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Increased Mitochondrial Calcium Levels Associated with Neuronal Death in a Mouse Model of Alzheimer’s Disease

By May 14, 2020July 22nd, 2020No Comments

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This week we profile a recent publication in Nature Communications from Dr. Maria Calvo-
Rodriguez (pictured front row, second from left) in the laboratory of Dr. Brian Bacskai (back
row, second from left) at Massachusetts General Hospital and Harvard Medical School.

Can you provide a brief overview of your lab’s current research focus?

The Bacskai lab uses cutting edge live imaging techniques to address fundamental questions in Alzheimer’s disease research. Particularly, we use multiphoton microscopy combined with fluorescent proteins and functional markers to image both structure and function in the living mouse brain. We use mouse models of Alzheimer’s disease that overexpress mutant human APP and/or tau to determine the role of each of these pathologies with longitudinal imaging during aging. In this way, we can image the neurovascular unit – neurons, astrocytes, and blood vessels – during resting or evoked responses, and evaluate the potential alterations (including neuronal toxicity, astrocytic dysfunction, mitochondrial alterations and intracellular calcium dyshomeostasis among others) that occur during senile plaque, cerebral amyloid angiopathy (CAA) or tau deposition in the mouse models.

What is the significance of the findings in this publication?

Bacskai lab mitochondrial calcium

Multiphoton microscopy image of the living mouse brain with Alzheimer’s-like pathology. Blue: amyloid plaques; green: calcium reporter targeted to mitochondria in neurons; red: blood vessels labeled with a fluorescent marker.

This work addresses the toxic effects of the protein amyloid beta (Aβ) – a primary component of the senile plaques in Alzheimer’s disease – on the mitochondrial calcium homeostasis in the living brain. Mitochondria calcium levels are tightly regulated, and persistent (non-transient) high calcium levels in mitochondria can lead to apoptosis. Aβ was known to cause cytosolic calcium overload, but whether Aβ increased mitochondrial calcium levels in vivo was an unresolved question.

Our paper has two main findings. First, we showed for the first time increased mitochondrial calcium levels in neurons in the living brain of a mouse model of Alzheimer’s disease (APP:PS1, which develops amyloid plaques comparable to those from human patients), after pathology deposition. To do that, we used intravital microscopy combined with a calcium reporter targeted to mitochondria (2mtYC3.6), a ratiometric reporter that allows for direct comparison of calcium levels between different cells. These effects were reproducible after application of soluble Aβ species, similar to those found in the human Alzheimer’s brain, onto a healthy naïve mouse brain in vivo. The mechanistic studies suggested that the “mitochondrial calcium uniporter” – the main pore for calcium influx to mitochondria – was required for this toxic process. Second, we showed that the elevated mitochondrial calcium levels preceded rare neuron death events in this transgenic model, linking high mitochondrial calcium levels to plaque deposition and neuronal cell death in vivo in Alzheimer’s disease.

What are the next steps for this research?

These findings open many new doors to our research. On one hand, this new evidence proposes that mitochondrial calcium overload could be a promising target for Alzheimer’s disease, and points the mitochondrial calcium uniporter as a therapeutic candidate for the development of neuroprotective disease-modifying drugs. The precise pharmacology and validation await further investigation. On the other hand, the neurons are not the only cell type in the brain. For instance, the astrocytes also play an active role in signaling and synapse maintenance, but little is known about the role of mitochondrial calcium in astrocytes in vivo and in the progression of Alzheimer’s disease. This understanding is essential to determine how mitochondrial calcium and hence astrocytes contribute to function and dysfunction in this pathology, and whether astrocytic mitochondria could be a therapeutic target in Alzheimer’s disease, a question that we are excited to pursue.

This work was funded by:

This work was supported by the National Institute on Aging (NIA), the National Institute for Neurodegenerative Diseases and Stroke (NINDS), the Tosteson & Fund for Medical Discovery (FMD), the BrightFocus Foundation and the Alzheimer’s Association.

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