2023 Alzheimer's Association Research Grant (AARG)
Mitochondrial optogenetic approaches to modulate tau pathology in vivo
Shedding light on how energy production affects brain changes seen in Alzheimer’s using an advanced light technique.
Andrew Wojtovich, Ph.D.
University of Rochester
Rochester, NY - United States
Background
Mitochondria are specialized structures that make energy for the cell in the form of “ATP”. ATP production is mediated by proton motive force (PMF), a chemical force that moves positively charged molecules across the mitochondrial membrane. PMF is essential for making ATP but also facilitates production of reactive oxygen species (ROS), reactive molecules that can build up and lead to cell damage.
Dysfunctional mitochondria and deposits of tau (a protein that accumulates to form tau tangles, a hallmark in Alzheimer's and other brain diseases) are found in the brains of individuals with Alzheimer’s. When mitochondria do not function properly, energy production decreases and ROS accumulate. Previous research has shown a decrease in ATP and an increase in ROS production in the brain tissue from individuals who had Alzheimer’s and suggests that mitochondrial dysfunction occurs before tau starts to accumulate. A clear association between mitochondrial dysfunction and accumulation of tau tangles has yet to be seen but could lead to more targeted therapeutics.
Research Plan
With an advanced technique called optogenetics, Dr. Andrew Wojtovich can use light pulses to precisely turn PMF “on” and “off” in the mitochondria in brain tissue from genetically engineered Alzheimer’s-like mice. These mice develop Alzheimer’s-like brain changes over time, specifically accumulating more tau tangles as they age. The scientists will control PMF activity during three different time points identified by the percentage of tau tangles present in the brain tissue. This will allow the team to understand the time course of mitochondrial dysfunction in relation to development of Alzheimer’s-like brain changes. Early work from the team has demonstrated that turning PMF “on” increased levels of ATP while turning PMF “off” increased levels of ROS.
Dr. Wojtovich’s team will then test how regulation of PMF activity in living mice affects the accumulation of tau tangles over time. They propose that turning PMF “off” prior to the development of tau tangles will protect against Alzheimer’s-like brain changes in the mice while turning PMF “on” after tau tangles have already started to appear will delay further Alzheimer’s-like brain changes.
Impact
This study may help researchers understand the specific impact of mitochondrial dysfunction in the appearance and progression of brain changes seen in Alzheimer’s and lead to the development of more targeted therapeutics.