Novel mechanisms of prevention in models of Alzheimer's disease
- Alzheimer's disease (AD) presents an enormous burden to society that will increase substantially in the next decades as the population ages. Because of this, it is essential to develop a more complete understanding of the underlying disease mechanisms to identify preventive and therapeutic strategies. AD is characterized by synergistic interactions among inflammation, amyloid beta (A[beta]) peptide accumulation, and neuronal network dysfunctions that contribute to eventual cognitive decline and memory loss. In the search for treatment strategies, an emerging consensus holds that preventive intervention before symptoms occur may be most effective. Multiple studies have demonstrated that chronic use of non-steroidal anti-inflammatory drugs (NSAIDs), a class of drugs that inhibit the synthesis of prostaglandins such as PGE2, prevents the onset of AD in normal aging populations. However, later administration in symptomatic AD patients is not effective in reducing cognitive decline. Moreover, the detrimental effects of NSAIDs in some contexts suggest that there is a balance between toxic and protective signaling downstream of NSAID activity. The studies presented in this dissertation aim to identify and characterize the mechanisms underlying this balance between toxicity and protection. The first study presented here investigates mechanisms that promote paradoxically protective effects of PGE2 signaling. Specifically, we find that the EP4 receptor for PGE2 drives a potent anti-inflammatory response in microglia exposed to A[beta], while at the same time promoting the clearance of A[beta] by microglia. Through genome-wide microarray analysis, we identify several novel targets of EP4 signaling that may mediate these protective effects. In a second study, we investigate the mechanism of protection by the NSAID ibuprofen in a mouse model of AD. Here, we show that ibuprofen treatment prevents the earliest memory behavior deficits in this AD model, but that it does so without altering A[beta] levels or the inflammatory response to A[beta]. Instead, another unbiased microarray study demonstrates that ibuprofen selectively reduces the expression of an enzyme involved in tryptophan catabolism, and thus increases the availability of tryptophan for serotonin production. These two studies identify promising new mechanisms in the effort to understand and ultimately prevent AD.
|Type of resource
|electronic; electronic resource; remote
|1 online resource.
|Woodling, Nathaniel Shattuck
|Stanford University, Neurosciences Program.
|Rando, Thomas A
|Rando, Thomas A
|Statement of responsibility
|Nathaniel Shattuck Woodling.
|Submitted to the Neurosciences Program.
|Thesis (Ph.D.)--Stanford University, 2013.
- © 2013 by Nathaniel Shattuck Woodling
- This work is licensed under a Creative Commons Attribution Non Commercial No Derivatives 3.0 Unported license (CC BY-NC-ND).
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