Aminopeptidase A contributes to biochemical, anatomical and cognitive defects in Alzheimer’s disease (AD) mouse model and is increased at early stage in sporadic AD brain

• Published in: Acta neuropathologica 2021-06, Vol.141 (6), p.823-839
• Main Authors: Valverde, Audrey, Dunys, Julie, Lorivel, Thomas, Debayle, Delphine, Gay, Anne-Sophie, Lacas-Gervais, Sandra, Roques, Bernard. P., Chami, Mounia, Checler, Frédéric
• Format: Article
• Language: English
• Subjects: Advertising executives; Alzheimer Disease - metabolism; Alzheimer Disease - physiopathology; Alzheimer's disease; Aminopeptidase; Amyloid beta-Peptides - metabolism; Animal models; Animals; Biotransformation; Brain - metabolism; Brain - pathology; Cell Line; Cognitive ability; Cognitive Dysfunction - metabolism; Disease Models, Animal; Enzymes; Ethylenediaminetetraacetic acid; Filopodia; Glutamate; Glutamyl Aminopeptidase - antagonists & inhibitors; Glutamyl Aminopeptidase - metabolism; Glutamyl Aminopeptidase - physiology; Hippocampus; Hippocampus - metabolism; Humans; Life Sciences; Mass spectroscopy; Medicine; Medicine & Public Health; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurodegenerative diseases; Neurons and Cognition; Neurosciences; Observational learning; Original Paper; Pathology; Peptides; Plaque, Amyloid - pathology; Proteolysis; Senile plaques; Spines; Target marketing
• ISSN: 0001-6322; 1432-0533
• DOI: 10.1007/s00401-021-02308-0

One of the main components of senile plaques in Alzheimer’s disease (AD)-affected brain is the Aβ peptide species harboring a pyroglutamate at position three pE3-Aβ. Several studies indicated that pE3-Aβ is toxic, prone to aggregation and serves as a seed of Aβ aggregation. The cyclisation of the glutamate residue is produced by glutaminyl cyclase, the pharmacological and genetic reductions of which significantly alleviate AD-related anatomical lesions and cognitive defects in mice models. The cyclisation of the glutamate in position 3 requires prior removal of the Aβ N-terminal aspartyl residue to allow subsequent biotransformation. The enzyme responsible for this rate-limiting catalytic step and its relevance as a putative trigger of AD pathology remained yet to be established. Here, we identify aminopeptidase A as the main exopeptidase involved in the N-terminal truncation of Aβ and document its key contribution to AD-related anatomical and behavioral defects. First, we show by mass spectrometry that human recombinant aminopeptidase A (APA) truncates synthetic Aβ1-40 to yield Aβ2-40. We demonstrate that the pharmacological blockade of APA with its selective inhibitor RB150 restores the density of mature spines and significantly reduced filopodia-like processes in hippocampal organotypic slices cultures virally transduced with the Swedish mutated Aβ-precursor protein (βAPP). Pharmacological reduction of APA activity and lowering of its expression by shRNA affect pE3-42Aβ- and Aβ1-42-positive plaques and expressions in 3xTg-AD mice brains. Further, we show that both APA inhibitors and shRNA partly alleviate learning and memory deficits observed in 3xTg-AD mice. Importantly, we demonstrate that, concomitantly to the occurrence of pE3-42Aβ-positive plaques, APA activity is augmented at early Braak stages in sporadic AD brains. Overall, our data indicate that APA is a key enzyme involved in Aβ N-terminal truncation and suggest the potential benefit of targeting this proteolytic activity to interfere with AD pathology.