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How does the release of components from damaged nerve cells impact the development of early Alzheimer’s?
Tatiana Alvarez Giovannucci, Ph.D.
University College London
London, United Kingdom
Background
Research suggests that the brain changes associated with Alzheimer’s start decades before memory loss and other clinical signs become evident. Such changes include early brain cell damage, which results in proteins called neurofilaments (components of nerve cell structure) being dispersed into the “extracellular” spaces between brain cells and, ultimately, the blood and cerebrospinal fluid (or CSF, the biological fluid surrounding the brain and spinal cord). Scientists have long measured one type of neurofilament, called neurofilament light chain protein (NfL), as a biological marker, or “biomarker,” of early Alzheimer’s. However, other types of neurofilament proteins, such as neurofilament medium (NfM) and neurofilament heavy (NfH), may also be linked to early brain damage in Alzheimer’s. Moreover, researchers have not yet clarified exactly how neurofilaments become secreted from nerve cells – whether this process results from nerve cell damage or from other disease-related mechanisms.
Research Plan
Dr. Tatiana Alvarez Giovannucci and colleagues will study the role of neurofilaments in early Alzheimer’s using a type of stem cell collected from adult human tissue called iPSCs (induced Pluripotent Stem Cells). iPSCs can be programmed to grow into any type of cell in the body, including nerve cells. The iPSCs used for this study will be collected from cells of individuals with familial Alzheimer’s, a rare inherited form of Alzheimer’s in which people develop the disease at an early age, usually in their forties.
First, the researchers will assess how the different neurofilament proteins are produced and secreted in iPSC nerve cells using a method called stable isotope labeling kinetics (SILK), which will “highlight” and measure changes in protein production and clearance in brain tissue. Next, the investigators will study the role of microglia (a type of immune cell in the brain) in the processing of neurofilament proteins. Microglia normally work to clear unwanted substances from the brain, including secreted neurofilaments. Dr. Alvarez Giovannucci and team will explore the links between microglia and neurofilaments by developing microglial cells from familial Alzheimer’s disease iPSCs. They will then incorporate these microglia into laboratory dishes with iPSC nerve cells, and use the SILK technique to study how microglial activity impacts neurofilament processing.
Lastly, the researchers will look for other secreted proteins from iPSC nerve cells that may be linked to early Alzheimer’s. They will also determine how microglia are involved in the processing of these proteins.
Impact
The results of this project could refine our understanding of how damage to neurons promotes the early development of dementia. Such work could lead to novel methods of diagnosing early-stage Alzheimer’s.
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