Dysfunction of Astrocytic Mitochondria in Alzheimer's Disease
With this project, we want to clarify if mitochondria mobility, distribution and dynamics are altered in astrocytes in the pathology of Alzheimer’s disease, and eventually determine the contribution of mitochondria and astrocytes to this disease. We will approach this issue by tracking mitochondria movement and distribution with the green fluorescent protein and the Ca2+ dynamics with a reporter molecule targeted to mitochondria. Imaging in the brain of living animals using multiphoton microscopy will be performed in mouse models of Alzheimer’s disease. Once we know this sequence, we plan to reverse the mitochondrial dysfunction with appropriate drugs, suggesting novel molecular targets for therapeutic development that can be used in people.
Our study aims to find alterations in the correct function and dynamics of mitochondria in astrocytes during the development of the pathology of Alzheimer’s disease (AD), in order to understand the contribution of mitochondria and astrocytes to this disease, with the final goal of identifying new therapeutic targets in AD.
To achieve this goal, we will longitudinally image mitochondria in the living brain of two complementary mouse models of AD, a model of cerebral beta amyloidosis and a model of tauopathy, using multiphoton microscopy. This is a unique and powerful tool to directly visualize both structure and function of targeted cell types and subcellular organelles in real-time in the living mouse brain. Mitochondria are the main suppliers of ATP to all cells. Additionally, they act as a calcium buffer and help shape calcium events. Malfunction in the regulation of mitochondrial dynamics in astrocytes may impair their capability to regulate metabolic demand, which may disturb glial-neuronal interactions. First, we will examine whether mitochondria distribution and mobility are altered in AD with a green fluorescent protein targeted to mitochondria. Then we will evaluate calcium dynamics in mitochondria with a calcium reporter targeted to mitochondria in astrocytes. We will start imaging the mice before the pathology is apparent, and we will longitudinally image until the deposition of amyloid plaques and neurofibrillary tangles. Finally, we will examine the movement and functional calcium dynamics in mitochondria in response to a sensory stimulus.
Since the vast majority of studies on mitochondrial dysfunction in AD have focused on neurons, little is known about the functional characteristics and dynamics of mitochondria in astrocytes in vivo and their role in the progression of AD. This project is a unique investigation into determining the role of mitochondria in astrocytes, that will allow answering much needed questions regarding the contribution of astrocytes during the development of AD.
Following the completion of this project, we will understand in a more concise way how Aβ and tau aggregates are able to alter the normal function of mitochondria, as well as to determine the involvement of astrocytes in the pathology. This is enormously beneficial to the research field, as this work can lead to the identification of novel therapeutic targets for the treatment of AD by restoring mitochondrial and astrocyte function. The ultimate goal of this project is to identify targets to approach the dysfunction depending on the timing of development of the disease, creating multiple drug-target interactions and facilitating the translation from mouse to human.
About the Researcher
I am currently a postdoctoral research fellow in the laboratory of Dr. Bacskai at the Massachusetts General Hospital and Harvard Medical School, in Boston. My long-term research goal is to understand the mechanisms that lead to the pathophysiology underlying neurodegenerative disorders, most particularly Alzheimer’s disease (AD). I majored in Organic Chemistry as an undergraduate, and then pursued a MS in “Therapeutic Targets in Cell Signaling” under Dr. Enrique Samper’s supervision, at the University of Alcala de Henares and the National Center for Cardiovascular Research (CNIC) (Madrid, Spain). I received my PhD in 2015 from the University of Valladolid (Spain), under the mentorship of Dr. Carlos Villalobos and Dr. Lucia Nuñez. The aim of my PhD project was to identify intracellular calcium alterations in healthy aging and disease, specifically in brain ischemia and neurodegenerative disorders such as AD. For that, I implemented an in vitro model of aging and AD from long-term cultured rat hippocampal neurons that allowed me to study the remodeling of cytosolic calcium and subcellular (endoplasmic reticulum and mitochondrial) calcium homeostasis in these pathologies. After receiving my PhD, I decided to pursue a post-doctoral fellowship and translate the phenomena that I studied in the in vitro models during my pre-doctoral work to a more complex and integrated system like the living brain. My current research in Dr. Bacskai’s group focuses on mitochondrial dysfunction in AD, particularly in mitochondrial calcium dysregulation and associated oxidative stress and neuronal cell death that accounts in AD. Specifically, I use in vivo multi-photon microscopy to study mitochondrial alterations in neurons in mouse models of cerebral amyloidosis and tau pathology. Now, I want to translate these techniques and address the pathophysiology of astrocytes in vivo at a mitochondrial subcellular level.
My interest in neuroscience and neurodegenerative disorders sparked when I started my pre-doctoral training. How connections are made, how neurons establish contact with other neurons, and how everything is interconnected in the brain (neurons, glia, vessels…) intrigues me. Since I was a little kid I wanted to perform research. I used to have a toy microscope -though the tiniest thing I could see through it was a hair. A few years ago my dream of being a researcher became true, and I had the opportunity to start my journey in biomedicine and then in the neuroscience field, more specifically in aging and Alzheimer’s disease research. Currently, I use state-of-the-art microscopy techniques that allow me to observe even the smallest subcellular structure like a mitochondrion in the living mouse brain. I understand how important it is to keep growing as a scientist and to contribute to find a cure for these diseases. The better we understand the brain, the better we will be able to treat neurodegenerative brain disorders. I have been performing research in Alzheimer’s disease for the past 9 years (since I started my graduate program) and it is frustrating to see how difficult it is to cure this disease. With this project I hope I can contribute my grain of sand and advance the research towards finding a cure for this devastating disease. I am extremely thankful to the BrightFocus Foundation, especially the donors, for funding this project that will allow me to address the contribution of astrocytes and mitochondria to the development of Alzheimer’s disease.
Calvo-Rodriguez M, Hernando-Pérez E, López-Vázquez S, Núñez J, Villalobos C, Núñez L. Remodeling of Intracellular Ca(2+) Homeostasis in Rat Hippocampal Neurons Aged In Vitro. Int J Mol Sci. 2020 Feb 24;21(4). pii: E1549. doi: 10.3390/ijms21041549. Review. PubMed PMID: 32102482
Calvo-Rodriguez M, Hou SS, Snyder AC, Dujardin S, Shirani H, Nilsson KPR, Bacskai BJ. In vivo detection of tau fibrils and amyloid β aggregates with luminescent conjugated oligothiophenes and multiphoton microscopy. Acta Neuropathol Commun. 2019 Nov 8;7(1):171. doi: 10.1186/s40478-019-0832-1. PubMed PMID: 31703739; PubMed Central PMCID: PMC6839235.
First published on: June 26, 2019
Last modified on: March 5, 2020