LC3-Associated Endocytosis Facilitates β-Amyloid Clearance and Mitigates Neurodegeneration in Murine Alzheimer’s Disease

Heckmann, Bradlee L.; Teubner, Brett J.W.; Tummers, Bart; Boada-Romero, Emilio; Harris, Lacie; Yang, Mei; Guy, Clifford S.; Zakharenko, Stanislav S.; Green, Douglas R.

doi:10.1016/j.cell.2020.11.033

Cited by 67 publications

(95 citation statements)

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“…This, together with the lack of LC3B recruitment suggest that the MavC is not targeted by autophagy. Although LC3B is also involved in alternative processes like LC3‐associated phagocytosis (LAP) 35 and ‐endocytosis (LANDO), 36 to effectuate autophagy of Mav the MavC needs to be targeted by LC3B /autophagophores—which we did not observe.…”

Section: Discussioncontrasting

confidence: 57%

“…This, together with the lack of LC3B recruitment suggest that the MavC is not targeted by autophagy. Although LC3B is also involved in alternative processes like LC3-associated phagocytosis (LAP)35 and -endocytosis (LANDO),36 to effectuate autophagy of Mav the MavC needs to be targeted by LC3B /autophagophores-which we did not observe.Endosomal TLRs are recruited to endosomes, phagosomes, and lysosomes. Recent studies have revealed differential anterograde and retrograde trafficking of the endosomal TLRs to their target organelles 37,38.…”

contrasting

confidence: 63%

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Frontline Science: Antibiotic treatment routes Mycobacterium avium to phagolysosomes without triggering proinflammatory cytokine production in human Mϕs

Åsberg

Mediaas

Marstad

et al. 2020

Journal of Leukocyte Biology

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Mycobacterium avium (Mav) causes chronic infections in immunocompromised patients that require long-term antibiotic treatment. We have previously shown that Mav takes residence in host M s and establishes a compartment (MavC) in which it is hidden from host defenses. Failure to establish the MavC traps Mav in Lamp1 + phagolysosomes where growth is prevented, and inflammatory signaling activated through TLRs 7/8. To elucidate how antibiotic treatment affects mycobacterial trafficking and host defenses, we infected human primary M s with Mav for 4 days prior to treatment with a macrolide, aminoglycoside, and ethambutol. We show that Mav is killed and the MavC fuses with Lamp1 + lysosomes following antibiotic treatment. However, this does not result in nuclear translocation of NF-B or production of inflammatory cytokines, suggesting different Lamp1 + lysosomal compartments can form that differ in their innate signaling capabilities. Thus, we show that upon antibiotic treatment of a chronic infection, Mav is quietly disposed of by M s.

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Section: Discussioncontrasting

confidence: 57%

contrasting

confidence: 63%

Frontline Science: Antibiotic treatment routes Mycobacterium avium to phagolysosomes without triggering proinflammatory cytokine production in human Mϕs

Åsberg

Mediaas

Marstad

et al. 2020

Journal of Leukocyte Biology

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“…Utilizing macrophages from mice with an Atg5-de ciency in myeloid cells (Castillo et al, 2012;Zhao et al, 2008), we examined if Atg5-de cient macrophages could still phagocytose MP. Atg5 is involved in multiple steps in the autophagic process (Hanada et al, 2007;Mizushima et al, 1998;Noda et al, 2013;Sakoh-Nakatogawa et al, 2013) as well as LAP (Heckmann et al, 2019). In comparison to wild-type macrophages, the uorescence intensity of intracellular MP was not signi cantly different compared to Atg5-de cient macrophages suggesting no change in the amount of MP internalization (Fig.…”

Section: Internalization Of Mp By Macrophages Does Not Results In Mp Degradationmentioning

confidence: 92%

Polystyrene microplastics induce an immunometabolic active state in macrophages

et al. 2021

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Anti-and pro-in ammatory responses in macrophages are in uenced by cellular metabolism.Macrophages are the primary phagocyte in mucosal environments (i.e., intestinal tract and lungs) acting as rst-line defense against microorganisms and environmental pollutants. Given we now face extensive microplastic contamination of our food and water sources, we aimed to examine the metabolic response in macrophages to microplastic particles (MP). Utilizing murine macrophages, we assessed the metabolic response of macrophages after polystyrene MP phagocytosis. The phagocytosis of MP by macrophages induced a metabolic shift toward glycolysis and a reduction in mitochondrial respiration that was associated with an increase of cell surface markers CD80 and CD86 and cytokine gene expression associated with glycolysis. The gastrointestinal consequences of this metabolic switch in the context of an immune response remains uncertain but the global rise of plastic pollution and MP ingestion potentially pose an unappreciated health risk.

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“…30,31 In Alzheimer's disease mice, a deficiency of LC3-associated endocytosis in microglia increases the production of proinflammatory cytokines in the hippocampus. 32 Impaired autophagy in microglia exacerbates dopaminergic neuron loss in an MPTP-induced mouse model of Parkinson's disease. 33 While restoring autophagic capacity in mucopolysaccharidosis IIIB (MPS IIIB), a murine model reveals improved clearance of autophagic vacuoles in microglia and reduces inflammation in the brain.…”

Section: Discussionmentioning

confidence: 99%

A GM1 gangliosidosis mutant mouse model exhibits activated microglia and disturbed autophagy

Liu

Feng

Huang

et al. 2021

Exp Biol Med (Maywood)

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GM1 gangliosidosis is a rare lysosomal storage disease caused by a deficiency of β-galactosidase due to mutations in the GLB1 gene. We established a C57BL/6 mouse model with Glb1G455R mutation using CRISPR/Cas9 genome editing. The β-galactosidase enzyme activity of Glb1G455R mice measured by fluorometric assay was negligible throughout the whole body. Mutant mice displayed no marked phenotype at eight weeks. After 16 weeks, GM1 ganglioside accumulation in the brain of mutant mice was observed by immunohistochemical staining. Meanwhile, a declining performance in behavioral tests was observed among mutant mice from 16 to 32 weeks. As the disease progressed, the neurological symptoms of mutant mice worsened, and they then succumbed to the disease by 47 weeks of age. We also observed microglia activation and proliferation in the cerebral cortex of mutant mice at 16 and 32 weeks. In these activated microglia, the level of autophagy regulator LC3 was up-regulated but the mRNA level of LC3 was normal. In conclusion, we developed a novel murine model that mimicked the chronic phenotype of human GM1. This Glb1G455R murine model is a practical in vivo model for studying the pathogenesis of GM1 gangliosidosis and exploring potential therapies.

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LC3-Associated Endocytosis Facilitates β-Amyloid Clearance and Mitigates Neurodegeneration in Murine Alzheimer’s Disease

Cited by 67 publications

References 0 publications

Frontline Science: Antibiotic treatment routes Mycobacterium avium to phagolysosomes without triggering proinflammatory cytokine production in human Mϕs

Frontline Science: Antibiotic treatment routes Mycobacterium avium to phagolysosomes without triggering proinflammatory cytokine production in human Mϕs

Polystyrene microplastics induce an immunometabolic active state in macrophages

A GM1 gangliosidosis mutant mouse model exhibits activated microglia and disturbed autophagy

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