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Increased expression of miRNA-146a in Alzheimer's disease transgenic mouse models
1LSU Neuroscience Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112-2272, USA.
Abstract:
A mouse and human brain-enriched micro-RNA-146a (miRNA-146a) is known to be important in modulating the innate immune response and inflammatory signaling in certain immunological and brain cell types. In this study we examined miRNA-146a levels in early-, moderate- and late-stage Alzheimer's disease (AD) neocortex and hippocampus, in several human primary brain and retinal cell lines, and in 5 different transgenic mouse models of AD including Tg2576, TgCRND8, PSAPP, 3xTg-AD and 5xFAD. Inducible expression of miRNA-146a was found to be significantly up-regulated in a primary co-culture of human neuronal-glial (HNG) cells stressed using interleukin1-beta (IL-1β), and this up-regulation was quenched using specific NF-кB inhibitors including curcumin. Expression of miRNA-146a correlated with senile plaque density and synaptic pathology in Tg2576 and in 5xFAD transgenic mouse models used in the study of this common neurodegenerative disorder.
Insights
MicroRNA-146a (miRNA-146a) is upregulated in Alzheimer's disease (AD) brain tissue and models. Its expression correlates with AD pathology, suggesting a role in neuroinflammation.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- MicroRNA-146a (miRNA-146a) is a brain-enriched microRNA involved in innate immune and inflammatory responses.
- Dysregulation of miRNA-146a is implicated in various neurological conditions.
Purpose of the Study:
- To investigate miRNA-146a expression levels in Alzheimer's disease (AD) across different stages and in various cellular and animal models.
- To explore the relationship between miRNA-146a and AD neuropathology.
Main Methods:
- Analysis of miRNA-146a levels in human AD neocortex and hippocampus samples.
- Examination of miRNA-146a in human primary brain and retinal cell lines.
- Assessment in five transgenic mouse models of AD (Tg2576, TgCRND8, PSAPP, 3xTg-AD, 5xFAD).
- Induction of miRNA-146a in human neuronal-glial (HNG) cells using interleukin-1 beta (IL-1β) and inhibition using NF-κB inhibitors.
Main Results:
- miRNA-146a was significantly upregulated in human AD brain tissue and in transgenic AD mouse models.
- Inducible expression of miRNA-146a was observed in IL-1β-stressed HNG cells.
- NF-κB inhibitors, such as curcumin, quenched the IL-1β-induced miRNA-146a upregulation.
- miRNA-146a expression correlated positively with senile plaque density and synaptic pathology in Tg2576 and 5xFAD mice.
Conclusions:
- miRNA-146a is upregulated in Alzheimer's disease and its expression is linked to key pathological hallmarks.
- The NF-κB signaling pathway regulates miRNA-146a expression in response to inflammatory stimuli in brain cells.
- miRNA-146a represents a potential therapeutic target for managing neuroinflammation in Alzheimer's disease.
