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Related Concept Videos

Export of Misfolded Proteins out of the ER01:32

Export of Misfolded Proteins out of the ER

After folding, the ER assesses the quality of secretory and membrane proteins. The correctly folded proteins are cleared by the calnexin cycle for transport to their final destination, while misfolded proteins are held back in the ER lumen. The ER chaperones attempt to unfold and refold the misfolded proteins but sometimes fail to achieve the correct native conformation. Such terminally misfolded proteins are then exported to the cytosol by ER-associated degradation or ERAD pathway for...
Amyloid Fibrils03:03

Amyloid Fibrils

Amyloid fibrils are aggregates of misfolded proteins.  Under most circumstances, misfolded proteins are either refolded by chaperone proteins or degraded by the proteasome. However, in the case of a mutation or a disease, these proteins can accumulate to form large clusters and often further assemble to form elongated fibers, called fibrils. 
Amyloid deposits were observed as early as 1639 in the liver and the spleen.   In 1854, Rudolph Virchow performed iodine staining, normally used to...
Amyloid Fibrils03:03

Amyloid Fibrils

Amyloid fibrils are aggregates of misfolded proteins.  Under most circumstances, misfolded proteins are either refolded by chaperone proteins or degraded by the proteasome. However, in the case of a mutation or a disease, these proteins can accumulate to form large clusters and often further assemble to form elongated fibers, called fibrils. 
Amyloid deposits were observed as early as 1639 in the liver and the spleen.   In 1854, Rudolph Virchow performed iodine staining, normally used to...
The Unfolded Protein Response01:37

The Unfolded Protein Response

The ER is the hub of protein synthesis in a cell. It has robust systems to quality control protein folding and also for degradation of terminally misfolded proteins. Under normal conditions, a small proportion of misfolded proteins that cannot be salvaged need to be transported to the cytoplasm by the ER-associated degradation or ERAD pathways. However, if the ERAD cannot handle the misfolded proteins, the cell activates the unfolded protein response or UPR to adjust the protein folding...
Alzheimer Disease ll: Pathophysiology01:23

Alzheimer Disease ll: Pathophysiology

Alzheimer disease involves structural changes in the brain that begin long before symptoms appear. The most distinctive features are extracellular neuritic plaques and intracellular neurofibrillary tangles.Neuritic plaques form in the cerebral cortex and around blood vessels. These plaques contain a dense core of beta-amyloid (Aβ)—a toxic protein fragment that clumps outside neurons. The core is surrounded by damaged neuronal extensions, as well as reactive astrocytes and microglia. Abnormal...
Regulation of the Unfolded Protein Response01:31

Regulation of the Unfolded Protein Response

Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...

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Related Experiment Video

Updated: Jun 2, 2026

Imaging the Intracellular Trafficking of APP with Photoactivatable GFP
07:55

Imaging the Intracellular Trafficking of APP with Photoactivatable GFP

Published on: October 17, 2015

Retromer disruption promotes amyloidogenic APP processing.

Christopher P Sullivan1, Anthony G Jay, Edward C Stack

  • 1Geriatric Research, Education, and Clinical Center, Edith Nourse Rogers Memorial Veteran's Administration Hospital, Bedford, MA, USA. chris.sullivan@va.gov

Neurobiology of Disease
|April 26, 2011
PubMed
Summary
This summary is machine-generated.

Retromer deficiency impairs cellular transport, increasing amyloidogenic Aβ42:Aβ40 ratios and promoting the export of harmful APP fragments via exosomes. This suggests retromer dysfunction contributes to Alzheimer's disease pathogenesis.

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Purification and Aggregation of the Amyloid Precursor Protein Intracellular Domain
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Purification and Aggregation of the Amyloid Precursor Protein Intracellular Domain

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Related Experiment Videos

Last Updated: Jun 2, 2026

Imaging the Intracellular Trafficking of APP with Photoactivatable GFP
07:55

Imaging the Intracellular Trafficking of APP with Photoactivatable GFP

Published on: October 17, 2015

Purification and Aggregation of the Amyloid Precursor Protein Intracellular Domain
10:08

Purification and Aggregation of the Amyloid Precursor Protein Intracellular Domain

Published on: August 28, 2012

Quantitative Analysis of Mitochondria-Associated Endoplasmic Reticulum Membrane (MAM) Stabilization in a Neural Model of Alzheimer's Disease (AD)
06:41

Quantitative Analysis of Mitochondria-Associated Endoplasmic Reticulum Membrane (MAM) Stabilization in a Neural Model of Alzheimer's Disease (AD)

Published on: January 10, 2025

Area of Science:

  • Neuroscience
  • Cell Biology
  • Molecular Biology

Background:

  • Retromer deficiency is linked to sporadic Alzheimer's disease (AD) and neurodegeneration.
  • Retromer facilitates retrograde transport, crucial for endosome-to-Golgi pathways.
  • Amyloid precursor protein (APP) and its processing occur in late endosomes.

Purpose of the Study:

  • To investigate the impact of retromer deficiency on amyloid precursor protein (APP) processing and trafficking.
  • To determine if disrupted retromer function enhances amyloidogenic APP processing.
  • To examine the role of retromer in the exosomal secretion of APP fragments.

Main Methods:

  • Knockdown of Vps35, an essential retromer component, to disrupt retromer activity.
  • Quantification of total APP and assessment of cell-surface APP internalization.
  • Measurement of secreted amyloid-beta (Aβ) peptides (Aβ42, Aβ40) and analysis of exosomal APP C-terminal fragments.

Main Results:

  • Retromer deficiency did not alter total APP levels or internalization.
  • A significant increase in the Aβ42:Aβ40 ratio was observed due to decreased Aβ40 secretion.
  • Levels of APP C-terminal fragments were elevated in exosomes from retromer-deficient cells.

Conclusions:

  • Reduced retromer activity enhances amyloidogenic APP processing, mimicking familial AD mutations.
  • Retromer deficiency promotes the exosomal secretion of amyloidogenic APP derivatives.
  • These findings implicate retromer dysfunction in Alzheimer's disease pathogenesis.