Original Article | Published:

Dysfunctional tubular endoplasmic reticulum constitutes a pathological feature of Alzheimer’s disease

Molecular Psychiatry volume 21, pages 12631271 (2016) | Download Citation

Abstract

Pathological features in Alzheimer’s brains include mitochondrial dysfunction and dystrophic neurites (DNs) in areas surrounding amyloid plaques. Using a mouse model that overexpresses reticulon 3 (RTN3) and spontaneously develops age-dependent hippocampal DNs, here we report that DNs contain both RTN3 and REEPs, topologically similar proteins that can shape tubular endoplasmic reticulum (ER). Importantly, ultrastructural examinations of such DNs revealed gradual accumulation of tubular ER in axonal termini, and such abnormal tubular ER inclusion is found in areas surrounding amyloid plaques in biopsy samples from Alzheimer’s disease (AD) brains. Functionally, abnormally clustered tubular ER induces enhanced mitochondrial fission in the early stages of DN formation and eventual mitochondrial degeneration at later stages. Furthermore, such DNs are abrogated when RTN3 is ablated in aging and AD mouse models. Hence, abnormally clustered tubular ER can be pathogenic in brain regions: disrupting mitochondrial integrity, inducing DNs formation and impairing cognitive function in AD and aging brains.

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Acknowledgements

We thank Xinghua Yin for capturing EM images and Hisashi Fujioka (Case Western Reserve University EM facility) for immune-EM, Qinyuan Fan and Hailong Hou for their helpful discussions during the study, and Chris Nelson for critical reading of this manuscript. This work is partially supported by NIH grants to RY (AG025493, NS074256 and AG046929), and an award from Alzheimer’s Association (NPSPAD-10-174543) as well as a gift from the Scholtz family fund to RY. XZ was supported by NIH R01NS083385 and GP was supported by Alzheimer's Association (IIRG-13-284849) and the Semmes Foundation.

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Affiliations

  1. Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA

    • M G Sharoar
    • , Q Shi
    • , Y Ge
    • , W He
    • , X Hu
    •  & R Yan
  2. The University of Texas at San Antonio, One UTSA Circle, San Antonio, TX, USA

    • G Perry
  3. Department of Pathology, Case Western University School of Medicine, Cleveland, OH, USA

    • X Zhu

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The authors declare no conflict of interest.

Corresponding author

Correspondence to R Yan.

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DOI

https://doi.org/10.1038/mp.2015.181

Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)

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