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Targeting Rab6-km23-1-mediated compartmentalized trafficking as a novel therapeutic approach to Alzheimers Disease

靶向 Rab6-km23-1 介导的区室化运输作为阿尔茨海默病的新型治疗方法

基本信息

批准号：
9756263
负责人：
Lance Allen Liotta
金额：
$ 19.14万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-15 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9756263
关键词：
Age Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid Amyloid beta-Protein Precursor Animal Model Area Binding Brain C-terminal Carrier Proteins Cell model Cells Clinical Trials Complex Computer Simulation DNA Sequence Alteration Dendrites Down Syndrome Drug Targeting Dynein ATPase Endosomes Engineering Enzymes Event Failure Family Functional disorder Golgi Apparatus Growth Hippocampus (Brain)Hot Spot Human Individual Lead Light Location MAP Kinase Gene Mediating Mediator of activation protein Modeling Motor Mus Mutation Nerve Neurites Neurons Organelles Outcome Paint Pathogenesis Pathology Pathway interactions Patients Peptides Play Presenile Alzheimer Dementia Prevention strategy Process Production Protein Family Protein Fragment Protein Region Proteins Proteolysis Recycling Regulation Rodent Role Route Senile Plaques Signal Transduction Site Sorting - Cell Movement Structural Models Surface Synapses Technology Testing Therapeutic Therapeutic Agents Transport Vesicles Vesicle Vesicle Transport Pathway alpha secretase amyloid peptide amyloid precursor protein processing axonopathy base beta secretase beta-site APP cleaving enzyme 1 design disease phenotype familial Alzheimer disease human model induced pluripotent stem cell inhibitor/antagonist link protein member mutant neuron loss neuronal cell body next generation novel novel strategies novel therapeutic intervention novel therapeutics peptide drug prevent protein complex protein protein interaction protein transport rab GTP-Binding Proteins retrograde transport spatiotemporal synthetic peptide targeted treatment therapeutic target trafficking

项目摘要

Summary The amyloid hypothesis as the cause for Alzheimer's Disease (AD) has recently come under fire due to the failure of so many clinical trials for amyloid peptide (Aß)-targeting therapies. However, it may be that amyloid precursor protein (APP) itself, or the C-terminal fragment-ß (CTFß) produced by ß-secretase (BACE1) cleavage, is the actual culprit in AD, having a more direct role in AD than previously thought. In the current proposal, we will study a novel approach to reducing early-stage AD by targeting the protein-protein interaction of a complex (km23-1–Rab6) that we propose controls the trafficking of APP and the rate-limiting enzyme (BACE1) in APP processing. More specifically, we will test the novel hypothesis that APP and BACE1 are transported in km23-1–Rab6 vesicles to the Golgi, where CTFß is produced to play a role in neurite outgrowth and dendritic branching. We hypothesize, further, that APP or CTFß accumulation here in AD causes exuberant and aberrant hippocampal axodentritic sprouting, eventually leading to diminish dendritic arbor complexity and breakage of neuronal branches. We will examine the km23-1–Rab6-mediated transport of APP and BACE1 to the Golgi, as well as the effects of the resulting APP fragments on dendritic branching. The results will provide a stronger basis for targeting the physical association of APP and BACE1 at Golgi sites, to reduce BACE1 activity and the subsequent production of APP intermediates. Α greater understanding of the mechanisms underlying km23-1–Rab6 regulation of APP and BACE1 interactions at the Golgi to control dendritic arborization should facilitate targeting this key trafficking event to reduce early AD-associated causal events. Our structural modeling of the km23-1–Rab6 complex revealed “hot spots” for the precise sites of protein- protein interaction. In Aim 1, we will examine the effects of site-specific mutants of the proteins on the spatiotemporal regulation of km23-1–Rab6 complexes, as well as on APP/BACE1 association and compartment location. The focus will be on APP and BACE1 association at soma Golgi, as well as at Golgi outposts (GOs) in developing dendrites, in order to better understand the mechanisms underlying APP trafficking, processing, and signaling at these specific regions. In Aims 2 and 3, we will us in silico modeling and apply a novel Protein Painting technology to reveal the unique interface by which km23-1 interacts with Rab6 in regulating APP trafficking and processing. The precise interaction region will be used to design corresponding peptide inhibitors to be tested for inhibitory effects on km23-1–Rab6 complex formation, APP processing, and AD-associated pathologies. While the majority of previous studies have used rodent familial AD (FAD) models, here we will apply human models that recapitulate sporadic AD (sAD) to test our novel km23-1–Rab6 inhibitors. The use of the hidden contact regions between these critical interacting proteins as drug targets will lead to paradigm-shifting therapies, overcoming the limitations with past therapeutic strategies. The novel therapeutic agents for AD developed as a result of the proposed studies will be among critical members of the next generation of AD-targeted therapeutics.

总结