Gerald D. Silverberg Professor of Neurosurgery (Research)

research overview

My research goals are to determine the effects of aging on the pathways of amyloid removal (clearance) from the brain. The accumulation of amyloid, a sticky protein composed of amyloid-beta peptides (Aβ), appears to be the cause of Alzheimer‬ôs disease (AD). Age is the primary risk factor for developing AD, so it is critical to assess the effects of aging on clearance of Aβ from the extra cellular fluid space (ISF) of the brain. Clearance of Aβ from the brain occurs via two major pathways: the cerebrospinal fluid (CSF) circulation and transport from the ISF into the blood stream directly across the brain capillaries. There are two transporters known that affect Aβ concentration in the ISF. The low density lipoprotein-related protein-1 (LRP-1) transports Aβ out of the ISF and into the plasma. The receptor for advanced glycated end-products (RAGE) transports Aβ from the plasma into the ISF. We postulate that age-related changes in the CSF circulation and in the BBB account for the inability to clear Aβ from the brain in aging and in the age-related dementias. We are examining these age-related changes in a model of aging provided by the Brown-Norway rat, an animal now available at 10, 20 and 30+ months of age, corresponding to early adult, middle age and aged in humans. Measurement of CSF production and CSF volume will yield the turnover rate of CSF at each age group. Studies of the choroid plexus, the main site of CSF production, as a function of aging will help determine the cause of diminished CSF turnover. Imunostaining of Aβ, LRP-1 and RAGE along with RT-PCR and Western blotting will determine if aging affects the expression of these receptors on the capillary endothelium and if these changes correlate with amyloid deposition.