An Aβ42 uptake and degradation via Rg3 requires an activation of caveolin, clathrin and Aβ-degrading enzymes in microglia

Jang, Sung Kyu; Yu, Jung Min; Kim, Seung Tae; Kim, Gwang Hoon; Park, Da Woon; Lee, Do Ik; Joo, Seong Soo

doi:10.1016/j.ejphar.2015.03.071

Cited by 20 publications

(18 citation statements)

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“…Life span studies were carried out at 25 or 30°C (adjusted by experimental condition), 70% humidity, on a 12 h light-dark cycle. Flies (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) were placed in a food vial. Food vials were changed every 3 to 4 d, and the dead flies were counted at that time.…”

Section: Survival Assaymentioning

confidence: 99%

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Dysfunction of different cellular degradation pathways contributes to specific β‐amyloid42‐induced pathologies

Cheng

Chen

et al. 2018

FASEB j.

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The endosomal-lysosomal system (ELS), autophagy, and ubiquitin-proteasome system (UPS) are cellular degradation pathways that each play a critical role in the removal of misfolded proteins and the prevention of the accumulation of abnormal proteins. Recent studies on Alzheimer's disease (AD) pathogenesis have suggested that accumulation of aggregated β-amyloid (Aβ) peptides in the AD brain results from a dysfunction in these cellular clearance systems. However, the specific roles of these pathways in the removal of Aβ peptides and the pathogenesis underlying AD are unclear. Our in vitro and in vivo genetic approaches revealed that ELS mainly removed monomeric β-amyloid42 (Aβ42), while autophagy and UPS clear oligomeric Aβ42. Although overproduction of phosphatidylinositol 4-phosphate-5 increased Aβ42 clearance, it reduced the life span of Aβ42 transgenic flies. Our behavioral studies further demonstrated impaired autophagy and UPS-enhanced Aβ42-induced learning and memory deficits, but there was no effect on Aβ42-induced reduction in life span. Results from genetic fluorescence imaging showed that these pathways were damaged in the following order: UPS, autophagy, and finally ELS. The results of our study demonstrate that different degradation pathways play distinct roles in the removal of Aβ42 aggregates and in disease progression. These findings also suggest that pharmacologic treatments that are designed to stimulate cellular degradation pathways in patients with AD should be used with caution.-Ji, X.-R., Cheng, K.-C., Chen, Y.-R., Lin, T.-Y., Cheung, C. H. A., Wu, C.-L., Chiang, H.-C. Dysfunction of different cellular degradation pathways contributes to specific β-amyloid42-induced pathologies.

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Section: Survival Assaymentioning

confidence: 99%

“…Increased autophagy accelerates intracellular Ab clearance and reverses cognitive impairments in amyloid precursor protein transgenic mice (19)(20)(21). The ELS endocytoses and degrades plasma membrane proteins, including Ab and amyloid precursor protein (22)(23)(24). Third, all three systems are damaged by Ab.…”

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confidence: 99%

Dysfunction of different cellular degradation pathways contributes to specific β‐amyloid42‐induced pathologies

Cheng

Chen

et al. 2018

FASEB j.

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“…The microglial degradation of Aβ monomers also occurs via secreted IDE without involving lysosomal degradation (Qiu et al, 1997 ; Vepsalainen et al, 2008 ). This involves the participation of clathrin- and caveolae-dependent processes through ERK and p38 kinase/JNK pathways, ultimately stimulating endocytosis or endocytic biogenesis, as reported in the study using the HMO6 human microglial cell line (Jang et al, 2015 ). In addition, lysosomal biogenesis, pH, and hydrolase properties of lysosomes influence astrocyte-mediated fibrillar and oligomeric Aβ clearance, as reported in a study involving primary astrocytes, immortalized mouse neural progenitor cell line, C17.2 cells, and APP/PS1 transgenic mice (Xiao et al, 2014 ).…”

Section: Amyloid Hypothesis and Role Of Neurons And Gliamentioning

confidence: 84%

Role of Neuron and Glia in Alzheimer’s Disease and Associated Vascular Dysfunction

Bandyopadhyay

2021

Front. Aging Neurosci.

