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Disturbances in signal transduction mechanisms in Alzheimer's disease

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Abstract

Many of the treatments directed towards alleviation of symptoms in Alzheimer's disease assume that target receptor systems are functionally intact. However, there is now considerable evidence that this is not the case. In human post-mortem brain tissue samples, the function of the GTP-binding protein Gs in regulating adenylyl cyclase is severely disabled, whereas that of Gi is intact. This difference in the function of the two G-protein types is also found in G-protein regulation of high- and low-affinity receptor recognition site populations. Measurement of G-protein densities using selective antibodies has indicated that the dysfunction in Gs-stimulation of cAMP production correlates with the ratio of the large to small molecular weight isoforms of the Gsα subunit. With respect to intracellular second messenger effects, there is a dramatic decrease in the density of brain receptor recognition sites for Ins(1,4,5)P3 that is not accompanied by a corresponding change in the Ins(1,3,4,5)P4 recognition site density. Protein kinase C function is also altered in Alzheimer's disease, a finding that may be of importance for the control of β-amyloid production. These studies indicate that signal transduction processes are severely compromised in Alzheimer's disease. Some of these disturbances are also seen in cultured fibroblasts from Alzheimer's disease patients, indicating that they are neither restricted to areas of histopathological change, nor non-specific changes found late in the course of the disease. Cellular models to investigate the relation between amyloid production and deficits in signal transduction are also discussed.

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Abbreviations

GTPγS:

guanosine-5′-O-(3-thiotriphosphate)

Gpp[NH]p:

5′-guanylylimidodiphosphate

Ins:

inositol

P:

phosphate

CGP-12177:

(±)-4-(3-t-butylamino-2-hydroxypropoxy)-[5,7-3H]benzimidazol-2-one

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Authors and Affiliations

  1. Alzheimer's Disease Research Centre, Department of Geriatric Medicine, Karolinska Institute, Huddinge University Hospital, S-141 86, Huddinge, Sweden

    Christopher J. Fowler, Richard F. Cowburn, Anita Garlind, Bengt Winblad & Cora O'Neill

  2. Novum Unit, Astra Pain Control AB, Preclinical R and D, S-14157, Huddinge, Sweden

    Christopher J. Fowler

  3. Department of Biochemistry, University College, Lee Maltings, Cork, Ireland

    Cora O'Neill

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  1. Christopher J. Fowler
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  2. Richard F. Cowburn
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  4. Bengt Winblad
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  5. Cora O'Neill
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Fowler, C.J., Cowburn, R.F., Garlind, A. et al. Disturbances in signal transduction mechanisms in Alzheimer's disease. Mol Cell Biochem 149, 287–292 (1995). https://doi.org/10.1007/BF01076590

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