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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...
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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...
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Related Experiment Video

Updated: Jun 5, 2026

Quantitative 3D In Silico Modeling (q3DISM) of Cerebral Amyloid-beta Phagocytosis in Rodent Models of Alzheimer's Disease
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Reticulophagy limits Alzheimer's disease pathology through FAM134B-dependent APP clearance.

Yuting Zhang1, Jun Sun1, Yixian Cui1

  • 1Department of Neurology, Department of Urology, Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China.

Autophagy
|June 4, 2026
PubMed
Summary

Impaired reticulophagy, a cellular waste removal process, contributes to Alzheimer's disease (AD) by allowing amyloid precursor protein (APP) to accumulate. Restoring the FAM134B receptor enhances APP clearance and improves cognitive function in AD models.

Keywords:
5XFAD miceFAM134B/RETREG1MAP1LC3B/LC3BTFE3TFEBamyloid beta precursor proteinautophagyepigenetic modificationlysosomereceptor

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Last Updated: Jun 5, 2026

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Area of Science:

  • Cell Biology
  • Neuroscience
  • Molecular Biology

Background:

  • Autophagy maintains cellular homeostasis, but its dysfunction is linked to Alzheimer's disease (AD) and endoplasmic reticulum (ER) abnormalities.
  • The role of reticulophagy, a selective form of autophagy targeting the ER, in AD pathogenesis and amyloid precursor protein (APP) turnover remains largely unknown.

Purpose of the Study:

  • To investigate the role of reticulophagy in Alzheimer's disease (AD) pathogenesis.
  • To identify specific receptors involved in ER turnover of APP.
  • To explore FAM134B as a potential therapeutic target for AD.

Main Methods:

  • Utilized patient samples and 5XFAD mouse models of AD.
  • Investigated the interaction between FAM134B, APP, and the autophagy machinery (LC3).
  • Assessed the impact of FAM134B restoration on ER turnover, APP/Aβ levels, neuronal integrity, and cognitive function.

Main Results:

  • Identified FAM134B/RETREG1 as a specific receptor mediating lysosomal degradation of ER-localized APP via LC3-dependent reticulophagy.
  • Found epigenetic repression of FAM134B in AD samples and mice, leading to impaired ER turnover, APP accumulation, and worsened amyloid pathology.
  • Demonstrated that restoring wild-type FAM134B, but not a LIR-mutant version, rescued reticulophagy, reduced APP and Aβ, preserved neurons, and improved cognition in 5XFAD mice.

Conclusions:

  • Impaired reticulophagy is an upstream pathogenic mechanism in Alzheimer's disease.
  • FAM134B-mediated ER turnover is crucial for limiting amyloidogenic APP accumulation.
  • Targeting FAM134B-dependent reticulophagy presents a potential therapeutic strategy for AD.