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Amyloidogenicity and vascular dysfunction are the key players in the pathogenesis of Alzheimer’s disease (AD), involving dysregulated cellular interactions. An intricate balance between neurons, astrocytes, microglia, oligodendrocytes and vascular cells sustains the normal neuronal circuits. Conversely, cerebrovascular diseases overlap neuropathologically with AD, and glial dyshomeostasis promotes AD-associated neurodegenerative cascade. While pathological hallmarks of AD primarily include amyloid-β (Aβ) plaques and neurofibrillary tangles, microvascular disorders, altered cerebral blood flow (CBF), and blood-brain barrier (BBB) permeability induce neuronal loss and synaptic atrophy. Accordingly, microglia-mediated inflammation and astrogliosis disrupt the homeostasis of the neuro-vascular unit and stimulate infiltration of circulating leukocytes into the brain. Large-scale genetic and epidemiological studies demonstrate a critical role of cellular crosstalk for altered immune response, metabolism, and vasculature in AD. The glia associated genetic risk factors include APOE, TREM2, CD33, PGRN, CR1, and NLRP3, which correlate with the deposition and altered phagocytosis of Aβ. Moreover, aging-dependent downregulation of astrocyte and microglial Aβ-degrading enzymes limits the neurotrophic and neurogenic role of glial cells and inhibits lysosomal degradation and clearance of Aβ. Microglial cells secrete IGF-1, and neurons show a reduced responsiveness to the neurotrophic IGF-1R/IRS-2/PI3K signaling pathway, generating amyloidogenic and vascular dyshomeostasis in AD. Glial signals connect to neural stem cells, and a shift in glial phenotype over the AD trajectory even affects adult neurogenesis and the neurovascular niche. Overall, the current review informs about the interaction of neuronal and glial cell types in AD pathogenesis and its critical association with cerebrovascular dysfunction.

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“…Cultured N2a cells were fixed in 4 % paraformaldehyde in PBS for 15 min, washed twice with PBS supplemented with 100 mM glycine for 5 min, and incubated with permeabilization buffer consisting of 0.1 % Triton X-100 (Sigma-Aldrich) in PBS for 30 min at room temperature. Blocking was performed with 1 % BSA for 30 min at room temperature as previously described [ 23 ]. Then, choline acetyltransferase (ChAT) or vesicular acetylcholine transporter (VAChT) mouse monoclonal antibody (1:200; Santa Cruz Biotechnology, Santa Cruz, CA, USA.)…”

Section: Methodsmentioning

confidence: 99%

The anti-aging properties of a human placental hydrolysate combined with dieckol isolated from Ecklonia cava

Jang

Lee

Kim

et al. 2015

BMC Complement Altern Med

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BackgroundsIn the present study, we aimed to examine the anti-aging properties of human placental hydrolysate (HPE) and dieckol (DE) from Ecklonia cava against free radical scavenging, muscle hypertrophy-related follistatin mRNA expression, amelioration of cognition-related genes and proteins, inhibition of collagenase-regulating genes, and elastinase activity.MethodsThe anti-aging effects were examined in human fibroblast (CCD986sk), mouse myoblast (C2C12), and neuroblastoma (N2a) cell models, by employing various assays such as 2,2-diphenyl-1-picrylhydrazyl hydrate (DPPH) scavenging, hydroxyl radical-mediated oxidation, quantitative real-time polymerase chain reaction, enzyme activity, and immunocytochemistry observation.ResultsOur results show that HPE combined with DE (HPE:DE) strongly scavenged DPPH radicals and protected proteins against degradation by hydroxyl radical attack. HPE:DE effectively inhibited matrix metalloproteinase-1 expression, protein kinase C alpha expression, and elastinase activity. Furthermore, HPE:DE improved the expression of cognition-related genes (choline acetyltransferase and vesicular acetylcholine transporter). These events may proactively contribute to retard the aging processes and the abrupt physiological changes probably induced by mitochondrial dysfunction with aging.ConclusionsBased on these findings, we conclude that the combined treatment of HPE:DE may be useful for anti-aging therapy in which the accumulation of oxidative damage is the main driving force.

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An Aβ42 uptake and degradation via Rg3 requires an activation of caveolin, clathrin and Aβ-degrading enzymes in microglia

Cited by 20 publications

References 40 publications

Dysfunction of different cellular degradation pathways contributes to specific β‐amyloid42‐induced pathologies

Dysfunction of different cellular degradation pathways contributes to specific β‐amyloid42‐induced pathologies

Role of Neuron and Glia in Alzheimer’s Disease and Associated Vascular Dysfunction

The anti-aging properties of a human placental hydrolysate combined with dieckol isolated from Ecklonia cava

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