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Molecular Insights into Alzheimer’s Disease

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Biological Markers of Alzheimer’s Disease

Part of the book series: Research and Perspectives in Alzheimer’s Disease ((ALZHEIMER))

Summary

Recent in vitro and in vivo 31P NMR studies demonstrate increased levels of PME and PDE in Alzheimer’s brain. The PME levels have an inverse correlation with the numbers of SP and are thought to represent an early molecular event in the pathogenesis of the disease. Similar high levels of PME are observed normally in the developing brain, especially during the period of dendritic proliferation. Cytological studies demonstrate the elaboration of dendritic processes in AD. The levels of PDE have a positive correlation with the numbers of SP and are thought to represent markers of neuronal degeneration. Fluorescence spectroscopy studies reveal that PME and PDE can alter membrane molecular dynamics. Solid-state 31P NMR studies reveal that PME but not PDE can alter the conformation of synthetic phospholipid model membranes and induce transformations from the bilayer phase to the hexagonal II and micellar phases. Similar transformations in vivo could induce the formation of vesicles (micellar) and the fusion of membranes (hexagonal II) with important biological consequences. Computer modeling studies demonstrate the PME to have striking conformational similarities with the neurotransmitters NMD A and l-glutamate. Recent studies reveal the PME to be neuromodulators at l-glutamate receptors in hippocampal CAI pyramidal cells. This finding suggests possible molecular mechanisms for memory loss and the degenerative features of the disease. The elevated levels of PME also could reflect enhanced phospholipase С activity, which could stimulate protein kinase С activity. Enhanced protein kinase С activity could lead to many diverse biological effects, including the hyperphosphorylation of proteins such as the ADAP and microtubule-associated tau proteins, resulting in altered posttranslational processing of these proteins. These findings provide insights into the molecular pathology of AD which could guide future therapeutic and preventive strategies.

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Authors
  1. J. W. Pettegrew
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Editors and Affiliations

  1. Inserm U324, 2 ter, rue d’Alesia, 75014, Paris, France

    François Boller

  2. University of California at San Diego, La Jolla, USA

    Robert Katzman

  3. Hôpital Purpan, Toulouse, France

    André Rascol

  4. Hôpital Salpêtrière, Paris, France

    Jean-Louis Signoret

  5. Fondation IPSEN pour la Recherche Thérapeutique, 30, rue Cambronne, F-75737, Paris Cédex, France

    Yves Christen

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Pettegrew, J.W. (1989). Molecular Insights into Alzheimer’s Disease. In: Boller, F., Katzman, R., Rascol, A., Signoret, JL., Christen, Y. (eds) Biological Markers of Alzheimer’s Disease. Research and Perspectives in Alzheimer’s Disease. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-46690-8_9

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  • DOI: https://doi.org/10.1007/978-3-642-46690-8_9

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