Elucidating Mechanisms Driving the Compromised Balance Between Mitophagy and cGAS-STING-Initiated Inflammation Towards a Treatment for Alzheimer’s Disease

There were over 55 million people living with dementia worldwide in 2020. This figure is projected to increase significantly, reaching 78 million in 2030 and 139 million in 2050. Alzheimer’s disease (AD) is the primary form of dementia, accounting for an estimated 60% to 80% of cases. In the brain of AD patients, amyloid beta and tau aggregate are accompanied by neuroinflammation. Mitochondria are the ‘powerhouse’ of the cell, generating most of the energy in the cell, and are damaged in AD brains. While dysfunctional mitochondria can trigger neurodegeneration, cells have a self-clearance system called “mitophagy” that eliminates damaged and aged mitochondria. However, this self-clearance system becomes compromised during aging and AD. Defective mitophagy increases the risk of AD. Boosting mitophagy may help reduce memory loss and pathologies associated with AD. Studies have shown that damaged mitochondria accumulate, leading to the release of more mitochondrial DAN and the induction of neuroinflammation. Therefore, maintaining mitochondrial quality control is essential for brain health. However, we still don’t know how defective mitophagy interacts with neuroinflammation in the AD brain. To address this, we propose studying the function of a protein called TANK-binding kinase 1 (TBK1), which regulates mitophagy and neuroinflammation. In this proposal, we will use an AD mouse model to mimic the AD phenotype. We will also use human microglial cell lines to study the function of TBK1 and determine TBK1 levels in the postmortem human brain and blood samples. Understanding how TBK1 affects mitophagy and neuroinflammation may help us develop new strategies to treat AD and improve the quality of life for millions of people worldwide.