[eta]-Secretase processing of APP inhibits neuronal activity in the hippocampus
- Autores: Michel Willem, Sabina Tahirovic, Marc Aurel Busche, Saak V. Ovsepian, Magda Chafai, Scherazad Kootar, Daniel Hornburg, Lewis D. B. Evans, Steve Moore
- Localización: Nature: International weekly journal of science, ISSN 0028-0836, Vol. 526, Nº 7573, 2015, págs. 443-447
- Idioma: inglés
- Enlaces
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Resumen
Alzheimer disease (AD) is characterized by the accumulation of amyloid plaques, which are predominantly composed of amyloid-[beta] peptide1. Two principal physiological pathways either prevent or promote amyloid-[beta] generation from its precursor, [beta]-amyloid precursor protein (APP), in a competitive manner1. Although APP processing has been studied in great detail, unknown proteolytic events seem to hinder stoichiometric analyses of APP metabolism in vivo2. 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 [eta]-secretase activity. [eta]-Secretase cleavage occurs primarily at amino acids 504–505 of APP695, 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 [eta]-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.
