Dysfunction of Astrocytic Mitochondria in Alzheimer's Disease

Principal Investigator

Summary

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.

Note: This grant was terminated by the investigator on April 23, 2021, when she left Massachusetts General Hospital for an industry position.

Detailed Non-Technical Summary

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.

Publications

Calvo-Rodriguez M, Bacskai BJ. High mitochondrial calcium levels precede neuronal death in vivo in Alzheimer's disease. Cell Stress. 2020 Jun 18;4(7):187-190. doi: 10.15698/cst2020.07.226. PMID: 32656500; PMCID: PMC7328672.

Calvo-Rodriguez M, Hou SS, Snyder AC, Kharitonova EK, Russ AN, Das S, Fan Z, Muzikansky A, Garcia-Alloza M, Serrano-Pozo A, Hudry E, Bacskai BJ. Increased mitochondrial calcium levels associated with neuronal death in a mouse model of Alzheimer's disease. Nat Commun. 2020 May 1;11(1):2146. doi: 10.1038/s41467-020-16074-2. PMID: 32358564; PMCID: PMC7195480.

First published on: June 26, 2019

Last modified on: July 01, 2022