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miR-124 Regulates the Expression of BACE1 in the Hippocampus Under Chronic Cerebral Hypoperfusion
Xiaowen Zhang1, Xiongweiye Huang1, Chen Fang1
1Department of Pathology, Capital Medical University, 10 Xi Tou Tiao, You An Men Street, Beijing, 100069, People's Republic of China.
Abstract:
Chronic cerebral hypoperfusion (CCH) is a high-risk factor of Alzheimer's disease (AD). MicroRNAs (miRNAs) are ideal mediators of hypoxic stress responses to facilitate cellular adaptation to long-term hypoxia. MiR-124 is a kind of nervous system-specific miRNAs, and one of its target genes is β-site amyloid precursor protein cleaving enzyme 1 (BACE1). In the present study, miR-124 was found to be inhibited all the time from early to late stage of cerebral hypoxia accompanying with the upregulation of BACE1 protein and overproduction of amyloid-β (Aβ) in the hippocampus from cerebral hypoperfusion rat models. Meanwhile, Aβ could further enhance the expression of BACE1 protein due to the inhibition of miR-124. Thus, miR-124 was the key factor in this hypoxia/Aβ-miR-124-BACE1-Aβ cycle. The activation of EPAC-Rap1 pathway was involved in the inhibition of miR-124 in hippocampus under hypoxia or Aβ insult. Our data suggest that, as an endogenous regulator of BACE1 protein, miR-124 may play a role in AD onset induced by CCH.
Insights
Chronic cerebral hypoperfusion (CCH) elevates Alzheimer's disease (AD) risk. This study reveals miR-124 inhibition drives a cycle of amyloid-beta production and BACE1 upregulation, suggesting miR-124's role in CCH-induced AD.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Chronic cerebral hypoperfusion (CCH) is a significant risk factor for Alzheimer's disease (AD).
- MicroRNAs (miRNAs) are crucial regulators of cellular responses to hypoxic stress.
- MiR-124, a nervous system-specific miRNA, targets BACE1, an enzyme involved in amyloid-beta (Aβ) production.
Purpose of the Study:
- To investigate the role of miR-124 in the pathogenesis of AD associated with CCH.
- To elucidate the molecular mechanisms linking CCH, miR-124, BACE1, and Aβ production in the hippocampus.
- To explore the involvement of the EPAC-Rap1 pathway in miR-124 regulation under hypoxic conditions.
Main Methods:
- Utilized rat models of chronic cerebral hypoperfusion.
- Measured miR-124, BACE1 protein, and Aβ levels in the hippocampus.
- Investigated the regulatory relationship between Aβ, miR-124, and BACE1.
- Examined the activation of the EPAC-Rap1 pathway.
Main Results:
- miR-124 was consistently inhibited from early to late stages of cerebral hypoxia.
- BACE1 protein and Aβ were upregulated in the hippocampus of hypoperfused rats.
- Aβ further enhanced BACE1 expression by inhibiting miR-124, establishing a hypoxia/Aβ-miR-124-BACE1-Aβ cycle.
- The EPAC-Rap1 pathway was activated, contributing to miR-124 inhibition under hypoxia or Aβ insult.
Conclusions:
- miR-124 acts as a key endogenous regulator of BACE1 protein.
- The inhibition of miR-124 plays a critical role in the CCH-induced exacerbation of AD pathology.
- Targeting the miR-124/BACE1 axis may offer a therapeutic strategy for AD associated with CCH.
