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The Association of Amyloid-β Protein Precursor With α- and β-Secretases in Mouse Cerebral Cortex Synapses Is Altered in Early Alzheimer’s Disease

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Abstract

Amyloid-β peptides (Aβ), the proposed triggers of synaptic dysfunction in early Alzheimer’s disease (AD), derive from the endoproteolytic cleavage of amyloid-β precursor protein (APP) by β-secretases (BACE1), whereas APP cleavage by α-secretases (ADAM10) abrogates Aβ formation. We now mapped the synaptic localization of APP, ADAM10, and BACE1 in the mouse cerebral cortex. All three proteins were present in cortical synapses and subsynaptic fractionation revealed that APP was located mainly in the pre-synaptic active zone (53 %) and in the post-synaptic density (37 %), whereas ADAM10 was enriched in the post-synaptic density (61 %) and BACE1 was concentrated in extra-synaptic regions (72 %). Immunocytochemistry analysis further showed that APP and BACE1 were co-localized in about 30 % of both glutamatergic and GABAergic terminals, whereas few terminals were endowed with ADAM10. This distribution is modified in a mouse model of early AD based on Aβ1–42-intracerebroventricular injection, where the synaptic levels of APP and ADAM10 increased by 30 %, whereas BACE1 levels were reduced. This suggests that, in early AD, there are compensatory mechanisms to avoid Aβ overload in cortical synapses favoring the non-amyloidogenic processing of APP.

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Acknowledgments

This work is funded by FEDER funds through the Operational Program Competitiveness Factors—COMPETE and national funds by Foundation for Science and Technology (project PTDC/SAU-NMC/114810/2009) and strategic project UID/NEU/04539/2013, Santa Casa da Misericórdia de Lisboa and QREN (CENTRO-07-ST24-FEDER-002006).

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  1. CNC—Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal

    Anna Pliássova, João P. Lopes, Cristina Lemos, Catarina R. Oliveira, Rodrigo A. Cunha & Paula Agostinho

  2. FMUC—Faculty of Medicine, University of Coimbra, 3004-504, Coimbra, Portugal

    Anna Pliássova, Catarina R. Oliveira, Rodrigo A. Cunha & Paula Agostinho

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  1. Anna Pliássova
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Correspondence to Paula Agostinho.

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Pliássova, A., Lopes, J.P., Lemos, C. et al. The Association of Amyloid-β Protein Precursor With α- and β-Secretases in Mouse Cerebral Cortex Synapses Is Altered in Early Alzheimer’s Disease. Mol Neurobiol 53, 5710–5721 (2016). https://doi.org/10.1007/s12035-015-9491-9

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