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P1‐149: Urea Cycle Enzymes and Peptidylarginine Deiminase in Alzheimer’s Superior Frontal Gyrus
Author(s) -
Cicolini Jody,
Jing Yu,
Waldvogel Henry J.,
Faull Richard L.M.,
Liu Ping
Publication year - 2016
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2016.06.897
Subject(s) - urea cycle , urea , citrulline , chemistry , medicine , carbamoyl phosphate synthetase , enzyme , endocrinology , biochemistry , biology , arginine , amino acid
Ab. Methods: Multiplex fluorescence in situ hybridization combined with immunofluorescence was used to characterize the expression of endothelin-converting enzyme-1 (ECE-1), ECE-2, neprilysin and insulin degrading enzyme (IDE) in mouse brain. ECE-2 activity was evaluated by measuring the conversion of big ET-1 to ET-1 in isolated brain synaptosomes. Results: In cortex, Ece2 and neprilysin mRNA were expressed by a limited number of cells in contrast to the broader expression of Ece1 and Ide. Most Ece2 expressing cells were identified as somatostatin (SST) positive interneurons. Consistent with the distribution of SST cells in hippocampus, Ece2+ cells were found along the stratum oriens and hilus of the dentate gyrus. Ece2 mRNA also followed a fiberlike pattern extending to regions where SST interneurons form synapses. In addition, ECE-2 specific activity was present in synaptosomes extracted from mouse brains, indicating that ECE-2 may be translated in synapses. Neprilysin was not expressed by SST+ cells but was instead found in a non-overlapping population of interneurons characterized by parvalbumin (PV) expression. Neprilysin mRNA was concentrated mostly in the soma of PV+ cells, but was also found in a fiber-like pattern in areas with non-somatic PV immunostaining. In contrast, little neprilysin protein was found in the soma of PV+ cells, and more intense staining was detected in GAD67+ processes surrounding the soma of pyramidal cells with strong parvalbuminergic input. Conclusions: The identification of somatostatinergic and parvalbuminergic synapses as hubs for Ab degradation raises the intriguing possibility that Ab may have a physiological function related to the regulation of inhibitory signaling. Impaired degradation leading to Ab accumulation at inhibitory synapses could disturb this putative function and result in synaptotoxicity, ultimately leading to cognitive impairment.