Alzheimer’s in the Human Brain: Focusing on One Neuron at a Time

Inma Cobos, MD, PhD
Stanford University (Stanford, CA)

Collaborators

Giovanni Coppola, MD
University of California, Los Angeles
Weizhe Hong, PhD
University of California, Los Angeles
Year Awarded:
2017
Grant Duration:
July 1, 2017 to June 30, 2021
Disease:
Alzheimer's Disease
Award Amount:
$300,000
Grant Reference ID:
A2017346S
Award Type:
Standard
Award Region:
US Southwestern

This grant is made possible in part by support from Alzheimer’s Los Angeles.

Inma Cobos, MD, PhD

The gift of brain donation from patients and their families is enabling our discoveries… [and is] a major driver to do our best for giving back hope and cures

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A Cell-Type Approach to Defining Selective Vulnerability to Alzheimer’s in the Human Brain

Summary

A close look at brain tissue from Alzheimer’s disease (AD) patients reveals that only some types of neurons have tau neurofibrillary tangles or others signs of neurodegeneration, while others in close vicinity appear healthy. What makes some neurons more vulnerable or resistant to disease? We are using a new technique, called single cell RNA sequencing, to isolate thousands of single neurons from human brain tissue, study all the genes that are expressed in each individual cell, and make cell-to-cell comparisons between normal, early stage and late stage AD. Our studies will clarify the precise identity of neurons involved by pathology and undergoing cell death in AD, and point to the main molecular pathways that confer vulnerability or resistance to disease. 

Details

A microscopic view of brain tissue from Alzheimer disease (AD) patients reveals that only some neurons display tau neurofibrillary tangles and others signs of neurodegeneration, while others in close vicinity appear healthy. What makes some neurons more vulnerable or resilient to disease?  

Our studies aim to define the precise identity of neurons that are affected in AD, and uncover the relevant genes and molecular pathways that confer cell-type specific vulnerability or resilience to disease. For that, we are using quantitative neuroanatomical studies combined with single cell RNA sequencing from postmortem human brains. Single cell RNA sequencing is a revolutionary new approach that can isolate thousands of single cells, study gene expression in each individual cell, and make robust cell-to-cell comparisons. We are studying cortical areas that are affected at early and late stages of disease progression to provide a comprehensive landscape of the progression of molecular changes. Neuroanatomical studies in the postmortem AD brain strengthen this study by adding validation, spatial resolution, and correlation with human pathology. The latter is key to bridge basic knowledge and clinical relevance. This study will identify the earliest affected disease pathways, as well as neuroprotective pathways, and potentially will aid early detection of AD and the design of targeted therapies.

About the Researcher

Dr. Inma Cobos received her MD in 1996, and PhD in 2000, from the University of Murcia, Spain, then did post-doctoral training in developmental neurobiology at the University of California, San Francisco (2001-07). She next pursued a clinical residency and fellowship in anatomic pathology and neuropathology at Massachusetts General Hospital (MGH), Harvard Medical School (2011-15). At MGH, Dr. Cobos trained with world-class leaders in neuropathology, neurology, neuroimaging and molecular pathology. As the Alzheimer Disease Research Center (ADRC) fellow, she was responsible for the processing, analysis and diagnosis of brains donated to the ADRC Brain Bank. This intensive training provided her with exceptional experience-based knowledge in the diagnosis and classification of neurodegenerative diseases and clinicopathological correlations. Dr. Cobos is currently an assistant professor in the Department of Pathology and Laboratory Medicine, Division of Neuropathology, at UCLA David Geffen School of Medicine and the Ronald Reagan Medical Center. Her laboratory focuses on understanding the basic mechanisms underlying the generation and maintenance of cell diversity in the brain, and the cellular and molecular basis of selective vulnerability in neurodegeneration. As a neuropathologist with extensive experience in molecular, cellular, and developmental neuroscience, Dr. Cobos is well positioned to significantly contribute to our understanding of the pathogenesis of neurodegenerative disorders.

Personal Story

Early on in my career, I became fascinated by the developmental processes that generate the myriad neuronal types in the brain and shape the neuronal circuit architectures that allow us to think, imagine, remember, and express sophisticated emotional and cognitive behaviors. My PhD and post-doctoral work used animal models to explore the basic mechanisms of neuronal specification, migration and differentiation in the developing and maturing brain, and how alterations in these mechanisms can lead to neuropsychiatric disorders. Eager to gain knowledge in the pathogenesis and diagnosis of human brain disorders, I then decided to pursue specialized training in neuropathology. I am currently an assistant professor at UCLA, where I participate in the Neuropathology clinical service and lead a research laboratory. My research combines diagnostic neuropathology skills, knowledge in developmental neuroscience, and state-of-the-art cellular and molecular techniques to advance our understanding of Alzheimer disease pathogenesis in the human brain. Our ultimate goal is to identify therapeutic targets that can alleviate symptoms and modify disease progression. The gift of brain donation from patients and their families is not only enabling our discoveries but also a major driver to do our best for giving back hope and cures. 

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