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

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Alzheimer's disease (AD) pathogenesis involves β-amyloid (Aβ) deposition.
• Aβ is produced through amyloid precursor protein (APP) cleavage via the amyloidogenic pathway.
• β-secretase 1 (BACE1) is the rate-limiting enzyme in this pathway, with its increased expression in AD patients remaining mechanistically unclear.

Purpose of the Study:

• To elucidate the regulatory mechanism of BACE1 in Alzheimer's disease.
• To investigate the role of Krüppel-like factor 5 (KLF5) in BACE1 regulation and AD pathogenesis.
• To explore potential therapeutic targets for AD based on KLF5 and BACE1 interactions.

Main Methods:

• Utilized APPswe/PS1dE9 (APP/PS1) transgenic mice to assess KLF5 and BACE1 levels in serum and brain.
• Employed HT22 cells to investigate the relationship between KLF5 and BACE1.
• Analyzed KLF5 binding to the BACE1 promoter to confirm its transcriptional regulatory role.

Main Results:

• Identified KLF5 as a novel transcription factor that positively regulates BACE1 by binding to its promoter.
• Observed significantly increased KLF5 levels in cerebrospinal fluid (CSF), serum, and brain tissue of AD patients and APP/PS1 mice, correlating with cognitive decline.
• Demonstrated that KLF5 accelerates APP amyloidogenic metabolism and Aβ synthesis via BACE1, and that BACE1 inhibition blocks this process. ML264 treatment ameliorated cognitive deficits in APP/PS1 mice.

Conclusions:

• KLF5 upregulation is a critical factor in AD progression, enhancing BACE1-mediated APP amyloidogenic cleavage.
• Inhibition of KLF5, or combined inhibition of KLF5 and the BACE1 promoter, presents a potential therapeutic strategy for preventing AD pathogenesis.
• Targeting the KLF5-BACE1 axis offers a promising avenue for novel AD treatments.