The Expression Of Calcium/calmodulin-dependent Protein Kinase Ⅱ-α In The Hippocampus Of Patients With Alzheimer's Disease And Its Links With AD-related Pathology

Introduction Alzheimer's disease (AD) is a kind of neurodegenerative diseasecharacterized clinically by progressively loss of memory and cognitivedysfunction and personality change. The hippocampus, an importantregion involved in learning and memory was severely affected in theAlzheimer process with neuronal loss and the presence ofneurofibrillary tangles (NFTs) and senile plaques (SPs). The cellularevents that underlie memory dysfunction, tangles formation andplaques deposition are unknown. Since calcium/calmodulin-dependentprotein kinase -a (CaMKII-a) is highly abundant in the brain andinvolved in memory and associated with tau and amyloid precursorprotein (APP) phosphorylation, it may be closely associated with AD.Objective In the present study, we aimed to observe the expression changes ofCaMKII-a in AD hippocampus compared with controls and itsrelationship with hyperphosphorylated tau and SPs. In this way wehope to understand the possible role of CaMKII-a in AD-relatedneuropathology and in the process of AD.Methods Samples of hippocampus were provided by the Nertherland Brain Bank. Using immunohistochemical and stereolgical methods wequantitatively analyzed the number and optical density of CaMKII-a expressing neurons in the CA1-CA4 hippocampal subfields of 10 female AD patients and 10 non-demented female age-matched controls. With double-labeling immunoflurenscence methods, we double labeled CaMK II -a containing neurons and AT-8 positive neurons to observe the distribution of CaMK II -a in hyperphosphorylated tau containing neurons, then analyzed the ratio of the neurons colocalizing CaMK II -a and hyperphosphorylated tau to the neurons expressing hyperphosphorylated tau in the hippocampal CA1 subfields of-AD patients. Futhermore, we double-labeled CaMK II-a with AB17.42 in AD hippocampus to observe the distribution CaMKII-a positively immunoreactive deposits in SPs and semi-quantitatively evaluated the frequency of CaMK II -a positive deposits and SPs.Results The number of CaMK II -a expressing neurons in all subfields of the hippocampus showed a decreased trend in AD patients compared with controls, however, the most significant decrease of CaMK II -a neurons was only found in the CA1 subregion (P < 0.001). The average optical density of CaMK II-a expressing neurons in the CA1-CA4 subfields of AD patients showed that the immunoreactivity of the remaining CaMK II-a neurons strikingly increased in the CA1 subfield in AD patients compared with the controls. In the double-labeling sections of CaMK II -a and AT-8, we found a large number of single labeled AT-8 or CaMK II-a immunoreactive neurons in AD hippocampus and small portion of double-labeled neurons. The quantantive analysis showed only 32 + 7.6 % of AT-8 positive neurons were immunoreactive for CaMK II -a. On the other hand, the percentage of the double-labeling AT-8 and CaMK II-a neurons with single-labeled CaMK II-a neuronswas 23 ?5.4 %. We found CaMK II-a immunohistochemistry disclosedareas of enhanced punctate and large coarse granules CaMK II-adepostis similar to SPs. Double-labeled immunoflurescence of theCaMK II-a with AB17-42, the marker of SPs, showed that most ofCaMK II -a deposits localized in SPs. Using semi-quantitatively methodswe analyzed the percentage of CaMK II -a deposits with SPs in AD.Conclusions In the present study , our results showed CaMK II-a containingneurons were selectively lost in the CA1 subfield of AD patients,however, CaMK II -a immunoreactivity was increased in the remamingneurons in CA1. CaMK II -a could colocalize with hyperphosphorylatedtau in neurons and the ratio was low. There were large amount ofCaMK II-a immuopositive deposits in AD hippocampus and theCaMK II-a deposits were closely related to the SPs. These resultssuggest that CaMK II -a may be involved the pathological process of AD,possibly more to the formation of SPs, less to the NFTs.