Human amylin aggregates release within exosomes as a protective mechanism in pancreatic β cells: Pancreatic β-hippocampal cell communication

Burillo, Jesús; Fernandez-Rhodes, Maria; Piquero, Marta; López‐Alvarado, Pilar; Menéndez, J. Carlos; Jiménez, Beatriz; González-Blanco, Carlos; Marqués, Patricia; Guillén, Carlos; Benito, Manuel

doi:10.1016/j.bbamcr.2021.118971

Cited by 19 publications

(12 citation statements)

References 41 publications

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“…Therefore, the reduction in NPC1 that can lead to impaired degradative function because of excess cholesterol is also responsible for generating more ILVs/exosomes, therefore a potential protective mechanism. The protective role of increasing exosome secretion has been evidenced on numerous occasions, mainly in pathological situations including neurodegeneration ( Rajendran et al, 2006 ; Perez-Gonzalez et al, 2012 ; Deng et al, 2017 ; Patel et al, 2017 ; Guix et al, 2018 ; Fussi et al, 2018 ; Miranda et al, 2018 ; Ferreira et al, 2019 ; Burillo et al, 2021 ). Supporting this role in our culture system, we showed that exosomes secreted by the older neurons in culture are enriched in the microtubule associated protein τ ( Fig S4 ), therefore reducing the risk of formation of stable intracellular oligomers and tangles inside the old neurons that should seriously disrupt neuronal function ( Shafiei et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Increased exosome secretion in neurons aging in vitro by NPC1-mediated endosomal cholesterol buildup

et al. 2021

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As neurons age, they show a decrease in their ability to degrade proteins and membranes. Because undegraded material is a source of toxic products, defects in degradation are associated with reduced cell function and survival. However, there are very few dead neurons in the aging brain, suggesting the action of compensatory mechanisms. We show in this work that ageing neurons in culture show large multivesicular bodies (MVBs) filled with intralumenal vesicles (ILVs) and secrete more small extracellular vesicles than younger neurons. We also show that the high number of ILVs is the consequence of the accumulation of cholesterol in MVBs, which in turn is due to decreased levels of the cholesterol extruding protein NPC1. NPC1 down-regulation is the consequence of a combination of upregulation of the NPC1 repressor microRNA 33, and increased degradation, due to Akt-mTOR targeting of NPC1 to the phagosome. Although releasing more exosomes can be beneficial to old neurons, other cells, neighbouring and distant, can be negatively affected by the waste material they contain.

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Section: Discussionmentioning

confidence: 99%

Increased exosome secretion in neurons aging in vitro by NPC1-mediated endosomal cholesterol buildup

et al. 2021

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“…It has been observed that autophagy-inducing compounds, such as rapamycin and resveratrol, could modulate hIAPP aggregates level by autophagy activation [ 193 , 254 ]. A new detoxifying system has been described by our laboratory; it has been proved that hIAPP aggregates could be included in MVB and be secreted by exosomes in order to counteract pancreatic β-cells cytoplasmic hIAPP aggregates accumulation and cell death [ 255 ].…”

Section: Human Amylin Misfolding and T2dmmentioning

confidence: 99%

Insulin Resistance and Diabetes Mellitus in Alzheimer’s Disease

Burillo

Marqués

Jiménez

et al. 2021

Cells

115

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Type 2 diabetes mellitus is a progressive disease that is characterized by the appearance of insulin resistance. The term insulin resistance is very wide and could affect different proteins involved in insulin signaling, as well as other mechanisms. In this review, we have analyzed the main molecular mechanisms that could be involved in the connection between type 2 diabetes and neurodegeneration, in general, and more specifically with the appearance of Alzheimer’s disease. We have studied, in more detail, the different processes involved, such as inflammation, endoplasmic reticulum stress, autophagy, and mitochondrial dysfunction.

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“…These results suggest that autophagy can eliminate amyloidogenic hIAPP and that autophagy deficiency contributes to the pathogenesis of human T2D. Burillo et al [ 21 ] reported that overexpressing hIAPP in INS-1E cells accumulated one amylin protein of approximately 16 kDa under high glucose conditions, suggesting that this band corresponds to the aggregation of 16 kDa amylin protein as a tetramer. Chatterjee Bhowmick and Jeremic [ 22 ] revealed that human pancreatic islets induced three amylin oligomers of approximately 6 kDa in size under high glucose with/without proteasomal inhibitor, indicating a relation between hIAPP turnover and proteasome function in human islet β-cells.…”

Section: Discussionmentioning

confidence: 83%

“…Rivera et al [ 30 ] reported that hIAPP aggregates impair the autophagy/lysosomal degradation pathway in pancreatic β cells, indicating that enhanced autophagy protects β-cells from hIAPP-induced apoptosis. However, overexpression of hIAPP in INS-1E cells induces MTORC1 activation and mitophagy inhibition [ 21 , 31 ]. These findings suggest that hIAPP aggregates can indirectly activate Bax/Bak, resulting in mitochondria dysfunction, oxidative stress, and ER stress.…”

Section: Discussionmentioning

confidence: 99%

Human Islet Amyloid Polypeptide Overexpression in INS-1E Cells Influences Amylin Oligomerization under ER Stress and Oxidative Stress

Yoo

Joo

2021

IJMS

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Human amylin or islet amyloid polypeptide (hIAPP) is synthesized in the pancreatic β-cells and has been shown to contribute to the pathogenesis of type 2 diabetes (T2D) in vitro and in vivo. This study compared amylin oligomerization/expression and signal transduction under endoplasmic reticulum (ER) stress and oxidative stress. pCMV-hIAPP-overexpressing INS-1E cells presented different patterns of amylin oligomerization/expression under ER stress and oxidative stress. Amylin oligomerization/expression under ER stress showed three amylin oligomers of less than 15 kDa size in pCMV-hIAPP-overexpressing cells, while one band was detected under oxidative stress. Under ER stress conditions, HIF1α, p-ERK, CHOP, Cu/Zn-SOD, and Bax were significantly increased in pCMV-hIAPP-overexpressing cells compared to the pCMV-Entry-expressing cells (control), whereas p-Akt, p-mTOR, Mn-SOD, catalase, and Bcl-2 were significantly decreased. Under oxidative stress conditions, HIF1α, p-ERK, CHOP, Mn-SOD, catalase, and Bcl-2 were significantly reduced in pCMV-hIAPP-overexpressing cells compared to the control, whereas p-mTOR, Cu/Zn-SOD, and Bax were significantly increased. In mitochondrial oxidative phosphorylation (OXPHOS), the mitochondrial complex I and complex IV were significantly decreased under ER stress conditions and significantly increased under oxidative stress conditions in pCMV-hIAPP-overexpressing cells compared to the control. The present study results demonstrate that amylin undergoes oligomerization under ER stress in pCMV-hIAPP-overexpressing cells. In addition, human amylin overexpression under ER stress in the pancreatic β cells may enhance amylin protein aggregation, resulting in β-cell dysfunction.

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Human amylin aggregates release within exosomes as a protective mechanism in pancreatic β cells: Pancreatic β-hippocampal cell communication

Cited by 19 publications

References 41 publications

Increased exosome secretion in neurons aging in vitro by NPC1-mediated endosomal cholesterol buildup

Increased exosome secretion in neurons aging in vitro by NPC1-mediated endosomal cholesterol buildup

Insulin Resistance and Diabetes Mellitus in Alzheimer’s Disease

Human Islet Amyloid Polypeptide Overexpression in INS-1E Cells Influences Amylin Oligomerization under ER Stress and Oxidative Stress

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