FBXL16: a new regulator of neuroinflammation and cognition in Alzheimer's disease through the ubiquitination-dependent degradation of amyloid precursor protein

Liqun Qu; Yong Tang; Jianhui Wu; Xiaoyun Yun; Hang Hong Lo; Linlin Song; Xingxia Wang; Huimiao Wang; Ruilong Zhang; Menghan Liu; Cairen Wang; Jerome P L Ng; Xianjun Fu; Io Nam Wong; Vincent Kam Wai Wong; Betty Yuen Kwan Law

doi:10.1186/s40364-024-00691-w

FBXL16: a new regulator of neuroinflammation and cognition in Alzheimer's disease through the ubiquitination-dependent degradation of amyloid precursor protein

Biomark Res. 2024 Nov 21;12(1):144. doi: 10.1186/s40364-024-00691-w.

Authors

Liqun Qu^#^{1

2

3}, Yong Tang^#⁴, Jianhui Wu^#¹, Xiaoyun Yun¹, Hang Hong Lo¹, Linlin Song¹, Xingxia Wang¹, Huimiao Wang¹, Ruilong Zhang¹, Menghan Liu¹, Cairen Wang¹, Jerome P L Ng¹, Xianjun Fu^{2

3}, Io Nam Wong^{5

6}, Vincent Kam Wai Wong⁷, Betty Yuen Kwan Law⁸

Affiliations

¹ Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau S.A.R, Avenida Wai Long, Macau, 999078, China.
² Research Institute for Marine Traditional Chinese Medicine, Key Laboratory of Marine Traditional Chinese Medicine in Shandong Universities, Shandong Engineering and Technology Research Center on Omics of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, 250355, China.
³ Qingdao Key Laboratory of Research in Marine Traditional Chinese Medicine, Qingdao Academy of Chinese Medical Sciences Shandong University of Traditional Chinese Medicine, Qingdao Key Technology Innovation Center of Marine Traditional Chinese Medicine's Deep Development and Industrialization, Qingdao, 266114, China.
⁴ Sichuan Key Medical Laboratory of New Drug Discovery and Druggability Evaluation, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica of Southwest Medical University, Luzhou, 646000, China.
⁵ Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau S.A.R, Avenida Wai Long, Macau, 999078, China. inwong@must.edu.mo.
⁶ Faculty of Medicine, Macau University of Science and Technology, Macau, 999078, China. inwong@must.edu.mo.
⁷ Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau S.A.R, Avenida Wai Long, Macau, 999078, China. kawwong@must.edu.mo.
⁸ Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau S.A.R, Avenida Wai Long, Macau, 999078, China. yklaw@must.edu.mo.

^# Contributed equally.

PMID: 39568047
DOI: 10.1186/s40364-024-00691-w

Abstract

Background: Activating the ubiquitin-proteasome system to dismantle disease- related proteins such as tau, β-amyloid, APP, and α-synuclein is an important focus in the research of neurodegenerative proteinopathy. By analyzing the serum RNA extracted from wild-type and Alzheimer's disease (AD) transgenic mice at different ages (4, 8, and 12 months), this study revealed a new protective role of FBXL16 in AD, primarily through facilitating the degradation of disease-related proteins via the ubiquitin proteasome system.

Methods: Proteomic analysis were conducted using protein lysates from HEK293 cells overexpressing FBXL16 to identify potential interacting proteins that interact with FBXL16. Subsequent experiments demonstrated that FBXL16 promotes the proteasomal degradation of the APP protein, as evidenced by co-immunoprecipitation with MG132 and cycloheximide (CHX), immunohistochemistry (IHC) and immunocytochemistry (ICC). Memory and cognitive improvements were observed in 3×Tg AD mice through the use of a lentivirus-mediated approach to generate a brain-specific AD mouse model overexpressing FBXL16 via stereotaxic injection. Furthermore, a brain-specific conditional knockout (cko) FBXL16 mouse model was generated and employed to further confirm the functional role of FBXL 16 in AD via various behavioral tests including Morris water maze and Y-maze.

Results: The level of FBXL16 in the brains of transgenic APP/PSEN mice with AD decreased with age. Accelerated degradation of APP was observed when FBXL16 was overexpressed in the hippocampi of these AD mice via a lentivirus. This process led to notable improvements in cognitive impairments and reductions in neuroinflammation. Further studies using proteomics and bioinformatics techniques identified transcription factors and binding proteins associated with FBXL16, providing deeper insights into the potential role of FBXL16 in the regulation of AD. Finally, the in vivo effects of FBXL16 deficiency were further substantiated in cko mice, which overexpress Aβ but specifically lack FBXL16 in the brain region.

Conclusions: These findings suggest that FBXL16 could be a new regulator of AD. These findings provide a foundation for further research into drug development and potential therapeutic strategies to combat other related neurodegenerative proteinopathies.

Keywords: Alzheimer’s disease; Amyloid precursor protein; FBXL16; Neuroprotection; Ubiquitin.

Abstract

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