Our research focuses on translating basic science in the lab into disease-modifying therapies for the prevention and treatment of Alzheimer’s disease (AD). The lab studies the temporal sequence of pathogenesis that occur in brain in AD, Down syndrome, and in animal models, which support the idea that the early accumulation of amyloid-β protein (Aβ) aggregates is integral to the onset of AD. We have a unique collection of briefly-fixed paraffin brain sections from humans (AD, FAD, DS, non-demented controls), as well as sections representing young to old ages from non-human primates, wildtype mice, and at least 3 different AD-like transgenic mouse models.
We are developing strategies to lower the levels of Ab in the brain, including Aβ immunotherapy targeting a specific pathogenic Ab form (pyroGlu3 Aβ), and believe that early vaccination, prior to the robust loss of synapses and neurons observed in AD, may be the most efficacious strategy for preventing or delaying the onset of AD. As part of a long-term collaboration with Probiodrug AG, we are currently testing in mice an anti-pyroGlu3 Aβ monoclonal antibodies modified to reduce complement activation and inflammation. In addition, our lab is interested in how the immune system, including complement, impacts Aβ clearance, gliosis and synaptic health during brain aging and neurodegeneration. We have data to suggest that life-long absence of complement C3 protects against hippocampal decline associated with aging and AD in mice, even in the presence of abundant Aβ plaques.
We are also investigating how AD risk-associated CR1 polymorphisms influence Aβ clearance and pathogenesis in humans. We have collaborated with GE to characterize their 18F-GE180 TSPO PET tracer in mice during aging and AD, and have incorporated PET imaging of neuroinflammation into several of our mouse studies. We collaborate with Revalesio Corporation (Tacoma, WA) to study the effects of their anti-inflammatory agent in AD mice, using 18F-GE180 PET imaging.
We also collaborate with the Behavioral Science Foundation in St. Kitts to examine protein changes in blood and cerebral spinal fluid in Caribbean vervet non-human primates that develop Ab plaques and cognitive decline with aging, in the search for early biomarkers and new therapeutic targets. Two years ago, we started a new project with NASA to examine the effects of deep space galactic cosmic radiation on brain aging and the risk of AD in mouse models.
In addition to lab research, we have mentored dozens of high school students, undergraduate college students, graduate students, and visiting scientists over the past 20+ years at BWH. We participated in two BWH student/mentor programs since their inception: the Student Success Job Program (16 years; highly competitive program for underrepresented metropolitan Boston high school students) and the STARS program (7 years; highly competitive national program for underrepresented minority pre-med college students).