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A Novel In Vitro Live-imaging Assay of Astrocyte-mediated Phagocytosis Using pH Indicator-conjugated Synaptosomes
Published on: February 5, 2018
Apolipoprotein E4 domain interaction induces endoplasmic reticulum stress and impairs astrocyte function.
Ning Zhong1, Gayathri Ramaswamy, Karl H Weisgraber
1Gladstone Institute of Neurological Disease, San Francisco, California 94158, USA.
The Journal of Biological Chemistry
|August 12, 2009
Summary
Apolipoprotein E4 (apoE4) domain interaction causes endoplasmic reticulum (ER) stress in astrocytes, leading to neurodegeneration. This ER stress and subsequent astrocyte dysfunction offer a new explanation for apoE4
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Biology
Background:
- Apolipoprotein E4 (apoE4) is linked to Alzheimer disease, potentially due to its structural domain interaction.
- Gene-targeted mice (Arg-61 apoE) modeling this interaction exhibit cognitive and synaptic deficits.
Purpose of the Study:
- To investigate if apoE4 domain interaction induces endoplasmic reticulum (ER) stress in astrocytes.
- To determine if ER stress leads to astrocyte dysfunction and contributes to neurodegeneration.
Main Methods:
- Analysis of intracellular apoE levels in primary Arg-61 apoE astrocytes.
- Measurement of unfolded protein response (UPR) markers (OASIS, ATF4, XBP-1) and downstream effectors.
- Assessment of astrocyte glucose uptake and neurite outgrowth promotion.
- Evaluation of age-dependent changes in brain OASIS levels in Arg-61 apoE mice.
Main Results:
- Arg-61 apoE astrocytes showed reduced intracellular apoE and upregulated UPR markers (OASIS, ATF4, XBP-1).
- ER stress correlated with decreased glucose uptake in astrocytes and impaired neurite outgrowth.
- Age-dependent increases in brain OASIS levels were observed in Arg-61 apoE mice.
Conclusions:
- ApoE4 domain interaction triggers ER stress and UPR in astrocytes.
- ER stress causes astrocyte dysfunction, impacting neuronal support and contributing to neurodegeneration.
- This ER stress-astrocyte dysfunction paradigm offers new insights into apoE4's role in Alzheimer disease.
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