This dissertation, "Evaluation of calcium/calmodulin kinase II as therapeutic target in beta-amyloid peptide neurotoxicity" by Kim-fung, Lin, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Abstract of thesis entitled "Evaluation 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's 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 (Aβ) peptides in neurons. Aβ peptides, in particular the Aβ, are known culprits of causing neuronal 1-42 death in AD. The Aβ 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 β, 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 2+ Ca -mediated pro-apoptotic signaling pathways provide possible ways of pharmaceutical intervention of AD. 2+ Despite of their association with Aβ-mediated neurotoxicity, intracellular Ca 2+ -responsive kinases and Ca -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 Aβ peptide neurotoxicity. By treating the primary cortical neurons exposed to Aβ peptides (Aβ and Aβ ) 25-35 1-42 with two selective CaMKII inhibitors: autocamtide-related inhibitory peptide (AIP) and KN93, Aβ peptides neurotoxicity was significantly reduced. Release of LDH and DNA fragmentation/condensation (by DAPI staining) in neurons exposed to Aβ peptides were significantly decreased in the presence of AIP and KN93. While these inhibitors significantly attenuated Aβ peptide-triggered activation of caspase-2 and caspase-3 and AIP significantly decreased the degree of tau phosphorylation of the Aβ 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 Aβ-induced LDH release, caspase-2 and -3 activities and neuronal apoptosis. Taken together, although CaMKII plays a role in Aβ peptide neurotoxicity, pharmacological inhibition cannot afford complete neuroprotection. _____