Alzheimer’s Disease (AD) is a condition that affects the brain, leading to memory loss and other problems as people age. In AD, clumps of a protein called amyloid build up in the brain, damaging brain cells and causing them to die. The brain is made up of different types of cells, including neurons (which send electrical signals and help us think), microglia (the brain’s immune cells), and cells that support neurons (astrocytes, oligodendrocytes, also called glial cells).
Historically, most research on AD focused on neurons because they can be directly affected by the buildup of amyloid protein and die. However, recent studies suggest that focusing only on amyloid might not be the best way to treat AD. Recently, and thanks to genetic studies, more attention has been given to microglial and glial cells. Since AD is closely linked to aging, scientists are now looking more at factors related to aging, such as changes in how cells get their energy.
This thesis of Alejandro Marmolejo Garza explores the role of mitochondria, which are the “powerhouses” of cells (in charge of providing energy to the cells), in AD by studying tissues from patients and animal models, as well as cells grown in the lab.
We showcase that different brain cells exhibit mitochondrial dysfunction in a cell- gender- and disease-specific manner.
We determined that mitochondrial calcium uptake is necessary for ferroptotic cell death (a type of cell death that occurs in Alzheimer's Disease) in neurons. Additionally, we explore the effects of targeting mitochondrial calcium uptake in microglia.
We report here that a human model of microglia has a different metabolic reprogramming than mouse microglia (which is currently employed for translational studies).
We highlight the importance of surveying the metabolism in human-relevant models before applying novel metabolic therapies for Alzheimer's Disease.
We generate brain organoids harboring a familial Alzheimer's Disease mutation and profile their transcriptome and proteome, showcasing a metabolic reprogramming resembling the "Fasted" brain. We added microglia into brain organoids to further improve the model and determined that transcriptomic signatures of these co-cultured organoids were modified in a disease-specific manner.
