Investigating the Role of EVs to Abate the Spreading of Neuroinflammation in FTD Linked to C9orf72 Aberrant Expansion
Abstract
Frontotemporal dementia (FTD) is a neurodegenerative disease that affects the lives of thousands of patients and families around the world. After the diagnosis of FTD, there are no available treatments to revert the pathology or to halt its progression. Moreover, FTD very often overlaps with a motor neurons disease, amyotrophic lateral sclerosis (ALS), making patient prognosis even worse. Up to now, we know that FTD is caused by the selective degeneration of neurons in two different regions of the brain, but there are still many questions that the scientific community is working restlessly to address. One of the processes that is least understood is how the disease progresses, very fast and irreversibly. One of the mechanisms that has been proposed so far is that the brain during FTD suffers a massive inflammation. The brain is composed of many different cells each one characterized by a specific role: the cells that are affected in FTD are neurons, astrocytes, and microglia. Neurons are the first ones that die, causing the clinical outcomes, but astrocytes and microglia can have a major role in inflammation and thus progression and worsening of the clinical symptoms. The investigation of mechanisms involved in neuroinflammation is thus critical to develop therapeutic targets effective in slowing the disease. In this project, I propose to study an unexplored pathway at the basis of FTD progression as well as to provide the first steps for the development of a novel and effective therapeutic. This study will focus on the C9orf72 mutation that is the most common cause of both sporadic and familial FTD. My hypothesis is that the mutation affects the proper communication between neurons, microglia, and astrocytes. This aberrant signaling is thus able to propagate the disease to other units, causing the above described inflammation. I speculate that C9orf72 mutation dysregulate the production of extracellular vesicles (EVs) that are a mean of signaling among cells in the brain and are regarded as “messengers.” My hypothesis is that abnormal EVs production leads to neuroinflammation and thus progression of FTD. Based on the observation that “bad” messengers, as are the EVs from C9orf72 mutated cells, are able to cause/initiate inflammation, “good” messengers (good EVs) might be able to revert this aberrant activation and to halt the propagation of the disease. A solid body of scientific evidence has shown that a particular class of EVs, the one produced by stem cells, are able to revert brain inflammation associated to multiple neurological disease. With this project, I will use the latest technology of the brain organoids to test the efficacy of stem cell-derived EVs in reverting neuroinflammation associated with FTD. The last part of this project will also be dedicated to the discovery of new therapeutic target, but the profile of EVs produced during neuroinflammation. This work is innovative because it explores pathways that despite being disease-relevant are poorly studied and understood; this study is also relevant because these findings will provide the scientific basis for the development of targeted and effective therapeutics able to mitigate or even halt the disease.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110134
Entities
People
- Maria Elena Cicardi
Organizations
- Thomas Jefferson University
- United States Army