Selective reduction of GSK-3 isoforms ameliorates pathological signatures of Alzheimer's disease / David E. Hurtado.

Format:

Book

Manuscript

Thesis/Dissertation

Author/Creator:

Hurtado, David E.

Contributor:

Lee, V. M.-Y. (Virginia M.-Y.), advisor.

University of Pennsylvania.

Language:

English

Subjects (All):

Penn dissertations--Neuroscience.

Neuroscience--Penn dissertations.

Neurosciences.

Academic Dissertations as Topic.

Medical Subjects:

Neurosciences.

Academic Dissertations as Topic.

Local Subjects:

Penn dissertations--Neuroscience.

Neuroscience--Penn dissertations.

Physical Description:

xi, 142 pages : color illustrations ; 29 cm

Production:

2011.

Summary:

The accumulation of extracellular senile plaques (SP) and interneuronal neurofibrillary tangles (NFTs) in the central nervous system (CNS) is a distinct histopathological hallmark of Alzheimer's Disease (AD). Senile plaques are extracellular lesions composed of beta-amyloid (Abeta peptides, which are derived from the proteolysis of the amyloid precursor protein (APP), mediated by beta- and gamma-secretase. Neurofibrillary tangles are intracellular aggregates composed of hyperphosphorylated tau protein, a microtubule-associated protein. These building blocks of pathology, Abeta peptides and hypersphosphorylated tau, have been the focus of scientific research with the purpose of understanding the molecular mechanisms that lead to their formation. This fundamental understanding may allow one to modulate these mechanisms and potentially reduce the formation of amyloid plaques and neurofibrillary tangles. What has emerged from some of these studies is the identification of a critical kinase, glycogen synthase kinase-3 (GSK-3) that regulates both Abeta peptide formation and tau phosphorylation. GSK-3 exists as two isoforms, GSK-3alpha and GSK-3beta.

This thesis examines the role of GSK-3 isoforms in both plaque and tangle formation. We initiated our project by generating a novel plaque and tangle murine model, which we characterized and demonstrated tangle distribution similarly found in Braak staging of AD cases. Additionally we observed an acceleration of tangle formation in the presence of APP. Utilizing this model we individually manipulated GSK-3 isoforms through two approaches: 1) RNAi: through the use of shRNAs targeting GSK-3 isoforms, and 2) Genetically: through the generation of conditional GSK-3alpha and GSK-3beta knock-out murine models. Through the use of shRNAs we identified that GSK-3alpha and GSK-3beta participate in divergent roles in both plaque formation and phosphorylation of tau, which lead to an amelioration of several pathological features of AD. Ultimately this work has increased our understanding of the individual roles of GSK-3 isoforms in the pathogenesis of AD development, and should aid in the development of targeted therapeutics to GSK-3.

Notes:

Adviser: Virginia M.-Y. Lee.

Thesis (Ph.D. in Neuroscience) -- University of Pennsylvania, 2011.

Includes bibliographical references.