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

Abstract

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.

Spatial Dissection of the Distinct Cellular Responses to Normal Aging and Alzheimer’s Disease in Human Prefrontal Cortex at Single-Nucleus Resolution

“…These two TFs are recognized for accelerating the progression of AD. Specifically, KLF4 was identified as a key mediator in promoting Aβ-induced neuroinflammation by exacerbating the release of pro-inflammatory factors (87), and KLF5 can accelerate APP amyloidogenic metabolism and promote Aβ synthesis through binding to the BACE1 promoter (88). Interestingly, one TF, ZNF460 showed the highest level of enrichment across Ex1, Inh1, and Inh2 gene modules ( Fig.…”

An integrated approach to identifying sex-specific genes, transcription factors, and pathways relevant to Alzheimer’s disease

“…Seefelder et al linked HMN3 to Huntington's disease [87], while IRF3 participates in AD progression and cognitive impairment [88]. Studies have linked KFL5 and KFL9 to AD progression and development [89,90],…”

“…Seefelder et al linked HMN3 to Huntington’s disease [87], while IRF3 participates in AD progression and cognitive impairment [88]. Studies have linked KFL5 and KFL9 to AD progression and development [89, 90], MAZ participates in amyloidosis [91], MBD3 induces neurotoxicity in mice [92], and MYNN has significant diagnostic value in AD patients [93]. Studies have linked PRDM14 to pluripotency, motor neurons, and brain germinoma [94], while Seznec et al associated SIX5 with abnormal tau expression [95].…”