scholarly journals Transmissible Endosomal Intoxication: A Balance between Exosomes and Lysosomes at the Basis of Intercellular Amyloid Propagation

Biomedicines ◽  
2020 ◽  
Vol 8 (8) ◽  
pp. 272
Author(s):  
Anaïs Bécot ◽  
Charlotte Volgers ◽  
Guillaume van Niel
Keyword(s):  
Amyloid Precursor Protein ◽  
Neurodegenerative Diseases ◽  
Multivesicular Body ◽  
Precursor Protein ◽  
Aβ Peptides ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
Novel Concept ◽  
The Brain

In Alzheimer′s disease (AD), endolysosomal dysfunctions are amongst the earliest cellular features to appear. Each organelle of the endolysosomal system, from the multivesicular body (MVB) to the lysosome, contributes to the homeostasis of amyloid precursor protein (APP) cleavage products including β-amyloid (Aβ) peptides. Hence, this review will attempt to disentangle how changes in the endolysosomal system cumulate to the generation of toxic amyloid species and hamper their degradation. We highlight that the formation of MVBs and the generation of amyloid species are closely linked and describe how the molecular machineries acting at MVBs determine the generation and sorting of APP cleavage products towards their degradation or release in association with exosomes. In particular, we will focus on AD-related distortions of the endolysomal system that divert it from its degradative function to favour the release of exosomes and associated amyloid species. We propose here that such an imbalance transposed at the brain scale poses a novel concept of transmissible endosomal intoxication (TEI). This TEI would initiate a self-perpetuating transmission of endosomal dysfunction between cells that would support the propagation of amyloid species in neurodegenerative diseases.

Interaction mechanism exploration of HEA derivatives as BACE1 inhibitors by in silico analysis

2016 ◽  
Vol 12 (4) ◽  
pp. 1151-1165 ◽  
Author(s):  
Qian Wu ◽  
Xianguo Li ◽  
Qingping Gao ◽  
Jinghui Wang ◽  
Yan Li ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
In Silico ◽  
Interaction Mechanism ◽  
In Silico Analysis ◽  
Precursor Protein ◽  
Aβ Peptides ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
Silico Analysis ◽  
Prime Target

The β-site amyloid precursor protein cleaving enzyme 1 (BACE1) initiates the generation of β-amyloid (Aβ) peptides which play a critical early role in the pathogenesis of Alzheimer's disease (AD), and thus it is a prime target for lowering the Aβ levels to treat AD.

Control of β-Site Amyloid Precursor Protein-Cleaving Enzyme-1 Expression by Protein Kinase C-λ/ι and Nuclear Factor κ-B

2021 ◽  
Vol 19 ◽  
Author(s):  
Mini P. Sajan ◽  
Michael Leitges ◽  
Colin Park ◽  
David M. Diamond ◽  
Jin Wu ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Proinflammatory Cytokine ◽  
Insulin Treatment ◽  
Precursor Protein ◽  
Nuclear Factor ◽  
Diabetic Mice ◽  
Aβ Peptides ◽  
Protein Levels ◽  
Total Body ◽  
The Brain

Βackground: β-Amyloid precursor protein-cleaving enzyme-1 (BACE1) initiates the production of Aβ-peptides that form Aβ-plaque in Alzheimer’s disease. Methods: Reportedly, acute insulin treatment in normal mice, and hyperinsulinemia in high-fat-fed (HFF) obese/diabetic mice, increase BACE1 activity and levels of Aβ-peptides and phospho- -thr-231-tau in the brain; moreover, these effects are blocked by PKC-λ/ι inhibitors. However, as chemical inhibitors may affect unsuspected targets, we presently used knockout methodology to further examine PKC-λ/ι requirements. We found that total-body heterozygous PKC-λ knockout reduced acute stimulatory effects of insulin and chronic effects of hyperinsulinemia in HFF/obese/diabetic mice, on brain PKC-λ activity and production of Aβ1-40/42 and phospho-thr-231-tau. This protection in HFF mice may reflect that hepatic PKC-λ haploinsufficiency prevents the development of glucose intolerance and hyperinsulinemia. Results: On the other hand, heterozygous knockout of PKC-λ markedly reduced brain levels of BACE1 protein and mRNA, and this may reflect diminished activation of nuclear factor kappa-B (NFκB), which is activated by PKC-λ and increases BACE1 and proinflammatory cytokine transcription. Accordingly, whereas intravenous administration of aPKC inhibitor diminished aPKC activity and BACE1 levels by 50% in the brain and 90% in the liver, nasally-administered inhibitor reduced aPKC activity and BACE1 mRNA and protein levels by 50-70% in the brain while sparing the liver. Additionally, 24-hour insulin treatment in cultured human-derived neurons increased NFκB activity and BACE1 levels, and these effects were blocked by various PKC-λ/ι inhibitors. Conclusion: PKC-λ/ι controls NFκB activity and BACE1 expression; PKC-λ/ι inhibitors may be used nasally to target brain PKC-λ/ι or systemically to block both liver and brain PKC-λ/ι, to regulate NFκB-dependent BACE1 and proinflammatory cytokine expression.

