Evaluation of calcium/calmodulin kinase II as therapeutic target in beta-amyloid peptide neurotoxicity
Abstract of thesis entitled
?valuation of calcium/calmodulin kinase II as therapeutic target in beta-amyloid peptide neurotoxicity?Submitted by
LIN Kim Fung
for the degree of Master of Philosophy
at The University of Hong Kong
in August 2004
Alzheimer? disease (AD), which produces progressive and inexorable loss of cognitive function, is one of the most common causes of dementia among the elderly. The exact cause of neurodegeneration in AD is unclear. Mutations of the genes encoding amyloid precursor protein, the presenilins and Apolipoprotein E have been suggested to enhance the production and deposition of beta-amyloid (A? peptides in neurons. A?peptides, in particular the A?-42, are known culprits of causing neuronal death in AD. The A?peptide-mediated neurotoxicity is though to act through disruption of intraneuronal calcium homeostasis. Abrupt increase in intracellular calcium leads to the activation of various calcium-responsive intracellular enzymes such as glycogen synthase kinase ? c-Jun-N-terminal kinase and calcium/calmodulin-dependent protein kinases (CaMKs). Stimulations of these kinases can result in activation of the caspase-mediated apoptotic cascades. Therefore, modulation of intracellular calcium increase or blockages of various Ca2+-mediated pro-apoptotic signaling pathways provide possible ways of pharmaceutical intervention of AD.
Despite of their association with A?mediated neurotoxicity, intracellular Ca2+
-responsive kinases and Ca2+-mediated pro-apoptotic signaling pathways have not been systematically studied. Among the numerous intracellular calcium-sensitive enzymes, calcium/calmodulin kinase II (CaMKII) is one of the most abundant types in the CNS. CaMKII belongs to the family of calcium/calmodulin dependent protein kinases (CaMKs). Besides CaMKII, CaM-kinase I (CaMKI), CaM-kinase II (CaMKII), CaM-kinase III (CaMKIII), CaM-kinase IV(CaMKIV), CaM-kinase kinase (CaMKK) and myosin light chain kinase are also members of the CaMKs. CaMKII activates directly upon increased intracellular calcium. It has been shown to correlate with neuronal apoptosis. Increased expression of CaMKII has also been shown in AD. Furthermore, CaMKII is one of the kinase responsible for tau hyperphosphorylation.
We have reported our study on the roles of CaMKII in A?peptide neurotoxicity. By treating the primary cortical neurons exposed to A?peptides (A?5-35 and A?-42) with two selective CaMKII inhibitors: autocamtide-related inhibitory peptide (AIP) and KN93, A?peptides neurotoxicity was significantly reduced. Release of LDH and DNA fragmentation/condensation (by DAPI staining) in neurons exposed to A?peptides were significantly decreased in the presence of AIP and KN93. While these inhibitors significantly attenuated A?peptide-triggered activation of caspase-2 and caspase-3 and AIP significantly decreased the degree of tau phosphorylation of the A?peptide-treated neurons, they could elicit partial neuroprotection only. Pharmacological inhibitor targeting calmodulin, W7, did not provide neuroprotection. Morphine which activates CaMKII via ?receptor augments A?induced LDH release, caspase-2 and -3 activities and neuronal apoptosis. Taken together, although CaMKII plays a role in A?peptide neurotoxicity, pharmacological inhibition cannot afford complete neuroprotection.
An extract of exactly 413 words
School:The University of Hong Kong
School Location:China - Hong Kong SAR
Source Type:Master's Thesis
Keywords:calcium calmodulin protein kinases amyloid beta neurotoxicology neurogenetics alzheimer s disease
Date of Publication:01/01/2005