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Quantitative 3D In Silico Modeling q3DISM of Cerebral Amyloid-beta Phagocytosis in Rodent Models of Alzheimer's Disease
Published on: December 26, 2016
Dysregulated expression of miR-140 and miR-122 compromised microglial chemotaxis and led to reduced restriction of AD
Chao Song1, Shufang Li1, Yingren Mai2
1School of Life Science and Technology, Jinan University, Guangzhou, Guangdong, 510632, China.
Background:
Deposition of amyloid β, which is produced by amyloidogenic cleavage of APP by β- and γ-secretase, is one of the primary hallmarks of AD pathology. APP can also be processed by α- and γ-secretase sequentially, to generate sAPPα, which has been shown to be neuroprotective by promoting neurite outgrowth and neuronal survival, etc. METHODS: The global expression profiles of miRNA in blood plasma samples taken from 11 AD patients as well as from 14 age and sex matched cognitively normal volunteers were analyzed using miRNA-seq. Then, overexpressed miR-140 and miR-122 both in vivo and in vitro, and knock-down of the endogenous expression of miR-140 and miR-122 in vitro. Used a combination of techniques, including molecular biology, immunohistochemistry, to detect the impact of miRNAs on AD pathology.
Results:
In this study, we identified that two miRNAs, miR-140-3p and miR-122-5p, both targeting ADAM10, the main α-secretase in CNS, were upregulated in the blood plasma of AD patients. Overexpression of these two miRNAs in mouse brains induced cognitive decline in wild type C57BL/6J mice as well as exacerbated dyscognition in APP/PS1 mice. Although significant changes in APP and total Aβ were not detected, significantly downregulated ADAM10 and its non-amyloidogenic product, sAPPα, were observed in the mouse brains overexpressing miR-140/miR-122. Immunohistology analysis revealed increased neurite dystrophy that correlated with the reduced microglial chemotaxis in the hippocampi of these mice, independent of the other two ADAM10 substrates (neuronal CX3CL1 and microglial TREM2) that were involved in regulating the microglial immunoactivity. Further in vitro analysis demonstrated that both the reduced neuritic outgrowth of mouse embryonic neuronal cells overexpressing miR-140/miR-122 and the reduced Aβ phagocytosis in microglia cells co-cultured with HT22 cells overexpressing miR-140/miR-122 could be rescued by overexpressing the specific inhibitory sequence of miR-140/miR-122 TuD as well as by addition of sAPPα, rendering these miRNAs as potential therapeutic targets.
Conclusions:
Our results suggested that neuroprotective sAPPα was a key player in the neuropathological progression induced by dysregulated expression of miR-140 and miR-122. Targeting these miRNAs might serve as a promising therapeutic strategy in AD treatment.
Insights
Elevated miR-140 and miR-122 in Alzheimer's disease (AD) patients target ADAM10, reducing neuroprotective sAPPα. Targeting these microRNAs offers a potential therapeutic strategy for AD.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Alzheimer's disease (AD) is characterized by amyloid-beta (Aβ) plaque deposition.
- Amyloid precursor protein (APP) can be cleaved via amyloidogenic (β- and γ-secretase) or non-amyloidogenic (α- and γ-secretase) pathways.
- The non-amyloidogenic pathway produces sAPPα, which is neuroprotective.
Purpose of the Study:
- To investigate the role of specific microRNAs (miRNAs) in Alzheimer's disease pathology.
- To identify potential therapeutic targets for AD based on miRNA dysregulation.
Main Methods:
- Global miRNA expression profiling using miRNA-seq in blood plasma from AD patients and controls.
- In vivo and in vitro overexpression and knockdown of miR-140 and miR-122.
- Molecular biology techniques and immunohistochemistry to assess miRNA impact on AD pathology.
Main Results:
- miR-140-3p and miR-122-5p were upregulated in AD patients' plasma and target ADAM10, the primary α-secretase in the central nervous system.
- Overexpression of these miRNAs in mice induced cognitive decline and exacerbated AD pathology.
- Downregulation of ADAM10 and sAPPα was observed, alongside increased neurite dystrophy and reduced microglial chemotaxis.
- In vitro studies showed that reduced neuritic outgrowth and Aβ phagocytosis could be rescued by inhibiting these miRNAs or adding sAPPα.
Conclusions:
- Dysregulated miR-140 and miR-122 contribute to neuropathological progression in AD by reducing neuroprotective sAPPα.
- Targeting miR-140 and miR-122 represents a promising therapeutic strategy for Alzheimer's disease.
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