alzheimer disease (fAD) are known to be caused by life-long, genetically determined perturbations in the production of the amyloid ß-protein (Aß), but the cause(s) of the vast majority of so-called sporadic AD (sAD) cases remains remarkably poorly defined. This proposal will use state-of-the-art mouse models of sAD together with several highly innovative approaches to address key temporal and spatial aspects of sAD pathogenesis for the first time, with critical implications for the development of effective therapies. Whereas fAD is attributable to chronic perturbations in the production of Aß, we hypothesize that sAD is triggered by impairments in the clearance of Aß—specifically by transient impairments in Aß clearance. This hypothesis is consistent with evidence showing that several established risk factors for sAD, such as brain trauma, stress, or poor sleep, lead to short-lived or episodic increases in cerebral Aß levels due to reduced Aß clearance. To model this novel mechanistic hypothesis, we employ innovative methods to inhibit Aß clearance transiently and reversibly by blocking either blood-brain barrier transport of Aß or its proteolytic degradation. Because we aim to define the triggers for sAD, we require an animal model that does not develop AD-type pathology on its own, as most AD mouse models do. To this end, we will use an innovative new sAD mouse model, the APPNL-F/hAß mice, which expresses wild-type human Aß only, under the control of the endogenous murine App promoter, with the minimal genetic mutations needed to model sAD. As is true for normal humans, this sAD mouse model develops diffuse deposits of human Aß in an age-dependent manner, and forms very minimal dense-core plaques only at very advanced ages. Accordingly, these mice are ideal for investigating the pathophysiological mechanisms responsible for triggering the conversion of “normal” Aß deposition to the pathological type in sAD. We hypothesize further that the Aß-dependent pathological mechanisms most relevant to sAD occur much earlier than the ages studied in clinical trials, with clinical symptoms emerging only much later, specifically in the context of aging. Accordingly, we will define the temporal window most relevant to the emergence of AD by increasing Aß levels in APPNL-F/hAß mice transiently at various ages, then evaluating the consequences for the development of AD-type pathology longitudinally, up to and including old age. Finally, we will test the novel hypothesize that spatially distinct pools of Aß (e.g., extra- vs. intracellular) impact the pathogenesis of AD in qualitatively different ways. Specifically, we postulate that intracellular Aß is more relevant than extracellular Aß to the neurodegeneration and memory loss that characterize AD. To test this, we will selectively increase extra- vs. intracellular pools of Aß by reversibly downregulating Aß-degrading proteases that, as our preliminary results show, selectively regulate these distinct pools of Aß. Collectively, these experiments will allow us to investigate, cleanly and for the first time, many critical temporal and spatial aspects of AD pathogenesis, yielding novel insights that will inform improved approaches to the treatment of sAD.

