eta-Secretase processing of APP inhibits neuronal activity in the hippocampus
2015 (English)In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 526, no 7573, 443-447 p.Article in journal (Refereed) Published
Alzheimer disease (AD) is characterized by the accumulation of amyloid plaques, which are predominantly composed of amyloid-beta peptide(1). Two principal physiological pathways either prevent or promote amyloid-beta generation from its precursor, beta-amyloid precursor protein (APP), in a competitive manne(r)1. Although APP processing has been studied in great detail, unknown proteolytic events seem to hinder stoichiometric analyses of APP metabolism in vivo(2). Here we describe a new physiological APP processing pathway, which generates proteolytic fragments capable of inhibiting neuronal activity within the hippocampus. We identify higher molecular mass carboxy-terminal fragments (CTFs) of APP, termed CTF-eta, in addition to the long-known CTF-alpha and CTF-beta fragments generated by the alpha- and beta-secretases ADAM10 (a disintegrin and metalloproteinase 10) and BACE1 (beta-site APP cleaving enzyme 1), respectively. CTF-eta generation is mediated in part by membrane-bound matrix metalloproteinases such as MT5-MMP, referred to as g-secretase activity. g-Secretase cleavage occurs primarily at amino acids 504-505 of APP(695), releasing a truncated ectodomain. After shedding of this ectodomain, CTF-eta is further processed by ADAM10 and BACE1 to release long and short A eta peptides (termed A eta-alpha and A eta-beta). CTFs produced by g-secretase are enriched in dystrophic neurites in an AD mouse model and in human AD brains. Genetic and pharmacological inhibition of BACE1 activity results in robust accumulation of CTF-eta and A eta-alpha. In mice treated with a potent BACE1 inhibitor, hippocampal long-term potentiation was reduced. Notably, when recombinant or synthetic A eta-alpha was applied on hippocampal slices ex vivo, long-term potentiation was lowered. Furthermore, in vivo single-cell two-photon calcium imaging showed that hippocampal neuronal activity was attenuated by A eta-alpha. These findings not only demonstrate a major functionally relevant APP processing pathway, but may also indicate potential translational relevance for therapeutic strategies targeting APP processing.
Place, publisher, year, edition, pages
2015. Vol. 526, no 7573, 443-447 p.
IdentifiersURN: urn:nbn:se:uu:diva-265812DOI: 10.1038/nature14864ISI: 000362730200054PubMedID: 26322584OAI: oai:DiVA.org:uu-265812DiVA: diva2:866688
FunderEU, European Research Council, 321366-AmyloidEU, European Research Council, 318987German Research Foundation (DFG), MU 1457/9-1German Research Foundation (DFG), MU 1457/9-2