Project Summary / Abstract
Traditionally, neurological diseases have been classified into mechanistically distinct categories, such as
neurodegenerative, inflammatory, and vascular. However, recent insights have led to a reassessment of the
complex relationship between diseases and their mechanisms. Emerging evidence supports a role for vascular
dysfunction as an early feature in AD that is an equal and independent predictor for cognitive decline compared
to amyloid and correlates with worse prognosis in AD. However, the cellular and molecular mechanisms at the
neurovascular interface that promote cognitive decline are poorly characterized. Furthermore, whether and how
vascular alterations contribute to neuronal network and synaptic dysfunction, one of the earliest manifestations
of AD, is unknown. A fundamental change at the neurovascular interface in AD is the deposition of the blood
coagulation factor fibrinogen, which is deposited as insoluble fibrin in the AD brain. Our ultimate goal is to
determine the dynamic interactions between innate immunity, vascular, and blood-derived signals and their
causal relationships in regulating impaired synaptic activity as a prerequisite for devising novel therapies to
improve synaptic and cognitive functions after vascular impairment. Studies from our laboratory and others have
shown that genetic or pharmacologic depletion of the blood coagulation factor fibrinogen protects from
neuroinflammation in several models of neurological disease. Our preliminary data demonstrate that dendritic
spine elimination occurs around fibrinogen deposits in AD mice and fibrinogen-CD11b signaling promotes
dendritic spine loss and cognitive impairment in AD mice. The four specific aims will are designed to determine
the role of fibrinogen/CD11b signaling in microglial-synapse interactions and neuronal network abnormality,
determine the mechanisms underlying fibrin-induced innate-immune driven neuronal dysfunction, and the
therapeutic implications of targeting fibrin-microglia interactions in protecting from spine elimination and neuronal
dysfunction. Our experimental design is based on a cutting-edge multi-pronged experimental approach
consisting of in vivo two-photon imaging of neuronal activity and microglial dynamics, EM co-registration,
iDISCO, unbiased transcriptomics and proteomics, and combined two-photon imaging with in vivo EEG
recordings. The proposed studies will set the foundation how neurovascular dysfunction regulates synapse
elimination and neuronal activity and the outcomes of this research would be applicable for the understanding of
the etiology and the development of new treatments for vascular cognitive impairment including in AD and related
conditions.