title: Major amyloid-β-degrading enzymes, endothelin-converting enzyme-2 and neprilysin, are expressed by distinct populations of GABAergic interneurons in hippocampus and neocortex.
abstract: Impaired clearance of amyloid-β peptide (Aβ) has been postulated to significantly contribute to the amyloid accumulation typical of Alzheimer's disease. Among the enzymes known to degrade Aβ in vivo are endothelin-converting enzyme (ECE)-1, ECE-2, and neprilysin (NEP), and evidence suggests that they regulate independent pools of Aβ that may be functionally significant. To better understand the differential regulation of Aβ concentration by its physiological degrading enzymes, we characterized the cell and region-specific expression pattern of ECE-1, ECE-2, and NEP by in situ hybridization and immunohistochemistry in brain areas relevant to Alzheimer's disease. In contrast to the broader distribution of ECE-1, ECE-2 and NEP were found enriched in GABAergic neurons. ECE-2 was majorly expressed by somatostatin-expressing interneurons and was active in isolated synaptosomes. NEP messenger RNA was found mainly in parvalbumin-expressing interneurons, with NEP protein localized to perisomatic parvalbuminergic synapses. The identification of somatostatinergic and parvalbuminergic synapses as hubs for Aβ degradation is consistent with the possibility that Aβ may have a physiological function related to the regulation of inhibitory signaling.
authors.affiliation: Atlantic Health System, Morristown, NJ, USA; Biomedical Research Institute of New Jersey, Cedar Knolls, NJ, USA.
authors.forename: Javier
authors.initials: J
authors.lastname: Pacheco-Quinto
authors.affiliation: Atlantic Health System, Morristown, NJ, USA; Biomedical Research Institute of New Jersey, Cedar Knolls, NJ, USA.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Eckman
authors.affiliation: Atlantic Health System, Morristown, NJ, USA; Biomedical Research Institute of New Jersey, Cedar Knolls, NJ, USA. Electronic address: elizabeth.eckman@atlantichealth.org.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Eckman
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D000072396:Endothelin-Converting Enzymes / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D059330:GABAergic Neurons / Q000201:enzymology*; D015870:Gene Expression; D006624:Hippocampus / Q000166:cytology* / Q000201:enzymology*; D008822:Mice, Transgenic; D019579:Neocortex / Q000166:cytology* / Q000201:enzymology*; D015260:Neprilysin / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D013569:Synapses / Q000201:enzymology
chemical_list: D016229:Amyloid beta-Peptides; D012333:RNA, Messenger; D015260:Neprilysin; C000606926:Ece2 protein, mouse; D000072396:Endothelin-Converting Enzymes
keywords: Alzheimer's disease; Aβ degradation; Endothelin-converting enzyme; GABA; Interneuron; Neprilysin; Parvalbumin; Somatostatin