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

Alzheimer disease (AD) is characterized by the accumulation of amyloid plaques, which are predominantly composed of amyloid-? peptide. Two principal physiological pathways either prevent or promote amyloid-? generation from its precursor, ?-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 processin...     »