Differential Effects of Alzheimer’s Disease Aβ40 and 42 on Endocytosis and Intraneuronal Trafficking

Omtri, Rajesh S.; Thompson, Kevin J.; Tang, Xiaojia; Gali, Chaitanya Chakravarthi; Panzenboeck, Ute; Davidson, Michael W.; Kalari, Krishna R.; Kandimalla, Karunya K.

doi:10.1016/j.neuroscience.2018.01.003

Cited by 12 publications

(14 citation statements)

References 38 publications

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“…TOM1 is predominantly present in the cytosol and interacts with proteins such as clathrin and toll-interacting protein (Tollip) to regulate endosomal trafficking and lysosomal degradation of ubiquitinated proteins (23, 27). Given that defects in intracellular protein clearance (e.g., autophagy and ubiquitin-proteasome system) and trafficking (e.g., endocytosis) have been implicated in the regulation of IL-1β signaling (24, 28) and AD (29–31), it is plausible that the disruption of these processes may result in overexpression of proinflammatory receptors leading to exacerbated immune responses and cognitive decline.…”

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confidence: 99%

Amyloid-beta impairs TOM1-mediated IL-1R1 signaling

Martini

Gómez-Arboledas

Forner

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Defects in interleukin-1β (IL-1β)–mediated cellular responses contribute to Alzheimer’s disease (AD). To decipher the mechanism associated with its pathogenesis, we investigated the molecular events associated with the termination of IL-1β inflammatory responses by focusing on the role played by the target of Myb1 (TOM1), a negative regulator of the interleukin-1β receptor-1 (IL-1R1). We first show that TOM1 steady-state levels are reduced in human AD hippocampi and in the brain of an AD mouse model versus respective controls. Experimentally reducing TOM1 affected microglia activity, substantially increased amyloid-beta levels, and impaired cognition, whereas enhancing its levels was therapeutic. These data show that reparation of the TOM1-signaling pathway represents a therapeutic target for brain inflammatory disorders such as AD. A better understanding of the age-related changes in the immune system will allow us to craft therapies to limit detrimental aspects of inflammation, with the broader purpose of sharply reducing the number of people afflicted by AD.

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confidence: 99%

Amyloid-beta impairs TOM1-mediated IL-1R1 signaling

Martini

Gómez-Arboledas

Forner

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…Much work on postmortem AD brains, the brains of numerous AD-relevant animal models, and cultured cells has been directed toward understanding how amyloid, primarily amyloid-␤ 1-42 (A␤ 42 ), is deposited in the brain within neurons and amyloid plaques throughout AD pathogenesis [3,7,8]. Although plaque formation in human AD brains is still generally considered an extracellular event, intracellular A␤ 42 deposition has been reported as an early pathological marker in AD brains, in the brains of AD-relevant transgenic animal models, and in various types of cultured neurons and neuron-like cells [9][10][11][12][13][14][15][16][17][18].…”

Section: Introductionmentioning

confidence: 99%

Evidence that Brain-Reactive Autoantibodies Contribute to Chronic Neuronal Internalization of Exogenous Amyloid-β1-42 and Key Cell Surface Proteins During Alzheimer’s Disease Pathogenesis

Goldwaser

Acharya

et al. 2020

JAD

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Blood-brain barrier (BBB) permeability is a recognized early feature of Alzheimer's disease (AD). In the present study, we examined consequences of increased BBB permeability on the development of AD-related pathology by tracking selected leaked plasma components and their interactions with neurons in vivo and in vitro. Histological sections of cortical regions of postmortem AD brains were immunostained to determine the distribution of amyloid-␤ 1-42 (A␤ 42), cathepsin D, IgG, GluR2/3, and alpha7 nicotinic acetylcholine receptor (␣7nAChR). Results revealed that chronic IgG binding to pyramidal neurons coincided with internalization of A␤ 42, IgG, GluR2/3, and ␣7nAChR as well as lysosomal compartment expansion in these cells in regions of AD pathology. To test possible mechanistic interrelationships of these phenomena, we exposed differentiated SH-SY5Y neuroblastoma cells to exogenous, soluble A␤ 42 peptide and serum from AD and control subjects. The rate and extent of A␤ 42 internalization in these cells was enhanced by serum containing neuron-binding IgG autoantibodies. This was confirmed by treating cells with individual antibodies specific for ␣7nAChR, purified IgG from AD or non-AD sera, and sera devoid of IgG, in the presence of 100 nM A␤ 42. Initial co-localization of IgG, ␣7nAChR, and A␤ 42 was temporally and spatially linked to early endosomes (Rab11) and later to lysosomes (LAMP-1). A␤ 42 internalization was attenuated by treatment with monovalent F(ab) antibody fragments generated from purified IgG from AD serum and then

