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Synaptic Plasticity and the Mechanism of Alzheimer's Disease pp 89–102Cite as

Soluble Oligomers of the Amyloid β-Protein: Impair Synaptic Plasticity and Behavior

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

Abstract

The central quest of research on Alzheimer’s disease (AD) is to identify precisely what molecular process first interferes with episodic declarative memory and then prevent that process. During the last 25 years, neuropathological, biochemical, genetic, cell biological and even therapeutic studies in humans have all supported the hypothesis that the gradual cerebral accumulation of soluble and insoluble assemblies of the amyloid β-protein (Aβ) in limbic and association cortices triggers a cascade of biochemical and cellular alterations that produce the clinical phenotype. Missense mutations in presenilin, an unusual intramembrane aspartyl protease, cause rare forms of early-onset AD by altering its cleavage of the amyloid precursor protein (APP) transmembrane domain to increase the ratio of Aβ42 to Aβ40 peptides, thereby promoting Aβ oligomerization. The reasons for elevated cortical Aβ42 levels in most patients with typical, late-onset AD are unknown, but based on recent work, these could turn out to include augmented neuronal release of Aβ during some kinds of synaptic activity. Elevated levels of soluble Aβ42 monomers enable formation of soluble oligomers that can diffuse into synaptic clefts. We have identified certain APP-expressing cultured cell lines that form low-n oligomers intracellularly and release a portion of them into the medium. We find that these naturally secreted soluble oligomers – at picomolar concentrations – can disrupt hippocampal LTP in slices and in vivo and can also impair the memory of a complex learned behavior in rats. Aβ trimers appear to be more potent in disrupting LTP than are dimers. The cell-derived oligomers also decrease dendritic spine density in organotypic hippocampal slice cultures, and this decrease can be prevented by administration of Aβ antibodies or small-molecule modulators of Aβ aggregation. The signaling pathways mediating these effects are under study. Intensive attempts to develop safe and effective Aβ-lowering agents have brought us into human trials that have provided preliminary evidence of cognitive benefit. This therapeutic progress has been accompanied by advances in imaging the Aβ deposits non-invasively in humans. A new diagnostic-therapeutic paradigm to successfully address AD and its harbinger, mild cognitive impairment-amnestic type, is emerging.

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Authors and Affiliations

  1. Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School, 02115, Boston, MA, USA

    Dennis J. Selkoe

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  1. Dennis J. Selkoe
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Editors and Affiliations

  1. Center for Neurologic Diseases, Brigham andWomen’s Ho, Harvard Medical School, 02115, Boston, MA, USA

    Dennis J. Selkoe

  2. Laboratoire de Biologie Cellulaire de la Synapse, Institut National de la Santé et de la Recherche, Médicale Unite 789, 46 rue d’Ulm, 75005, Paris, France

    Antoine Triller

  3. Pour la Recherche Thérapeutique, Fondation IPSEN, 24, rue Erlanger, 75781, Paris Cedex 16, France

    Yves Christen

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Selkoe, D. (2008). Soluble Oligomers of the Amyloid β-Protein: Impair Synaptic Plasticity and Behavior. In: Selkoe, D., Triller, A., Christen, Y. (eds) Synaptic Plasticity and the Mechanism of Alzheimer's Disease. Research and Perspectives in Alzheimer's Disease. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-76330-7_8

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