scholarly journals Copper inhibits β-amyloid production and stimulates the non-amyloidogenic pathway of amyloid-precursor-protein secretion

1999 ◽  
Vol 344 (2) ◽  
pp. 461-467 ◽  
Author(s):  
Thilo BORCHARDT ◽  
James CAMAKARIS ◽  
Roberto CAPPAI ◽  
Colin L. MASTERS ◽  
Konrad BEYREUTHER ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Protein Secretion ◽  
Chinese Hamster ◽  
Oxidative Modification ◽  
Precursor Protein ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
Aβ Generation ◽  
Aβ Production ◽  
Stimulation Of

Previous studies have demonstrated that amyloid precursor protein (APP) can bind and reduce Cu(II) to Cu(I), leading to oxidative modification of APP. In the present study we show that adding copper to Chinese-hamster ovary (CHO) cells greatly reduced the levels of amyloid Aβ peptide (Aβ) both in parental CHO-K1 and in copper-resistant CHO-CUR3 cells, which have lower intracellular copper levels. Copper also caused an increase in the secretion of the APP ectodomain, indicating that the large decrease in Aβ release was not due to a general inhibition in protein secretion. There was an increase in intracellular full-length APP levels which paralleled the decrease in Aβ generation, suggesting the existence of two distinct regulating mechanisms, one acting on Aβ production and the other on APP synthesis. Maximal inhibition of Aβ production and stimulation of APP secretion was achieved in CHO-K1 cells at about 10 μM copper and in CHO-CUR3 cells at about 50 μM copper. This dose ‘window of opportunity’ at which copper promoted the non-amyloidogenic pathway of APP was confirmed by an increase in the non-amyloidogenic p3 fragment produced by α-secretase cleavage. Our findings suggest that copper or copper agonists might be useful tools to discover novel targets for anti-Alzheimer drugs and may prove beneficial for the prevention of Alzheimer's disease.

Methotrexate-Related Nonnecrotizing Multifocal Axonopathy Detected by β-Amyloid Precursor Protein Immunohistochemistry

2002 ◽  
Vol 126 (1) ◽  
pp. 79-81 ◽  
Author(s):  
Brian E. Moore ◽  
Nathan P. Somers ◽  
Thomas W. Smith
Keyword(s):  
Amyloid Precursor Protein ◽  
Axonal Injury ◽  
Neurological Complications ◽  
Precursor Protein ◽  
Intrathecal Methotrexate ◽  
Nerve Roots ◽  
Marked Decline ◽  
Β Amyloid ◽  
The Brain ◽  
Biphenotypic Leukemia

Abstract We describe a 64-year-old woman with biphenotypic leukemia involving the meninges who received 2 doses of intrathecal methotrexate. Soon after treatment, the patient developed postural rigidity and a marked decline in mental status. The patient died of respiratory failure 1 month after methotrexate treatment was initiated. At autopsy, the brain was grossly normal. Routine microscopy showed no evidence of leukemic infiltrates or necrotizing lesions. However, when stained with β-amyloid precursor protein, multifocal axonal injury was evident in the brain, spinal cord, and nerve roots. Our findings show that immunohistochemical staining for β-amyloid precursor protein can effectively demonstrate axonal injury associated with methotrexate neurotoxicity, even when conventional staining procedures are negative. This technique may therefore reveal a possible pathologic substrate for some of the neurological complications seen in patients with methotrexate neurotoxicity.

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