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Molecular pathways leading to neurodegeneration in vivo

导致体内神经变性的分子途径

基本信息

批准号：
9472989
负责人：
Brian J Bacskai
金额：
$ 46.73万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-15 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9472989
关键词：
Affect Age Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid Amyloid beta-Protein Antibodies Biological Assay Biological Neural Networks Biology Brain Brain imaging Calcium Caspase Cell Death Cell physiology Cells Cellular Structures Cellular biology Central Nervous System Diseases Chemicals Clinic Clinical Communities Complex Consensus Dementia Diffuse Disease Disease Progression Disease model Elderly Etiology Event Functional disorder Generations Genetic Goals Health Homeostasis Image Individual Intervention Lead Link Measures Microscopy Mitochondria Modeling Molecular Monitor Mus Nerve Degeneration Neurites Neurodegenerative Disorders Neurofibrillary Tangles Neuronal Dysfunction Neurons Neurosciences Outcome Oxidative Stress Pathologic Pathology Pathway interactions Patients Peptides Physiological Preparation Process Production Protective Agents Reaction Reactive Oxygen Species Research Risk Senile Plaques Structure Techniques Testing Therapeutic Therapeutic Intervention Time Toxic effect Transgenic Mice Transgenic Model Transgenic Organisms Translating Vertebral column Work amyloid pathology amyloid peptide antioxidant therapy base cellular imaging cellular targeting cytotoxic effective therapy fluorescence imaging functional outcomes imaging probe in vivo in vivo imaging insight intravital imaging misfolded protein mitochondrial dysfunction molecular imaging molecular targeted therapies mouse model network dysfunction neurodegenerative phenotype neuron loss pathology imaging prevent protein aggregate public health relevance therapeutic candidate tool treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Alzheimer's disease is the leading cause of dementia in the elderly, and because the number of at risk individuals is rapidly increasing, AD represents a major health crisis. At this point, while a number of key insights and clinical tools have arisen there are still no effective treatments to prevent or reverse the disease. The genetics of AD have led to a simple and plausible hypothesis of disease progression: amyloid-ß, a known cytotoxic peptide that forms both small diffusible and large insoluble aggregates, leads to neurodegeneration and AD. This simple hypothesis has led to myriad studies using high concentrations of synthetic amyloid peptide that is almost impossible to work with from a chemical biology standpoint, and absolutely leads to cell toxicity in every cell based assay used. Indiscriminate use of synthetic amyloid preparations have confounded the field, for the most part hampering and not helping research progress in AD. It is clear now that the progression of disease is a much more complex process. AD is a multifactorial disease that must include a spectrum of cellular and molecular events that change over time. Therefore, while it is impossible to ignore that Aß is somehow central to the disease, there is a clear need to determine the sequence of events in physiologically relevant models that will identify age sensitive treatment strategies. There are other key tenets of disease progression that are central, but still not clearly defined. It is well established that oxidative stress, mitochondrial alterations, and calcium dyshomeostasis are key molecular components on the pathway to cell death. However, there is no consensus as to whether these events are related, causal, or reflective of the disease. Therefore, we aim to systematically evaluate the temporal sequence of these molecular and cellular events in the living brain of the most thoroughly characterized transgenic mouse models of AD to identify the contribution of these factors, the causality of these factors, and the appropriate timing of these factors in the course of the disease to inform multifactorial therapeutic strategies based on duration and extent of progression. We will test the hypothesis that Aß leads to neurodegeneration through a pathway involving calcium dyshomeostasis, ROS generation, and mitochondrial dysregulation. To test this hypothesis, we will develop tools to image each of these endpoints in the living brain of APP mice using multiphoton microscopy that in and of themselves will be broadly useful to the neuroscience community. Finally, we will explore interventions to identify therapeutic pathways that ultimately will lead to treatments for Alzheimer's disease in patients.

项目成果

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Brian J Bacskai其他文献

Bringing amyloid into focus

将淀粉样蛋白置于焦点

DOI：
10.1038/nbt0505-552
发表时间：
2005-05-01
期刊：
NATURE BIOTECHNOLOGY
影响因子：
41.700
作者：
Todd E Golde;Brian J Bacskai
通讯作者：
Brian J Bacskai

Apolipoprotein E, especially apolipoprotein E4, increases the oligomerization of amyloid beta peptide. Gordon Research Conferences, Neurobiology of brain disorders

载脂蛋白E，尤其是载脂蛋白E4，增加淀粉样β肽的寡聚化。

DOI：
发表时间：
2012
期刊：
影响因子：
0
作者：
Tadafumi Hashimoto;Alberto Serrano-Pozo;Yukiko Hori;Hwan-Ching Tai;Kenneth W Adams;Shuko Takeda;Daniel Joyner;Diana H Thyssen;Brian J Bacskai;Matthew P Frosch;Tara L Spires-Jones;Mary Beth Finn;David M Holtzman;and Bradley T Hyman
通讯作者：
and Bradley T Hyman