Blood flow in the brain of Alzheimer disease patients is substantially decreased as compared to age-matched healthy controls. Recently, it was found that blood flow in Alzheimer?s disease mouse models is reduced because neutrophils plug up capillaries resulting in a small, but impactful number of stalled capillaries. Removing these plugs by interfering with neutrophil adhesion improves blood flow in minutes and also improves performance on tasks involving short term or episodic memory within hours. This extremely rapid change in cognitive performance suggests that no alterations in structure or connectivity of neurons are needed to recover sizable amounts of cognitive function in Alzheimer disease. Instead, there must be a change in the neural activity that reflects the improvement in function. This phenomena enables the investigation of these changing activity patterns by recording from the same cells before and after improving the blood flow. Cutting-edge approaches, such as multiphoton microscopy of genetically encoded calcium indicators, will be used to record activity from numbers of neurons deep inside the brain while still resolving individual cells in an awake animal. Neurons with aberrant activity may underlie the observed cognitive deficits will be identified by measuring how the activity in each cell changes before and after the blood flow treatment that rescues cognition. This gives a direct measurement of how individual neurons and circuits change when an Alzheimer mouse?s cognitive symptoms are improved. Several types of aberrant neural activity are known to be associated with Alzheimer?s disease and also with impaired blood flow, suggesting that these types of neural activity patterns might change during blood flow rescue. Studies in Alzheimer disease models show some neurons are abnormally quiet or silent and other neurons fire spontaneously at excessively high rates. Imaging of neural activity is used to evaluated changes in such activity in the hours and days after blood flow rescue. Such aberrant firing patterns can contribute to a decrease in the accuracy of neural representations of stimuli. Neural fidelity is assayed by measuring tuning curves in neurons that respond to directional whisker stimulation. Imaging of somatosensory cortex tests whether blood flow rescue improves these tuning curves and sensitivity to weak stimuli. Alzheimer?s disease patients and experimental models exhibit seizure-like discharges, so EEG recording is used to evaluate epileptiform activity and any changes with blood flow rescue. Interestingly, the blood-flow-mediated cognitive changes are so fast that there is little time for slower changes such as rewiring of circuits. Understanding what are the changes that are caused by blood flow rescue that are correlated with the fast behavioral improvement is critical to understanding how the cognitive symptoms emerge in the disease. This work suggests that a metabolic component is critical to cognitive function, and treatment of the newly identified capillary stalling mechanism might provide a future target for improving patient cognition.

Public Health Relevance

Blood flow in Alzheimer disease mouse models can be improved by preventing inflammatory cells from plugging capillaries in the brain. This leads to a rapid increase in performance on memory tests, suggesting that addressing blood flow at the capillary level might be a good strategy for improving cognitive symptoms in patients.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Exploratory/Developmental Grants (R21)
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Cell Death in Neurodegeneration Study Section (CDIN)
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Wagster, Molly V
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Cornell University
Engineering (All Types)
Biomed Engr/Col Engr/Engr Sta
United States
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