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Updated: Oct 1, 2025
A Novel In Vitro Live-imaging Assay of Astrocyte-mediated Phagocytosis Using pH Indicator-conjugated Synaptosomes
Published on: February 5, 2018
Microglial VPS35 deficiency impairs Aβ phagocytosis and Aβ-induced disease-associated microglia, and enhances Aβ
Xiao Ren1, Lingling Yao1, YongGang Wang2,3
1Department of Neurosciences, Case Western Reserve University, Cleveland, OH, USA.
Background:
Vacuolar sorting protein 35 (VPS35), a key component of the retromer, plays an essential role in selectively retrieval of transmembrane proteins from endosomes to trans-Golgi networks. Dysfunctional retromer is a risk factor for neurodegenerative disorders, including Alzheimer's disease (AD). Microglial VPS35 deficiency is found in AD patients' brain; however, it remains unclear if and how microglial VPS35-loss contributes to AD development.
Methods:
We used mice with VPS35 cKO (conditional knockout) in microglial cells in 5XFAD, an AD mouse model. The AD related brain pathology (Aβ and glial activation), behavior, and phagocytosis of Aβ were accessed by a combination of immunofluorescence staining analyses and neurological behavior tests.
Results:
A decrease in learning and memory function, but increases in insoluble, fibrillar, and plaques of β-amyloids (Aβ), dystrophic neurites, and reactive astrocytes are observed in microglial VPS35 deficient 5XFAD mice. Further examining microglial phenotype demonstrates necessity of microglial VPS35 in disease-associated microglia (DAM) development and microglial uptake of Aβ, revealing a tight association of microglial Aβ uptake with DAM development.
Conclusions:
Together, these results uncovered a mechanism by which microglial VPS35-deficiency precipitates AD pathology in 5XFAD mice likely by impairing DAM development and DAM mediated Aβ uptake and clearance, and thus accelerating the cognition decline.
Insights
Microglial VPS35 deficiency worsens Alzheimer's disease (AD) pathology by impairing the development of disease-associated microglia (DAM) and their ability to clear amyloid-beta (Aβ) plaques, accelerating cognitive decline.
Area of Science:
- Neuroscience
- Cell Biology
- Genetics
Background:
- Vacuolar sorting protein 35 (VPS35) is crucial for endosome-to-Golgi retrieval via the retromer complex.
- Retromer dysfunction is linked to neurodegenerative diseases like Alzheimer's disease (AD).
- Microglial VPS35 deficiency is observed in AD brains, but its role is unclear.
Purpose of the Study:
- To investigate the impact of microglial VPS35 deficiency on AD pathogenesis.
- To elucidate the mechanisms by which microglial VPS35 loss contributes to AD development.
Main Methods:
- Utilized 5XFAD transgenic mice with microglial-specific VPS35 conditional knockout (cKO).
- Assessed AD-related brain pathology, glial activation, and Aβ phagocytosis using immunofluorescence and behavioral tests.
Main Results:
- Microglial VPS35 deficiency in 5XFAD mice led to impaired learning and memory.
- Observed increased Aβ plaques, dystrophic neurites, and reactive astrocytes.
- Demonstrated that microglial VPS35 is essential for disease-associated microglia (DAM) development and Aβ uptake.
Conclusions:
- Microglial VPS35 deficiency exacerbates AD pathology in a mouse model.
- Impaired DAM development and reduced Aβ clearance by microglia contribute to cognitive decline in AD.