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“…Rab protein transfections. m-Cherry fluorescent protein fused to Rab5 (m-CFP/Rab5), green fluorescent protein fused to Rab7 (GFP/Rab7) and green fluorescent protein fused to Rab11 (GFP/Rab11) plasmids were obtained as described in our previous publications 25 . Transfections of hCMEC/D3 cell monolayers were performed using Lipofectamine reagent (Invitrogen, CA) as per manufacturer's protocol.…”

Section: Clathrin/caveolin-1 Knockdowns and K44-negative Dominant Dyn...mentioning

confidence: 99%

Amyloid-beta peptides 40 and 42 employ distinct molecular pathways for cell entry and intracellular transit at the BBB endothelium

Wang

Sharda

Omtri

et al. 2022

Preprint

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Blood-brain barrier (BBB) is a critical portal regulating the bidirectional transport of amyloid beta (Aβ) proteins between blood and brain. Disrupted trafficking at the BBB may not only promote the build-up of Aβ plaques in the brain parenchyma, but also facilitate Aβ accumulation within the BBB endothelium, which aggravates BBB dysfunction. Soluble Aβ42:Aβ40 ratios in plasma and cerebrospinal fluid have been reported to decrease during Alzheimer's disease (AD) progression. Our previous publications demonstrated that trafficking of Aβ42 and Aβ40 at the BBB is distinct and is disrupted under various pathophysiological conditions. However, the intracellular mechanisms that allow BBB endothelium to differentially handle Aβ40 and Aβ42 have not been clearly elucidated. In this study, we identified mechanisms of fluorescently labeled Aβ (F-Aβ) endocytosis in polarized human cerebral microvascular endothelial (hCMEC/D3) cell monolayers using pharmacological inhibition and siRNA knock-down approaches. Further, intracellular transit of F-Aβ following endocytosis was tracked using live cell imaging. Our studies demonstrated that both F-Aβ peptides were internalized by BBB endothelial cells via energy, dynamin and actin dependent endocytosis. Interestingly, endocytosis of F-Aβ40 is found to be clathrin-mediated, whereas F-Aβ42 endocytosis is caveolae-mediated. Following endocytosis, both isoforms were sorted by the endo-lysosomal system. While Aβ42 was shown to accumulate more in the lysosome which could lead to its higher degradation and/or aggregation at lower lysosomal pH, Aβ40 demonstrated robust accumulation in recycling endosomes which may facilitate its transcytosis across the BBB. These results provide a mechanistic insight into the selective ability of BBB endothelium to transport Aβ40 versus Aβ42. This knowledge contributes to the understanding of molecular pathways underlying Aβ accumulation in the BBB endothelium and associated cerebrovascular dysfunction as well as amyloid deposition in the brain parenchyma which are implicated in AD pathogenesis.

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Differential Effects of Alzheimer’s Disease Aβ40 and 42 on Endocytosis and Intraneuronal Trafficking

Cited by 12 publications

References 38 publications

Amyloid-beta impairs TOM1-mediated IL-1R1 signaling

Amyloid-beta impairs TOM1-mediated IL-1R1 signaling

Evidence that Brain-Reactive Autoantibodies Contribute to Chronic Neuronal Internalization of Exogenous Amyloid-β1-42 and Key Cell Surface Proteins During Alzheimer’s Disease Pathogenesis

Amyloid-beta peptides 40 and 42 employ distinct molecular pathways for cell entry and intracellular transit at the BBB endothelium

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