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      Biology and pathophysiology of the amyloid precursor protein

      review-article
      Author(s): 1 , , 2
      Publication date (Electronic):
      Journal: Molecular Neurodegeneration
      Publisher: BioMed Central

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          Abstract

          The amyloid precursor protein (APP) plays a central role in the pathophysiology of Alzheimer's disease in large part due to the sequential proteolytic cleavages that result in the generation of β-amyloid peptides (Aβ). Not surprisingly, the biological properties of APP have also been the subject of great interest and intense investigations. Since our 2006 review, the body of literature on APP continues to expand, thereby offering further insights into the biochemical, cellular and functional properties of this interesting molecule. Sophisticated mouse models have been created to allow in vivo examination of cell type-specific functions of APP together with the many functional domains. This review provides an overview and update on our current understanding of the pathobiology of APP.

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          Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity.

          M S Wolfe, W. Xia, B Ostaszewski … (1999)
          Accumulation of the amyloid-beta protein (Abeta) in the cerebral cortex is an early and invariant event in the pathogenesis of Alzheimer's disease. The final step in the generation of Abeta from the beta-amyloid precursor protein is an apparently intramembranous proteolysis by the elusive gamma-secretase(s). The most common cause of familial Alzheimer's disease is mutation of the genes encoding presenilins 1 and 2, which alters gamma-secretase activity to increase the production of the highly amyloidogenic Abeta42 isoform. Moreover, deletion of presenilin-1 in mice greatly reduces gamma-secretase activity, indicating that presenilin-1 mediates most of this proteolytic event. Here we report that mutation of either of two conserved transmembrane (TM) aspartate residues in presenilin-1, Asp 257 (in TM6) and Asp 385 (in TM7), substantially reduces Abeta production and increases the amounts of the carboxy-terminal fragments of beta-amyloid precursor protein that are the substrates of gamma-secretase. We observed these effects in three different cell lines as well as in cell-free microsomes. Either of the Asp --> Ala mutations also prevented the normal endoproteolysis of presenilin-1 in the TM6 --> TM7 cytoplasmic loop. In a functional presenilin-1 variant (carrying a deletion in exon 9) that is associated with familial Alzheimer's disease and which does not require this cleavage, the Asp 385 --> Ala mutation still inhibited gamma-secretase activity. Our results indicate that the two transmembrane aspartate residues are critical for both presenilin-1 endoproteolysis and gamma-secretase activity, and suggest that presenilin 1 is either a unique diaspartyl cofactor for gamma-secretase or is itself gamma-secretase, an autoactivated intramembranous aspartyl protease.
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            Neuroligin expressed in nonneuronal cells triggers presynaptic development in contacting axons.

            Peter Scheiffele, Jinhong Fan, Jenny Choih … (2000)
            Most neurons form synapses exclusively with other neurons, but little is known about the molecular mechanisms mediating synaptogenesis in the central nervous system. Using an in vitro system, we demonstrate that neuroligin-1 and -2, postsynaptically localized proteins, can trigger the de novo formation of presynaptic structure. Nonneuronal cells engineered to express neuroligins induce morphological and functional presynaptic differentiation in contacting axons. This activity can be inhibited by addition of a soluble version of beta-neurexin, a receptor for neuroligin. Furthermore, addition of soluble beta-neurexin to a coculture of defined pre- and postsynaptic CNS neurons inhibits synaptic vesicle clustering in axons contacting target neurons. Our results suggest that neuroligins are part of the machinery employed during the formation and remodeling of CNS synapses.
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              Neurexins induce differentiation of GABA and glutamate postsynaptic specializations via neuroligins.

              Ethan R. Graf, XueZhao Zhang, Shan-Xue Jin … (2004)
              Formation of synaptic connections requires alignment of neurotransmitter receptors on postsynaptic dendrites opposite matching transmitter release sites on presynaptic axons. beta-neurexins and neuroligins form a trans-synaptic link at glutamate synapses. We show here that neurexin alone is sufficient to induce glutamate postsynaptic differentiation in contacting dendrites. Surprisingly, neurexin also induces GABA postsynaptic differentiation. Conversely, neuroligins induce presynaptic differentiation in both glutamate and GABA axons. Whereas neuroligins-1, -3, and -4 localize to glutamate postsynaptic sites, neuroligin-2 localizes primarily to GABA synapses. Direct aggregation of neuroligins reveals a linkage of neuroligin-2 to GABA and glutamate postsynaptic proteins, but the other neuroligins only to glutamate postsynaptic proteins. Furthermore, mislocalized expression of neuroligin-2 disperses postsynaptic proteins and disrupts synaptic transmission. Our findings indicate that the neurexin-neuroligin link is a core component mediating both GABAergic and glutamatergic synaptogenesis, and differences in isoform localization and binding affinities may contribute to appropriate differentiation and specificity.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Mol Neurodegener
                Title: Molecular Neurodegeneration
                Publisher: BioMed Central
                ISSN (Electronic): 1750-1326
                Publication date Collection: 2011
                Publication date (Electronic): 28 April 2011
                Volume: 6
                Page: 27
                Affiliations
                [1 ]Huffington Center on Aging and Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
                [2 ]Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA
                Article
                Publisher ID: 1750-1326-6-27
                DOI: 10.1186/1750-1326-6-27
                PMC ID: 3098799
                PubMed ID: 21527012
                SO-VID: 15a16e93-1c51-4ece-968c-fac400a6a3b6
                Copyright statement: Copyright ©2011 Zheng and Koo; licensee BioMed Central Ltd.
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 13 February 2011
                Date accepted : 28 April 2011
                Product
                Self URI: http://www.molecularneurodegeneration.com/content/6/1/27
                Categories
                Subject: Review

                ScienceOpen disciplines: Neurosciences
                Data availability:
                ScienceOpen disciplines: Neurosciences

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