The binding of Sirtuin 1 to PCSK9 is important to reduce PCSK9 levels and reduce low density lipoprotein cholesterol. The role of increased PCSK9 levels with low Sirtuin 1 levels may determine the peripheral sink amyloid beta clearance with accelerated amyloidosis and defective treatment of Alzheimer’s disease (AD). The role of PCSK9 may interfere with the Apolipoprotein E and Sirtuin 1 interaction with relevance to brain cholesterol and amyloid beta clearance.
RELEVANT REFERENCES:
1. Campagna, J., Spilman, P., Jagodzinska, B. et al. A small molecule ApoE4-targeted therapeutic candidate that normalizes sirtuin 1 levels and improves cognition in an Alzheimer’s disease mouse model. Sci Rep 8, 17574 (2018).
2. Veena Theendakara, Alexander Patent, Clare A. Peters Libeu, Brittany Philpot, Sonia Flores, Olivier Descamps, Karen S. Poksay, Qiang Zhang, Gabriellee Cailing, Matthew Hart, Varghese John, Rammohan V. Rao, and Dale E. Bredesena. Neuroprotective Sirtuin ratio reversed by ApoE4. Proc Natl Acad Sci U S A. 2013 Nov 5; 110(45): 18303–18308.
3. Appetite Regulation and the Peripheral Sink Amyloid beta Clearance Pathway in Diabetes and Alzheimer’s Disease. Top 10 Commentaries in Alzheimer’s Disease (e-book). 2019;2:1-11. www.avidscience.com
4. Picard C, Poirier A, Bélanger S, Labonté A, Auld D, Poirier J. Proprotein convertase subtilisin/kexin type 9 (PCSK9) in Alzheimer's disease: A genetic and proteomic multi-cohort study. PLoS One. 2019 Aug 22;14(8):e0220254.
5. Mazura AD, Ohler A, Storck SE, Kurtyka M, Scharfenberg F, Weggen S, Becker-Pauly C, Pietrzik CU. PCSK9 acts as a key regulator of Aβ clearance across the blood-brain barrier. Cell Mol Life Sci. 2022 Mar 27;79(4):212.
6. Xue-Qin Bai, Juan Peng, Mei-Mei Wang, Jun Xiao, Qiong Xiang, Zhong Ren, Hong-Yan Wen , Zhi-Sheng Jiang , Zhi-Han Tang, Lu-Shan Liu. PCSK9: A potential regulator of apoE/apoER2 against inflammation in atherosclerosis? Clin Chim Acta. 2018;483:192-196.
7. Brandon Ason, José W. A. van der Hoorn, Joyce Chan, Edward Lee, Elsbet J. Pieterman, Kathy Khanh Nguyen, Mei Di, Susan Shetterly, Jie Tang, Wen-Chen Yeh, Margrit Schwarz, J. Wouter Jukema, Rob Scott, Scott M. Wasserman, Hans M. G. Princen, and Simon Jackson. PCSK9 inhibition fails to alter hepatic LDLR, circulating cholesterol, and atherosclerosis in the absence of ApoE. J Lipid Res. 2014 Nov; 55(11): 2370–2379.
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