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

A close look at brain tissue from Alzheimer’s disease (AD) patients reveals that only some types of neurons have tau neurofibrillary tangles or other signs of neurodegeneration. In contrast, 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.

Grantee institution at the time of this grant: University of California, Los Angeles

A microscopic view of brain tissue from Alzheimer’s disease (AD) patients reveals that only some neurons display tau neurofibrillary tangles and other 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 the 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.