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Glycogen synthase kinase-3 signaling in Alzheimer's disease : regulation of beta-amyloid precursor protein processing and amyloid beta protein production

University of British Columbia

Glycogen synthase kinase 3 (GSK3) is a serine/threonine kinase that plays a part in a number of physiological processes ranging from glycogen metabolism to gene transcription. Recent studies indicated that GSK3 also involved in the formation of Alzheimer’s disease (AD) pathologies: neurofibrillary tangles and amyloid plaques. Neurofibrillary tangles develop when abnormal tau proteins accumulate inside neurons and form insoluble filaments, and amyloid plaques develop when the amyloid β protein (Aβ) accumulates in increasingly insoluble forms. The Aβ peptide is generated through sequential cleavages of the β-amyloid precursor protein by β-secretase (BACE1) and γ-secretase. Accumulation of insoluble Aβ is believed to trigger the initial series of neurodegenerative events leading to AD. Therefore, inhibition of the pathways that lead to Aβ generation will have therapeutic implications for AD treatment. The mechanism by which GSK3 affects APP processing and Aβ production has been controversial. Previous published reports have found differential effects on GSK3-mediated APP processing. This thesis entails a thorough investigation of GSK3’s role in APP processing and Aβ production. First, the therapeutic effects of the anti-convulsant drug, valproic acid (VPA) were tested in AD modeled mice. VPA, a known GSK3 inhibitor could interfere with Aβ production, and rescued memory deficits. In addition to inhibiting GSK3 activity, VPA also stimulate a plethora of signaling cascades. To further our understanding of GSK3’s effect on APP processing, a GSK3 specific pharmacological inhibitor (AR-A014418) and siRNA technologies were used in our systems. With specific GSK3β inhibition, we showed that BACE1-mediated cleavage of APP and Aβ production were reduced. Moreover, GSK3β induced BACE1 gene expression depends on NFκB activity. Additionally, specific inhibition of GSK3 also reduced Aβ production and neuritic plaque formation in AD modeled mice, as well as improved memory functions. Finally, this thesis examined in detail the role of GSK3 in AD pathogenesis. This study demonstrated for the first time that the GSK3β signaling pathway regulates BACE1 transcription and facilitates Aβ production. These findings reinforced the notion that specific GSK3 inhibition is a safe and effective approach for treating AD.

Text

2012-07-31

Attribution-NonCommercial-NoDerivs 3.0 Unported

http://hdl.handle.net/2429/42848

Neuroscience

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/3.0/