Chemistry Reference
In-Depth Information
CHAPTER 2
The Role of Glycogen Synthase Kinase 3β in Alzheimer's Disease, with
Implications in Drug Design
Adriana Mieco Namba and Carlos Henrique Tomich de Paula da Silva
School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Av. do Café, s/n, Monte Alegre,
14040-903, Ribeirão Preto, São Paulo, Brazil
Abstract
:
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 -amilóide peptide (A). Glycogen Synthase Kinase-3 (GSK-3), 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-3 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-3 inhibitors.
INTRODUCTION
Alzheimer's disease (AD) [1-3] is a chronic, neurodegenerative disorder which is characterized by progressive
memory loss and impairments in language and behaviour that ultimately leads to death. At autopsy, the AD brain is
characterized by a number of important pathological changes, including selective neuronal and synaptic losses [4],
intracellular neurofibrillary tangles (NFTs) and extracellular senile plaques [5]. The senile plaques are mainly
composed of the 40-42 amino acid-long amyloid β-peptide (Aβ) in fibrillar form, called A-40 and A-42,
respectively, which are produced by proteolytic cleavage of the amyloid -protein precursor (APP) [6-9], through
sequential cleavages by two proteases, - and -secretase.
The neurofibrillary tangles are polymers of paired helical filaments generated by the aggregation of protein tau in
the abnormal hyperphosphorylated state [10-15]. Tau is a microtubule-associated protein that stabilizes microtubules
within neurites and axons [16]. Microtubules are the essential components of the cytoskeleton; they are responsible
for the formation and maintenance of the neuronal morphology and their specific connections. The microtubule
associated proteins contribute to regulate the dynamism and stability of the microtubules, and therefore they are
essential to maintain the correct function of the microtubules. The hyperphosphorylated tau of the paired helical
filaments is highly insoluble and is incapable of binding to microtubules and promoting microtubules assembly.
Consequently, tau abnormal phosphorylation causes the loss of tau function, microtubule instability, and
neurodegeneration in AD brain [17,18].
Early-onset Alzheimer's, an usual form of dementia that strikes people younger than age 65, is linked to three
genes: APP gene on chromosome 21 and Presenilins 1 (PS1) and 2 (PS2), located on chromosome 14 and 1,
respectively. Missense mutations in PS1, PS2 or APP changes the proteases activities, increasing the production of
the A-42 [19-28]. A-42 is the species initially deposited in plaques in the brain, contributing to cell death and
neuronal loss. [29-31].
The etiology of AD has not yet been established for most of the cases known as the 'sporadic' forms of AD [32].
The most widely accepted hypothesis regarding the pathogenesis of AD is the so-called 'amyloid cascade'
hypothesis [2,6,25,33], which proposes that abnormal processing of APP and the subsequently increased production,
aggregation and deposition of A-peptides are the primary events in AD. Fibrillar aggregates of the -amyloid
peptide would then act as neurotoxic agents, causing tau hyperphosphorylation, NFT formation, synaptic
degeneration and neuronal cell death [2,33]. Studies have shown that large numbers of amyloid plaques are found in
