Anti-malaria drug artesunate prevents development of amyloid-β pathology in mice by upregulating PICALM at the blood-brain barrier

Molecular Neurodegeneration

Research Article

Anita Ramanathan¹  Divna Lazic¹  Zhen Zhao¹  Sam Bazzi¹  Amy R. Nelson¹  Abhay P. Sagare¹  Erica Lawson¹  Berislav V. Zlokovic¹  Yaoming Wang¹  Ching-Ju Hsu¹  Kassandra Kisler¹ 

[1] Department of Physiology and Neuroscience and the Zilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, 1501 San Pablo St, 90089, Los Angeles, CA, USA;

关键词: Artesunate;    PICALM;    Blood-brain barrier;    Alzheimer’s disease;    Amyloid-β;    Mice;   

DOI  :  10.1186/s13024-023-00597-5

 received in 2022-08-17, accepted in 2023-01-13,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundPICALM is one of the most significant susceptibility factors for Alzheimer’s disease (AD). In humans and mice, PICALM is highly expressed in brain endothelium. PICALM endothelial levels are reduced in AD brains. PICALM controls several steps in Aβ transcytosis across the blood-brain barrier (BBB). Its loss from brain endothelium in mice diminishes Aβ clearance at the BBB, which worsens Aβ pathology, but is reversible by endothelial PICALM re-expression. Thus, increasing PICALM at the BBB holds potential to slow down development of Aβ pathology.MethodsTo identify a drug that could increase PICALM expression, we screened a library of 2007 FDA-approved drugs in HEK293t cells expressing luciferase driven by a human PICALM promoter, followed by a secondary mRNA screen in human Eahy926 endothelial cell line. In vivo studies with the lead hit were carried out in Picalm-deficient (Picalm+/−) mice, Picalm+/−; 5XFAD mice and Picalmlox/lox; Cdh5-Cre; 5XFAD mice with endothelial-specific Picalm knockout. We studied PICALM expression at the BBB, Aβ pathology and clearance from brain to blood, cerebral blood flow (CBF) responses, BBB integrity and behavior.ResultsOur screen identified anti-malaria drug artesunate as the lead hit. Artesunate elevated PICALM mRNA and protein levels in Eahy926 endothelial cells and in vivo in brain capillaries of Picalm+/− mice by 2–3-fold. Artesunate treatment (32 mg/kg/day for 2 months) of 3-month old Picalm+/−; 5XFAD mice compared to vehicle increased brain capillary PICALM levels by 2-fold, and reduced Aβ42 and Aβ40 levels and Aβ and thioflavin S-load in the cortex and hippocampus, and vascular Aβ load by 34–51%. Artesunate also increased circulating Aβ42 and Aβ40 levels by 2-fold confirming accelerated Aβ clearance from brain to blood. Consistent with reduced Aβ pathology, treatment of Picalm+/−; 5XFAD mice with artesunate improved CBF responses, BBB integrity and behavior on novel object location and recognition, burrowing and nesting. Endothelial-specific knockout of PICALM abolished all beneficial effects of artesunate in 5XFAD mice indicating that endothelial PICALM is required for its therapeutic effects.ConclusionsArtesunate increases PICALM levels and Aβ clearance at the BBB which prevents development of Aβ pathology and functional deficits in mice and holds potential for translation to human AD.

【 授权许可】

CC BY   
© The Author(s) 2023

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