Graduation Year

2005

Document Type

Dissertation

Degree

Ph.D.

Degree Granting Department

Biochemistry and Molecular Biology

Major Professor

Huntington Potter, Ph.D.

Committee Member

Larry P. Solomonson, Ph.D.

Committee Member

W. Lee Adair,Jr., Ph.D.

Committee Member

R. Kennedy Keller, Ph.D.

Committee Member

David G. Morgan, Ph.D.

Keywords

Alzheimer's disease, Transgenic mouse, Amyloid, Apolipoprotein E, Parabiosis, Environmental enrichment

Abstract

Besides age, inheritance of the apoE-ε4 allele is the main risk factor for late-onset AD. To determine the role of apoE in amyloid deposition, we studied mice expressing both mutant human amyloid ß-protein precursor (APP) and presenilin 1 (PS1) that were either normal or knocked-out for apoE. By 7 months, amorphous Aß deposition developed equally in both lines, indicating that Aß alone is sufficient for deposition to occur. In contrast, filamentous amyloid deposition was catalyzed at least 3000 fold by apoE. Electron micrographs further illustrate the filamentous nature of these plaques. These results and other, behavioral, data indicate that the primary function of apoE in AD is to promote the polymerization of Aß into mature, neurotoxic, amyloid.

ApoE is also synthesized in the liver and is crucial in cholesterol metabolism, for mice lacking apoE exhibit hypercholesterolemia. We investigated neuropathology in mice using an uncommon technique, parabiosis, to determine whether apoE in the peripheral circulation influences brain amyloid formation. This surgical procedure allows exchange of proteins via peripheral circulation. We show that plasma apoE is found in parabiosed PS/APP/apoE-KO mice, rescuing their hypercholesterolemia. Unexpectedly, amyloid deposition is reduced in parabiosed PS/APP/apoE-KO mice compared to PS/APP controls. ApoE in the periphery seems to slightly reduce amyloid burden, by likely promoting efflux of Aß from the brain. These findings reinforce that the mechanisms whereby apoE affects Aß metabolism are complex, and the modulation of peripheral apoE metabolism is not likely to impact AD neuropathology.

Since cognitive stimulation is associated with lower risk of AD, we sought to investigate the preventative potential of environmental enrichment (EE) using our mouse model. At weaning, mice were placed into either enriched or standard housing (SH). Behavioral testing at 4½-6 months showed that EE-PS1/APP mice outperformed mice in SH, and were behaviorally indistinguishable from nontransgenic mice. PS1/APP mice given both EE and behavioral testing had 50% less brain ß-amyloid (Aß), but did not exhibit changes in dendritic morphology. Microarray analysis of hippocmapal RNA revealed large EEinduced changes in the expression of genes/proteins related to memory, neuroprotection, and Aß sequestration. Inhibition of one such protein, PDE4, a cAMP-phosphodiesterase, by Rolipram, mimicked the cognitive benefits of EE.

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