Summary: Substantial reductions in brain blood flow are found in patients and mouse models of
neurodegenerative diseases, including frontotemporal dementia (FTD). These blood flow reductions likely
contribute to disease symptoms and progression, but the mechanism remains unknown.
Recently, two new mechanisms contributing to brain blood flow reductions in Alzheimer's disease were
proposed. Interestingly, both capillary stalling and pericyte constriction are associated with microvasculature
dysfunction. In preliminary experiments, the PI has shown that capillary stalling found in Alzheimer's disease
mice, also occurs in Progranulin (PGRN) deficient mice, a model for FTD. Thus, the project proposed here
will investigate the contribution of stalled blood flow and pericyte constriction in capillaries to brain blood flow
reductions. Further, this project aims to elucidate the mechanism behind these phenomena using
transcriptome analyses and cell-surface proteomics of microvessels from PGRN-deficient mice.
The pathology and region predicted to suffer from blood flow reductions in the PGRN deficient mice is the
prefrontal cortex, which can be readily studied with the two-photon excited fluorescence imaging tools used
previously by the PI. Preliminary data suggests that PRGN-deficient mice display increased capillary stalling
caused by white blood cells adhered to the endothelium. For Aim 1, we will use high-resolution, multiphoton,
in vivo imaging approaches to structurally and functionally determine blood flow rates in individual capillaries,
measure capillary stalling and pericyte constriction, and their interplay. This data will identify the cause of
brain blood flow reduction associated with FTD.
Aim 2 will elucidate the molecular mechanism linking vascular inflammation to brain blood flow reductions in
PGRN-deficient mice by using transcriptomic and cell-surface proteomics to profile microvessels. These
experiments will generate two datasets that will allow us to pinpoint molecular aberrations in microvessels of
PGRN deficient mice. The data will also shed light on the role of vascular inflammation and vascular
obstructions contributing to blood flow reductions. Selected genes and proteins identified in these screens
will be independently confirmed and later further analyzed by functional in vivo multiphoton imaging, labeling
antibodies, inhibiting drugs, and/or cell-type-specific mouse models. We predict that candidate genes and
proteins will be involved in vascular inflammation and associated with oxidative stress, blood-brain barrier
breakdown, protein degradation, and lysosomal dysfunction.
The idea of capillary stalling is new, and - if confirmed -, could represent a mechanism contributing to brain
blood flow reductions in neurodegenerative disease in general, and not just specifically to FTD. If correct,
novel therapeutic strategies targeting microvascular inflammation could be developed to improve brain blood
flow in patients with FTD and possibly in other neurogenerative diseases with reductions in brain blood flow.