Alzheimer’s disease (AD) includes several hallmarks comprised of amyloid-β (Aβ) deposition, tau neuropathology, inflammation, and memory impairment. Brain metabolism becomes uncoupled due to aging and other AD risk factors, which ultimately lead to impaired protein clearance and aggregation. Increasing evidence indicates a role of arginine metabolism in AD, where arginases are key enzymes in neurons and glia capable of depleting arginine and producing ornithine and polyamines. However, currently, it remains unknown if the reduction of arginase 1 (Arg1) in myeloid cell impacts amyloidosis. Herein, we produced haploinsufficiency of Arg1 by the hemizygous deletion in myeloid cells using Arg1fl/fl and LysMcreTg/+ mice crossed with APP Tg2576 mice. Our data indicated that Arg1 haploinsufficiency promoted Aβ deposition, exacerbated some behavioral impairment, and decreased components of Ragulator-Rag complex involved in mechanistic target of rapamycin complex 1 (mTORC1) signaling and autophagy. Additionally, Arg1 repression and arginine supplementation both impaired microglial phagocytosis in vitro. These data suggest that proper function of Arg1 and arginine metabolism in myeloid cells remains essential to restrict amyloidosis.
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Funding for this work is provided by the NIH NIA R21-AG055996 (to DL), NIA R01-AG054559 (to DL), NIA R01-AG051500 (to DM), NINDS R01-NS091582 (to JG), NIAID R01-AI095307 (to DF), Alzheimer’s Association AARGD-16-441534 (to DL) and MNIRGD-12-242665 (to DL), Florida Department of Health Ed and Ethel Moore Alzheimer’s disease (8AZ30) (to DL, PB), and IKBX004214 (to PB). CM is awarded by USF Health Neuroscience Institute Dorothy Benjamin Graduate Fellowship in Alzheimer’s Disease.
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
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Primary macrophages with Arg1 deficiency showed reduced arginase activity and failed to improve neuron viability. (A) In macrophage arginase activity assay, primary macrophages isolated from both nTg/Arg1+/+ mice (wild type control) and nTg/Arg1fl/fl mice (Arg1flox transgenic control) showed increased arginase activity post IL-4 treatment with or without LPS (p < 0.0001); however, macrophages of nTg/Arg1fl/fl/LysMcreTg/+ mice did not induce arginase activity in both conditions. In addition, in IL-4 treatment with or without LPS co-stimulation, primary macrophages isolated from nTg/Arg1fl/fl/LysMcreTg/+ mice showed decreased arginase activity compared to macrophages from either nTg/Arg1+/+ mice (p < 0.0001) or nTg/Arg1fl/fl mice (p < 0.0001). n = 3 independent replicates from three independent biological replication experiments. (B) In measuring Neuro-2a viability using macrophage conditioned medium (MCM), neuroprotection drug azithromycin (AZM) co-incubation with LPS/IFN-γ increased neuron viability compared to LPS/IFN-γ stimulation, a phenomenon only observed using MCM from nTg/Arg1+/+ mice (p < 0.0001), but not in nTg/Arg1fl/fl/LysMcreTg/+ mice. In addition, AZM co-incubation with LPS/IL-4 showed increased trend in neuron viability than LPS/IL-4 stimulation using MCM from nTg/Arg1+/+ mice (p = 0.051), but not in nTg/Arg1fl/fl/LysMcreTg/+ mice. n = 10 independent replicates from three independent biological replication experiments. ****, p < 0.0001; n.s. (not significant), p > 0.05. Two-way ANOVA followed by multiple comparisons with Dunnett’s or Sidak’s post-hoc tests. Values represent mean ± SEM.
Ma, Chao; Hunt, Jerry B.; Selenica, Maj-Linda B.; Sanneh, Awa; Sandusky-Beltran, Leslie A.; Watler, Mallory; Daas, Rana; Kovalenko, Andrii; Liang, Huimin; Placides, Devon; Cao, Chuanhai; Lin, Xiaoyang; Orr, Michael B.; Zhang, Bei; Gensel, John C.; Feola, David J.; Gordon, Marcia N.; Morgan, Dave; Bickford, Paula C.; and Lee, Daniel C., "Arginase 1 Insufficiency Precipitates Amyloid-β Deposition and Hastens Behavioral Impairment in a Mouse Model of Amyloidosis" (2021). Sanders-Brown Center on Aging Faculty Publications. 158.