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The protective role of miR-132 targeting HMGA2 through the PI3K/AKT pathway in mice with Alzheimer's disease
Xichang Liu1, Haitao Wang2, Jiawei Bei3
1Department of Neurology, Taizhou Hospital of Zhejiang Province Taizhou, Zhejiang Province, China.
Objective:
To explore the role and of miR-132, HMGA2 and PI3K/AKT pathway in mice with Alzheimer's disease (AD).
Methods:
The mice were divided into 7 groups: the normal group, the model group (AD model mice), the NC group (AD mice injected with negative control (NC) vector), the miR-132 mimic group (AD mice injected with miR-132 mimics), the miR-132 inhibitor group (AD mice injected with miR-132 inhibitor), the si-HMGA2 group (AD mice injected with HMGA2 silencing vector), and the miR-132 inhibitor + si-HMGA2 group (model mice treated with miR-132 inhibitor and si-HMGA2). Y-maze experiment and related molecular biology experiments were performed.
Results:
The double-luciferase reporter assay verified that miR-132 could target and inhibit the expression of HMGA2A. Compared with the NC group, model mice had decreased learning and memory ability, reduced miR-132, p-PI3K/PI3K, p-AKT/AKT, AQP4 expression as well as GFAP GSH-Px, SOD, ATP, and T-AOC levels, but increased expression of HMGA2 and the levels of TNF-α, IL-6, NO, IL-1β, MAO, and MDA (P<0.017). Up-regulation of miR-132 or silencing HMGA2 could partly reverse the changes, but inhibition of miR-132 would exaggerate the brain injury and these molecular changes (P<0.017). The combination uses of si-HMGA2 and miR-132 inhibitor could reverse the changes caused by miR-132 inhibitor (P<0.017).
Conclusion:
miR-132 could downregulate the expression of HMGA2 and promote the expression of the PI3K/AKT pathway, so as to achieve a protective effect on brain in AD mice.
Insights
MicroRNA-132 (miR-132) protects the brain in Alzheimer
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline.
- The roles of microRNAs (miRNAs), such as miR-132, and their target genes, like HMGA2, are increasingly implicated in AD pathogenesis.
- The PI3K/AKT signaling pathway is crucial for neuronal survival and function and its dysregulation is observed in AD.
Purpose of the Study:
- To investigate the functional relationship between miR-132, HMGA2, and the PI3K/AKT pathway in a mouse model of Alzheimer's disease.
- To determine the therapeutic potential of modulating miR-132 and HMGA2 levels for AD treatment.
Main Methods:
- Establishment of an Alzheimer's disease mouse model.
- Experimental groups included normal, AD model, negative control, miR-132 mimic, miR-132 inhibitor, si-HMGA2, and combination treatment groups.
- Assessment of cognitive function using the Y-maze test and molecular analyses of gene/protein expression and oxidative stress markers.
Main Results:
- miR-132 directly targets and inhibits HMGA2 expression.
- AD model mice exhibited impaired learning and memory, reduced miR-132, and altered PI3K/AKT pathway activity, alongside increased oxidative stress and neuroinflammation markers.
- miR-132 upregulation or HMGA2 silencing partially reversed AD-associated deficits, while miR-132 inhibition exacerbated brain injury. Combined inhibition of miR-132 and HMGA2 partially reversed the detrimental effects of miR-132 inhibition.
Conclusions:
- miR-132 exerts a neuroprotective effect in Alzheimer's disease by downregulating HMGA2 and activating the PI3K/AKT pathway.
- Modulation of the miR-132/HMGA2 axis represents a potential therapeutic strategy for Alzheimer's disease.
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