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SNX15 Regulates Cell Surface Recycling of APP and Aβ Generation

Tuancheng Feng1, Mengmeng Niu1, Chengxiang Ji1

  • 1Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Pharmaceutical Sciences, College of Medicine, Xiamen University, Xiamen, 361102, China.

Molecular Neurobiology
|June 28, 2015
PubMed

Insights

Sorting nexin 15 (SNX15) regulates amyloid precursor protein (APP) recycling, impacting amyloid-beta (Aβ) production. Modulating SNX15 in Alzheimer

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Cell Biology

Background:

  • Alzheimer's disease (AD) pathogenesis involves amyloid-beta (Aβ) peptide, derived from amyloid precursor protein (APP).
  • APP, BACE1, and γ-secretase trafficking is crucial for Aβ generation; dysregulation contributes to AD.
  • Sorting nexin 15 (SNX15) is a known regulator of protein trafficking.

Purpose of the Study:

  • To investigate the role of Sorting nexin 15 (SNX15) in amyloid-beta (Aβ) production and Alzheimer's disease (AD) pathology.
  • To determine if SNX15 influences the trafficking and cell surface levels of amyloid precursor protein (APP).
  • To evaluate the therapeutic potential of SNX15 in an AD mouse model.

Main Methods:

  • Assessed SNX15 expression in mouse neurons and astrocytes.
  • Manipulated SNX15 levels (overexpression and downregulation) to study effects on APP, BACE1, γ-secretase, and Aβ production.
  • Investigated SNX15's impact on APP cell surface levels and recycling using cell-based assays.
  • Utilized adeno-associated virus (AAV) to deliver human SNX15 into the hippocampus of a double transgenic AD mouse model (APPswe/PSEN1dE9).
  • Evaluated Aβ pathology and short-term working memory in treated AD mice.

Main Results:

  • SNX15 is abundant in mouse neurons and astrocytes.
  • SNX15 modulation did not alter APP, BACE1, or γ-secretase component levels or enzyme activity, but affected Aβ production (reduced with overexpression, promoted with downregulation).
  • SNX15 overexpression enhanced APP cell surface levels by promoting recycling; downregulation had the opposite effect.
  • AAV-mediated SNX15 expression in the hippocampus reduced Aβ pathology and improved memory in AD mice.

Conclusions:

  • SNX15 regulates APP recycling to the cell surface, thereby influencing Aβ generation.
  • SNX15 plays a significant role in modulating amyloid pathology in Alzheimer's disease.
  • SNX15 represents a potential therapeutic target for reducing Aβ production and improving cognitive function in AD.
Keywords:
Alzheimer’s diseaseAmyloid-βAmyloid-β precursor proteinSNX15Trafficking

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