Alzheimer’s disease (AD) develops slowly over many years, and growing evidence shows that the brain’s immune system plays a major role in how the disease progresses. When cells experience stress or damage, they can release fragments of DNA or RNA in the wrong place, which the immune system interprets as a danger signal. This can spark chronic inflammation that harms neurons and accelerates neurodegeneration. While one major pathway that responds to this kind of stress (the cGAS–STING pathway) is known to worsen inflammation and cognitive decline in AD models, other related sensors have received far less attention. One of these, called ZBP1, detects unusual forms of DNA and RNA that accumulate with aging and disease. ZBP1 triggers strong inflammatory responses and certain forms of cell death, but its role in AD has not been tested directly, despite evidence that these processes contribute to disease.
Dr. Lukens and his lab are exploring this gap. They discovered that ZBP1 levels are increased in AD brains, suggesting that the pathway is active in human disease. When they removed ZBP1 from a tauopathy mouse model (PS19), they found decreased levels of harmful forms of tau and reduced activation of microglia and astrocytes. The mice were also protected against neuronal loss. These results suggest that ZBP1 helps drive the inflammatory and degenerative changes associated with tau pathology and may represent a new therapeutic target. Based on these data, they hypothesize that ZBP1 is a key sensor that links cellular stress to inflammation and neurodegeneration in AD, particularly by amplifying tau-related pathology.
They will investigate this hypothesis using two aims. In Aim 1, they will explore how ZBP1 influences tau accumulation, inflammation, and cell death. They will use a combination of PS19 tauopathy mice and human iPSC-derived neurons and glial cells, applying molecular analyses such as immunofluorescence, RNA sequencing, and cytokine profiling to track inflammatory and degenerative changes at cellular and tissue levels. In Aim 2, they will test whether disrupting ZBP1 can protect the brain. They will block ZBP1 in mouse models using genetic knockouts or pharmacological inhibitors and assess outcomes, including tau aggregation, microglial and astrocyte activation, neuronal survival, and behavioral measures of cognition and memory.
By clarifying how ZBP1 contributes to AD, this project could reveal a previously unrecognized driver of disease progression and point to new therapeutic strategies focused on calming damaging immune responses in the brain.
