The Role of Glycogen Synthase Kinase 3β in Alzheimer’s Disease, with Implications in Drug Design
Pp. 57-69 (13)
Adriana Mieco Namba and Carlos Henrique Tomich de Paula da Silva
The main neuropathological hallmark of Alzheimer's disease (AD) is the accumulation of aberrant
hyperphosphorylated microtubule-associated protein tau, forming the intracellular neurofibrillary tangles and the
extracellular deposits of β-amilóide peptide (βA). Glycogen Synthase Kinase-3β (GSK-3β), a serine/threonine
kinase, has emerged as one of the most attractive therapeutic targets for the treatment of AD. This enzyme has
been linked to all the primary abnormalities associated with Alzheimer’s disease, including hyperphosphorylation
of the microtubule-associated protein tau, which contributes to the formation of neurofibrillary tangles, and its
interactions with others Alzheimer’s disease-associated proteins. Thus, the significant role of GSK-3β in essential
events in the pathogenesis of AD makes this kinase an attractive therapeutic target for neurological disorders.
This chapter explores the nature and the structure of this promising enzyme, focusing on the structure-based
design of new GSK-3β inhibitors.
School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Av. do Cafe, s/n, Monte Alegre, 14040-903, Ribeirao Preto, Sao Paulo, Brazil.