Graduation Year


Document Type




Degree Granting Department

Molecular Pharmacology and Physiology

Major Professor

David Morgan, Ph.D.


Alzheimer's disease, Amyloid, Angiopathy, Microglia, Transgenic mice


Alzheimer's disease (AD) is the most common form of dementia, a disease that gradually destroys brain cells and leads to progressive decline in mental function. The presence of high densities of neuritic plaques composed of Abeta in the cerebral cortices is a criterion for the post-mortem diagnosis of AD. The view that Abeta deposition drives the pathogenesis of AD (amyloid hypothesis) has received support from a wide range of molecular, genetic, and animal studies. This hypothesis has been the focus of therapeutic intervention leading to the development of anti-Abeta immunotherapy as a potential treatment. There is a great deal of evidence that supports the capacity of immunization against Abeta to reduce amyloid pathology and restore memory function in transgenic mouse models of amyloidogenesis.

However, as a result of anti-Abeta immunotherapy, many investigators have reported increased severity of cerebral amyloid angiopathy (CAA) and increased incidences of microhemorrhage. The mechanism/s responsible for the redistribution of Abeta to the vasculature is unclear. We examine two possible mechanisms that may influence the severity of CAA following immunization; the rate of Abeta clearance with deglycosylated antibodies via a dose response study and anti-Abeta antibody epitope specificity. Dose response results with a deglycosylated antibody showed that lower doses resulted in greater clearance of amyloid and significant improvements in cognition, suggesting that clearance mechanisms become saturated with high doses of antibody.

Treatment with antibodies directed against different epitopes of Abeta implied that the degree of parenchymal Abeta clearance determines the extent of vascular Abeta accumulation; epitope specificity is not critical in directing the vascular accumulation. Passive anti-Abeta immunization can prevent Abeta deposition in APP transgenic mice. We investigated amyloid accumulation after immunization was terminated, and discovered that after treatment, amyloid began to accumulate as a factor of time and gradually built up but never reached the Abeta levels in control APP mice. These data suggest that delayed deposition of amyloid leads to long term delays in AD associated pathology. These data strongly support the use of prophylactic immunotherapy treatments, and it appears that existing amyloid deposits will require interventions that actively clear amyloid as the only means to efficiently reduce brain Abeta in AD.