η-Secretase processing of APP inhibits neuronal activity in the hippocampus

Abstract

Alzheimer disease (AD) is characterized by the accumulation of amyloid plaques, which are predominantly composed of amyloid-β peptide. Two principal physiological pathways either prevent or promote amyloid-β generation from its precursor, β-amyloid precursor protein (APP), in a competitive manner. Although APP processing has been studied in great detail, unknown proteolytic events seem to hinder stoichiometric analyses of APP metabolism in vivo. 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-η, in addition to the long-known CTF-α and CTF-β fragments generated by the α- and β-secretases ADAM10 (a disintegrin and metalloproteinase 10) and BACE1 (β-site APP cleaving enzyme 1), respectively. CTF-η generation is mediated in part by membrane-bound matrix metalloproteinases such as MT5-MMP, referred to as η-secretase activity. η-Secretase cleavage occurs primarily at amino acids 504-505 of APP695, releasing a truncated ectodomain. After shedding of this ectodomain, CTF-η is further processed by ADAM10 and BACE1 to release long and short Aη peptides (termed Aη-α and Aη-β). CTFs produced by η-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-η and Aη-α. In mice treated with a potent BACE1 inhibitor, hippocampal long-term potentiation was reduced. Notably, when recombinant or synthetic Aη-α 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 Aη-α. 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.

APP mouse models for Alzheimer's disease preclinical studies

“…Overproduced non‐Aβ APP fragments may interact unphysiologically with cellular proteins (Chang & Suh, 2005; Mitani et al , 2012; Nicolas & Hassan, 2014; Kerridge et al , 2015; Nhan et al , 2015; Willem et al , 2015; Xia et al , 2016). See Fig 3.…”

Ion channel regulation by β-secretase BACE1 – enzymatic and non-enzymatic effects beyond Alzheimer's disease

“…d-secretase and h-secretase, is just beginning to emerge. 13,14 In healthy brain, non-amyloidogenic and amyloidogenic processing are balanced, with Ab peptides being important effectors in synaptic transmission and plasticity. 15,16 In 2003, Yang et al reported enhanced BACE1-mediated amyloidogenic cleavage in AD.…”

New tricks from an old dog: Another synaptotoxic fragment from APP

“…Subsequent cleavage by γ-secretase generates Aβ peptide that is believed to play a seminal role in AD pathogenesis [2]. In this report, Willem and colleagues investigated APP fragments at approximately 25kDa that ends at the APP C-terminus [1]. They reasoned correctly that these fragments are processed by alternative proteases that cleave APP at a position N-terminal to the β-secretase cleavage site ( Figure 1).…”

“…It is usually inconsequential but when this happens in science, then the opportunity to discover something new and potentially exciting is lost. History has just repeated itself when the Haass lab reported previously unrecognized proteolytic cleavages of the amyloid precursor protein (APP) that generate fragments intermediate in size between full length APP and C-terminal fragments (CTFs), the latter being precursors to the Aβ peptide [1]. With the attention given to the pathways of APP processing and Aβ production, it is almost shocking that this newly reported processing pathway has been uniformly ignored by the research community collectively for the past 25 years, even though the fragments are readily detected by western blotting.…”

“…Sheue-Houy Tyan 1 , Edward H Koo 1,2 and Aη-α peptide. As such, there is the possibility of previously unrecognized toxicity of BACE inhibitors, now in the midst of late phase clinical trials testing for AD treatment.…”