Activation and intracellular signal transduction in lymphocytes in relation to Alzheimer disease

Projektdetails:

Thematik: Grundlagenforschung
Förderstatus: abgeschlossen
Art der Förderung: Standard Projekt
Institution: Universität Leipzig, Abteilung für Neuroanatomie
Projektleiter: Prof. Dr. Thomas Arendt
Laufzeit: 01. November 1998 - 31. Oktober 1999
Fördersumme: 38.347,00 Euro
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Projektbeschreibung

Compared to reparative neuronal changes that occur after neurodegeneration during normal ageing, the changes in Alzheimer’s disease patients are aberrant with respect to their localisation, morphology and composition. These aberrant reparative processes in Alzheimer’s disease are related to a disturbed mechanism of intra-neuronal signal transduction. Activation of the p21ras/MAP kinase pathway is involved in the intracellular signalling. As a result, a number of mechanisms are triggered including protein phosphorylation contributing to the formation of ß-amyloid and tau deposits.

Prof. Arendt wants to investigate whether the aberrancies in signalling related to the p21ras/MAP kinase pathway are central to the chain of pathological events in Alzheimer’s disease. As this pathway is not restricted to the central nervous system, but can similarly be observed on peripheral lymphocytes, alterations of this pathway in Alzheimer’s disease patients can be analysed here. This study will provide a better understanding of pathogenic processes of the nervous system, and will characterise a peripheral biological marker with potential diagnostic implications.

Abschlussbericht

Neurodegeneration in Alzheimer's disease is associated with plastic changes of neuronal repair that are aberrant with respect to their localization, morphological appearance and composition of cytoskeletal components. These reparative processes are related to an aberrant activation of signalling and effector pathways that mediate the actions of mitogenic compounds

As a result, a number of mechanisms are triggered contributing to the formation of neuritic plaques and neurofibrillary tangles as well as to the activation of mitotic processes eventually resulting in cell death. Aberrancies in mitogenic signalling might be central to this cascade of pathological events and might, therefore, be of primary importance in the pathomechanism of the disease. Preliminary studies indicate that disturbances of mitogenic signalling are not restricted to central neurons but can similarly be observed on peripheral lymphozytes.

Therefore, it was the objective of the present project to analyse alterations in mitogenic signalling in peripheral lymphozytes in Alzheimer's disease and to characterize changes of the proliferative response after mitogenic stimulation. It was, thus, the aim of the project, to identify pathological alterations of a peripheral biological marker and to characterize its potential diagnostic significance. Anticipated results, moreover, will contribute to the identification of potential molecular targets for pharmacological and/or molecularbiological approaches of treatment.

The results of the present project clearly demonstrate alterations in the proliferation response of peripheral lymphocytes in Alzheimer's disease compared to normal elderly. Different subpopulations of lymphozytes are differentially involved in these changes. Based on this abnormal proliferative response of lymphocytes after mitogenic stimulation, it was possible to identify patients with Alzheimer's disease with a sensitivity close to 90% and a specificity close to 80% which indicates the potential diagnostic value of these parameters.

Alterations in the proliferative response of lymphocytes are highly correlated to the reduced mental abilities of the patients. The analysis is currently continued on a much larger cohort of clinically and autoptically well assessed patients with Alzheimer's disease.

Wissenschaftliche Publikationen auf Basis des geförderten Projekts

Stieler, J.T., Lederer, C., Brückner, M.K., Wolf, H., Holzer, M., Gertz, H.J., Arendt,T. (2001). Impairment of mitogenic activation of peripheral blood lymphocytes in Alzheimer's disease. Neuroreport, 12(18):3969-72.


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