PCSK6 exacerbates Alzheimer's disease pathogenesis by promoting MT5-MMP maturation
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Visualization of Amyloid β Deposits in the Human Brain with Matrix-assisted Laser Desorption/Ionization Imaging Mass Spectrometry
Published on: March 7, 2019
Mingliang Xu1, Junjie Li2, Lei Xia2
1Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Children's Hospital of Chongqing Medical University, Chongqing 400014, China; Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, Sichuan Province, China.
Abstract:
Proprotein convertase subtilisin/kexin type 6 (PCSK6) is a calcium-dependent serine proteinase that regulates the proteolytic activity of various precursor proteins and facilitates protein maturation. Dysregulation of PCSK6 expression or function has been implicated in several pathological processes including nervous system diseases. However, whether and how PCSK6 is involved in the pathogenesis of Alzheimer's disease (AD) remains unclear. In this study, we reported that the expression of PCSK6 was significantly increased in the brain tissues of postmortem AD patients and APP23/PS45 transgenic AD model mice, as well as N2AAPP cells. Genetic knockdown of PCSK6 reduced amyloidogenic processing of APP in N2AAPP cells by suppressing the activation of membrane-type 5-matrix metalloproteinase (MT5-MMP), referred to as η-secretase. We further found that PCSK6 cleaved and activated MT5-MMP by recognizing the RRRNKR sequence in its N-terminal propeptide domain in N2A cells. The mutation or knockout of this cleavage motif prevented PCSK6 from interacting with MT5-MMP and performing cleavage. Importantly, genetic knockdown of PCSK6 with adeno-associated virus (AAV) reduced Aβ production and ameliorated hippocampal long-term potentiation (LTP) and long-term spatial learning and memory in APP23/PS45 transgenic mice. Taken together, these results demonstrate that genetic knockdown of PCSK6 effectively alleviate AD-related pathology and cognitive impairments by inactivating MT5-MMP, highlighting its potential as a novel therapeutic target for AD treatment.
Insights
Proprotein convertase subtilisin/kexin type 6 (PCSK6) is elevated in Alzheimer's disease (AD). Reducing PCSK6 alleviates AD pathology and cognitive deficits by inhibiting MT5-MMP activation.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Proprotein convertase subtilisin/kexin type 6 (PCSK6) is a serine proteinase implicated in nervous system diseases.
- The role of PCSK6 in Alzheimer's disease (AD) pathogenesis is not well understood.
Purpose of the Study:
- To investigate the involvement of PCSK6 in Alzheimer's disease.
- To elucidate the mechanism by which PCSK6 influences AD pathology.
- To evaluate PCSK6 as a potential therapeutic target for AD.
Main Methods:
- Quantitative analysis of PCSK6 expression in postmortem AD brain tissues, AD model mice, and cell lines.
- Genetic knockdown of PCSK6 using siRNA or AAV vectors.
- Assessment of amyloid precursor protein (APP) processing and secretase activity.
- Investigation of the interaction between PCSK6 and membrane-type 5-matrix metalloproteinase (MT5-MMP).
- Evaluation of cognitive functions, including long-term potentiation (LTP) and spatial learning/memory, in AD model mice.
Main Results:
- PCSK6 expression is significantly increased in AD patient brains, AD model mice, and N2AAPP cells.
- Genetic knockdown of PCSK6 reduces amyloidogenic APP processing by suppressing MT5-MMP activation (η-secretase).
- PCSK6 directly cleaves and activates MT5-MMP via a specific recognition sequence (RRRNKR).
- PCSK6 knockdown in APP23/PS45 mice reduced amyloid-beta (Aβ) production and improved hippocampal LTP and spatial memory.
Conclusions:
- PCSK6 plays a critical role in AD pathogenesis by activating MT5-MMP.
- Genetic reduction of PCSK6 ameliorates AD-related neuropathology and cognitive impairments.
- PCSK6 inhibition represents a promising therapeutic strategy for Alzheimer's disease.
