Resumen de [eta]-Secretase processing of APP inhibits neuronal activity in the hippocampus
Michel Willem, Sabina Tahirovic, Marc Aurel Busche, Saak V. Ovsepian, Magda Chafai, Scherazad Kootar, Daniel Hornburg, Lewis D. B. Evans, Steve Moore
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.