项目概要/摘要罕见形式的家族性阿尔茨海默病 (fAD) 已知是由终生遗传决定的 β-淀粉样蛋白 (Aß) 的产生受到干扰，但绝大多数所谓的散发性 AD (sAD) 病例的定义仍然非常模糊。该提案将使用最先进的鼠标。 SAD 模型以及几种高度创新的方法来解决关键的时间和空间方面首次揭示了 sAD 的发病机制，对有效疗法的开发具有重要意义。尽管 fAD 归因于 Aß 产生的慢性扰动，但我们勇敢地说，sAD 是被触发的 Aß 清除率受损，特别是 Aß 清除率短暂受损。与表明一些已确定的 SAD 危险因素的证据一致，例如脑外伤、压力、或睡眠不佳，由于 Aß 清除率降低，导致大脑 Aß 水平短暂或间歇性升高。为了模拟这种新的机制假设，我们采用创新方法来暂时抑制 Aß 清除，通过阻断 Aß 的血脑屏障转运或其蛋白水解降解来可逆地实现这一目标。为了定义 SAD 的触发因素，我们需要一个不会自行发展 AD 型病理的动物模型，与大多数 AD 小鼠模型一样，我们将使用创新的新型 sAD 小鼠模型 APPNL-F/hAß。小鼠，仅表达野生型人类 Aß，在内源性鼠 App 启动子的控制下，与正常人类一样，该 sAD 小鼠模型具有最少的基因突变。以年龄依赖性方式形成人类 Aß 的弥漫性沉积，并形成非常小的致密核心因此，这些小鼠非常适合研究病理生理学。负责触发“正常”Aß 沉积转化为 SAD 病理类型的机制。我们进一步认为，与 sAD 最相关的 Aß 依赖性病理机制发生得很多比临床试验中研究的年龄更早，临床症状出现的时间要晚得多，特别是在因此，我们将定义与 AD 出现最相关的时间窗口：在不同年龄阶段短暂增加 APPNL-F/hAß 小鼠的 Aß 水平，然后评估其后果 AD 型病理的纵向发展，直至并包括老年。最后，我们将测试空间上不同的 Aß 池（例如，细胞外与细胞内）影响的新颖性具体来说，我们假设细胞内的 Aß 更重要。与细胞外 Aß 相比，AD 特征的神经变性和记忆丧失更相关。通过可逆性下调 Aß 降解蛋白酶，选择性增加细胞外和细胞内的 Aß 池正如我们的初步结果所示，选择性地调节这些不同的 Aß 池。实验将使我们能够第一次彻底地研究许多关键的时间和空间方面 AD 发病机制的研究，产生新的见解，将为改进 SAD 的治疗方法提供信息。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Prominent tauopathy and intracellular β-amyloid accumulation triggered by genetic deletion of cathepsin D: Implications for Alzheimer disease pathogenesis.

组织蛋白酶 D 基因缺失引发的显着 tau 病和细胞内 β-淀粉样蛋白积累：对阿尔茨海默病发病机制的影响。

DOI：
发表时间：
2023-10-23
期刊：
影响因子：
0
作者：
Terron, Heather M;Parikh, Sagar J;Abdul;Sahara, Tomoko;Kang, Dongcheul;Dickson, Dennis W;Saftig, Paul;LaFerla, Frank M;Lane, Shelley;Leissring, Malcolm A
通讯作者：
Leissring, Malcolm A

Prominent tauopathy and intracellular β-amyloid accumulation triggered by genetic deletion of cathepsin D: implications for Alzheimer disease pathogenesis.

组织蛋白酶 D 基因缺失引发的显着 tau 病和细胞内 β 淀粉样蛋白积累：对阿尔茨海默病发病机制的影响。

DOI：
发表时间：
2024-04-04
期刊：
影响因子：
0
作者：
Terron, Heather M;Parikh, Sagar J;Abdul;Sahara, Tomoko;Kang, Dongcheul;Dickson, Dennis W;Saftig, Paul;LaFerla, Frank M;Lane, Shelley;Leissring, Malcolm A
通讯作者：
Leissring, Malcolm A

Insulin-Degrading Enzyme: Paradoxes and Possibilities.

胰岛素降解酶：悖论和可能性。

DOI：
发表时间：
2021
期刊：
影响因子：
6
作者：
Leissring; Malcolm A
通讯作者：
Malcolm A

Effects of Fasting and Feeding on Transcriptional and Posttranscriptional Regulation of Insulin-Degrading Enzyme in Mice.

禁食和进食对小鼠胰岛素降解酶转录和转录后调节的影响。

DOI：
发表时间：
2021
期刊：
影响因子：
6
作者：
González;Cámara;Merino, Beatriz;Diez;Postigo;Leissring, Malcolm A;Cózar;Perdomo, Germán
通讯作者：
Perdomo, Germán

A Dual-Function "TRE-Lox" System for Genetic Deletion or Reversible, Titratable, and Near-Complete Downregulation of Cathepsin D.

用于组织蛋白酶 D 基因删除或可逆、可滴定和近乎完全下调的双功能“TRE-Lox”系统。

DOI：
发表时间：
2023-04-04
期刊：
影响因子：
5.6
作者：
Terron, Heather M;Maranan, Derek S;Burgard, Luke A;LaFerla, Frank M;Lane, Shelley;Leissring, Malcolm A
通讯作者：
Leissring, Malcolm A