Our lab studies the protein tau and how it relates to neuron loss in Alzheimer’s disease.  In a healthy brain, tau helps stabilize microtubules in neurons, a major component of the cytoskeleton.  In Alzheimer’s disease, tau becomes modified by enzymes that increase phosphorylation, reduce its ability to bind microtubules and increase its propensity to form aggregates.  These aggregates deposit in the cell body as neurofibrillary tangles.  The presence of neurofibrillary tangles in the brain are the best correlate for neuron loss and disease severity. Despite this understanding, many questions remain unanswered regarding the cause of neuron death in Alzheimer’s.  Our goal is to answer these questions including:

• Do neurofibrillary tangles directly contribute to neuron loss?

  To examine this, we have developed tools to track individual neurons in experimental models using two-photon microscopy.  This allows us to identify spatial relationships between neuron loss and pathological tau aggregates.

• Does tau pathology impact vascular function in the brain?

  We have discovered that the presence of tau pathology in the brain contributes to several functional changes in brain vasculature. This includes blood flow alterations, reduced oxygen extraction, and vascular remodeling. We are continuing to explore these changes using a combination of two photon microscopy and neuroimaging methods to better understand how this impacts brain health.

• How does microvascular stress contribute to disease?

  The endothelial cells that make up the smallest blood vessels in the brain express more inflammatory markers in Alzheimer’s disease than in healthy brain.  We are closely examining these changes using RNA sequencing and histology methods to identify specific alterations that could be targeted with therapeutics to improve vascular function and reduce neuron loss.

Research

Above: In a healthy neuron tau protiein in the neuronal axon binds microtubules. In a brain with Alzheimer’s disease, tau forms fibrillar aggegates that disrupt function. Created with biorender.com

Above: A histological stain for tau (brown) shows neurofibrillary tangles in the inferior temporal gyrus of an Alzheimer’s brain. H&E counterstain labels other cells (blue).