Neurovascular and Immune Mechanisms in AD Pathogenesis

By elucidating the mechanisms of blood clotting factors in immune activation and memory loss, our study will provide the basis for novel strategies for therapeutic intervention in AD. This proposal will use a multi-pronged experimental design to examine the cerebrovascular mechanisms regulating neuronal dysfunction in AD. We will use state-of-the-art imaging to study neurons in living mice and with subcellular resolution. We will determine the transcriptional machinery of neurotoxic brain immune cells in the brain of AD mice at the single-cell level.

This project will fill a major knowledge gap, namely the mechanisms that link cerebrovascular damage with pathogenic immune activation and neuronal dysfunction in AD. Emerging evidence shows that cerebrovascular pathology, BBB disruption, and fibrinogen deposition in AD brains is not merely a consequence of disease but plays a causal role in inflammation, oxidative stress and neurodegeneration. This proposal will discover novel neurotoxic mechanisms and therapeutic targets for AD at the neurovascular interface. This proposal will revolutionize our understanding of the cellular and molecular triggers of neurodegeneration in AD. By elucidating the molecular mechanism of blood clotting factors in brain immune activation and memory loss, our study will provide the basis for novel strategies for therapeutic intervention to protect from cerebrovascular dysfunction in AD.

This project will fill a major knowledge gap, namely the mechanisms that link cerebrovascular damage with pathogenic immune activation and neuronal dysfunction in AD. Emerging evidence shows that cerebrovascular pathology, BBB disruption, and fibrinogen deposition in AD brains is not merely a consequence of disease but plays a causal role in inflammation, oxidative stress and neurodegeneration. This proposal will discover novel neurotoxic mechanisms and therapeutic targets for AD at the neurovascular interface.

This proposal will revolutionize our understanding of the cellular and molecular triggers of neurodegeneration in AD. By elucidating the molecular mechanism of blood clotting factors in brain immune activation and memory loss, our study will provide the basis for novel strategies for therapeutic intervention to protect from cerebrovascular dysfunction in AD.