Graduation Year

2004

Document Type

Dissertation

Degree

Ph.D.

Degree Granting Department

Pharmacology and Therapeutics

Major Professor

David Morgan Ph.D.

Keywords

Immunization, Transgenic mice, Inflammation, Alzheimers disease

Abstract

Alzheimers disease (AD) is defined as a progressive neurodegenerative disorder that gradually destroys a persons memory and ability to learn. There are three pathological hallmarks of the disease which are necessary for diagnosis of AD, these are; extracellular amyloid plaques composed of [beta]-amyloid (A[beta]) protein, intracellular neurofibrillary tangles and neuronal loss. Amyloid plaques exist as both compact deposits which stain with Congo red and more numerous diffuse deposits. Active immunization against A[beta] 1-42 or passive immunization with monoclonal anti-A[beta] antibodies reduces amyloid deposition and improves cognition in APP transgenic mice.Over several studies of active immunization in APP+PS1 transgenic mice we showed a strong correlation between reduction of compact amyloid deposits and the degree of microglial activation suggesting a potential role of microglia in the removal of A[beta].

Injection of anti-A[beta] antibodies into the frontal cortex and hippocampus of aged APP transgenic mice revealed an early phase of A[beta] removal which was removal of only diffuse amyloid deposits with no associated activation of microglia. A later phase was the removal of compact amyloid deposits. This was associated with significant activation of microglia. Prevention of this microglial activation by anti-A[beta] F(ab)2 fragments or its inhibition by dexamethasone also precluded the removal of compact amyloid deposits but did not affect the removal of the diffuse deposits. Systemic injection of anti-A[beta] antibodies weekly over a period of 1, 2, 3 and 5 months transiently activated microglia associated with the removal of compact amyloid deposits and elevated plasma A[beta], suggesting a peripheral mechanism contributes to removal of brain A[beta].

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