Krüppel-like factor 5 accelerates the pathogenesis of Alzheimer's disease via BACE1-mediated APP processing

Background: The deposition of β-amyloid (Aβ) in the brain plays a major role in the pathogenesis of Alzheimer's disease (AD). Aβ is generated via amyloid precursor protein (APP) cleavage through the amyloidogenic pathway. In this pathway, β-secretase (BACE1) is the first and rate-limiting enzyme. Its expression increases through an unknown mechanism in patients with AD. Thus, the key regulatory mechanism of BACE1 in the AD process should be revealed to understand the pathogenesis of AD and explore the key treatment targets of AD.

Methods: Here, APPswe/PS1dE9 (APP/PS1) mice were employed to observe the Krüppel-like factor 5 (KLF5) and BACE1 levels in the serum and brain tissues. HT22 cells were used to explore the relationship between KLF5 and BACE1.

Results: In this study, KLF5 was found to be a novel transcription factor that positively regulated BACE1 by binding to the BACE1 promoter. The KLF5 levels significantly increased not only in the CSF and serum of patients with AD but also in the brain tissue of APP/PS1 mice. They were closely related to cognitive capacity. KLF5 accelerated APP amyloidogenic metabolism and promoted Aβ synthesis through BACE1. Silencing BACE1 could block the KLF5-induced amyloidogenic process of APP. ML264 ameliorated the cognitive deficits and slowed down APP amyloidogenic cleavage in APP/PS1 mice.

Conclusion: The findings above suggest that upregulation of KLF5 might be a critical element in AD progression by accelerating BACE1-mediated APP amyloidogenic cleavage. The inhibition of KLF5 or the combined inhibitory effect of KLF5 and the BACE1 promoter might be a potential strategy to prevent AD pathogenesis.

 

Comments:

The study you described investigated the role of Krüppel-like factor 5 (KLF5) in the regulation of β-secretase (BACE1), which is involved in the production of β-amyloid (Aβ) in Alzheimer's disease (AD). Here's a breakdown of the key findings:

1. KLF5 is a transcription factor: KLF5 was identified as a novel transcription factor that binds to the BACE1 promoter, suggesting that it plays a role in regulating BACE1 expression.

2. Increased KLF5 levels in AD: The study observed elevated levels of KLF5 in the cerebrospinal fluid (CSF) and serum of AD patients, as well as in the brain tissue of APP/PS1 mice (a commonly used AD mouse model). These increased levels of KLF5 were associated with cognitive impairment.

3. KLF5 promotes BACE1-mediated amyloidogenic cleavage: KLF5 was found to accelerate the amyloidogenic metabolism of amyloid precursor protein (APP) and promote the synthesis of Aβ through its positive regulation of BACE1. This suggests that KLF5 contributes to the generation of Aβ plaques, a hallmark of AD.

4. Silencing BACE1 blocks KLF5-induced amyloidogenic process: In experiments using HT22 cells, silencing BACE1 prevented the amyloidogenic effects induced by KLF5. This indicates that BACE1 is a key mediator of KLF5's role in promoting APP amyloidogenic cleavage.

5. ML264 as a potential treatment: ML264, a compound mentioned in the results section, was found to improve cognitive deficits and slow down APP amyloidogenic cleavage in APP/PS1 mice. This suggests that targeting KLF5 or the combined inhibition of KLF5 and the BACE1 promoter, possibly using ML264 or similar compounds, could be a potential strategy for preventing AD pathogenesis.

In summary, the study identifies KLF5 as a novel regulator of BACE1 and demonstrates its involvement in promoting the amyloidogenic pathway leading to Aβ production. The findings suggest that targeting KLF5 or its downstream effects, such as BACE1, may hold promise as a therapeutic approach for AD. However, further research is needed to validate these findings and explore the potential clinical applications.

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Related Targets

KLF