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Published on: February 9, 2020
Role of spindle pole body component 25 in neurodegeneration
Feilun Cui1, Zhipeng Xu1, Yumei Lv2
1Department of Urology, Affiliated People's Hospital of Jiangsu University, Zhenjiang, China.
Background:
Aberrant growth and polarization of microglia are critical for pathological initiation and progression of neurodegenerative conditions like Alzheimer's disease (AD). However, the molecular signals that govern the outgrowth of microglia have not yet been fully determined. Spindle pole body component 25 (SPC25) is an important part for forming NDC80 complex, which plays a key role in the assembly of the microtubule-binding domain of kinetochores. Nevertheless, the role of SPC25 in microglial growth during neurodegeneration has not been described before, and was thus addressed in the current study.
Methods:
We generated an adeno-associated virus (AAV) serotype PHP.B carrying short hairpin RNA (shRNA) for SPC25 (shSPC25) under a microglia-specific TMEM119 promoter (AAV-pTMEM-shSPC25). Serotype PHP.B allowed the virus to cross blood-brain barrier, while TMEM119 promoter allowed specific targeting microglia in vitro and in vivo. We intravenously administrated AAV-pTMEM-shSPC25 to AD-prone APP/PS1 male and female mice and determined this effect on microglia proliferation and mouse behavior.
Results:
Depletion of SPC25 did not alter polarization of microglia cell polarization in vitro. On the other hand, AD-prone APP/PS1 mice that had received AAV-pTMEM-shSPC25 significantly decreased SPC25 levels in microglia and attenuated microglia proliferation, resulting in significant improvement of the performance of the mice in behavior tests.
Conclusions:
Specific depletion of SPC25 in microglia may prevent AD development through suppression of microglia outgrowth. SPC25 may be a promising novel target for preventing AD through microglia.
Insights
Spindle pole body component 25 (SPC25) depletion in microglia reduced outgrowth and improved behavior in Alzheimer's disease (AD) models. SPC25 may be a therapeutic target for AD by controlling microglial proliferation.
Area of Science:
- Neuroscience
- Cell Biology
- Genetics
Background:
- Microglial growth and polarization are key in neurodegenerative diseases like Alzheimer's disease (AD).
- Molecular signals regulating microglial outgrowth are not fully understood.
- Spindle pole body component 25 (SPC25) is crucial for the NDC80 complex and kinetochore assembly, but its role in microglial neurodegeneration was unknown.
Purpose of the Study:
- To investigate the role of Spindle pole body component 25 (SPC25) in microglial proliferation and its potential impact on Alzheimer's disease (AD) pathogenesis.
- To determine if targeting SPC25 in microglia can mitigate AD-related pathology and cognitive deficits.
Main Methods:
- Generated adeno-associated virus (AAV) serotype PHP.B with short hairpin RNA (shRNA) for SPC25 under a microglia-specific TMEM119 promoter.
- Administered AAV-pTMEM-shSPC25 intravenously to AD-prone APP/PS1 mice.
- Assessed effects on microglia proliferation, SPC25 levels, and mouse behavior.
Main Results:
- SPC25 depletion did not affect microglia polarization in vitro.
- In vivo, SPC25 knockdown in AD-prone mice significantly reduced microglia proliferation.
- Mice treated with AAV-pTMEM-shSPC25 showed improved performance in behavioral tests.
Conclusions:
- Targeting SPC25 specifically in microglia can suppress microglial outgrowth, potentially preventing Alzheimer's disease (AD) development.
- SPC25 represents a promising novel therapeutic target for AD intervention through modulation of microglial activity.
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