Natural medicine HLXL targets multiple pathways of amyloid-mediated neuroinflammation and immune response in treating alzheimer's disease

Yingxia Liang; David Y W Lee; Sherri Zhen; Haoqi Sun; Biyue Zhu; Jing Liu; Dan Lei; Chih-Chung Jerry Lin; Siyi Zhang; Nicholas A Jacques; Luisa Quinti; Chongzhao Ran; Changning Wang; Ana Griciuc; Se Hoon Choi; Rong Hua Dai; Thomas Efferth; Rudolph E Tanzi; Can Zhang

doi:10.1016/j.phymed.2022.154158

Natural medicine HLXL targets multiple pathways of amyloid-mediated neuroinflammation and immune response in treating alzheimer's disease

Phytomedicine. 2022 Sep:104:154158. doi: 10.1016/j.phymed.2022.154158. Epub 2022 May 13.

Authors

Yingxia Liang¹, David Y W Lee², Sherri Zhen³, Haoqi Sun⁴, Biyue Zhu⁵, Jing Liu⁶, Dan Lei³, Chih-Chung Jerry Lin³, Siyi Zhang³, Nicholas A Jacques³, Luisa Quinti³, Chongzhao Ran⁵, Changning Wang⁵, Ana Griciuc³, Se Hoon Choi³, Rong Hua Dai⁶, Thomas Efferth⁷, Rudolph E Tanzi⁸, Can Zhang⁹

Affiliations

¹ Genetics and Aging Research Unit, McCance Center for Brain Health, Mass General Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA; Department of Anesthesiology, Weifang Medical University, Weifang, Shandong, China.
² Bio-Organic and Natural Products Research Laboratory, Department of Psychiatry, McLean Hospital and Harvard Medical School, Belmont, MA, USA. Electronic address: dlee@mclean.harvard.edu.
³ Genetics and Aging Research Unit, McCance Center for Brain Health, Mass General Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
⁴ Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
⁵ Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
⁶ Bio-Organic and Natural Products Research Laboratory, Department of Psychiatry, McLean Hospital and Harvard Medical School, Belmont, MA, USA; Natural Pharmacia International Inc., Burlington, MA 01803, USA.
⁷ Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz 55128, Germany.
⁸ Genetics and Aging Research Unit, McCance Center for Brain Health, Mass General Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA. Electronic address: rtanzi@mgh.harvard.edu.
⁹ Genetics and Aging Research Unit, McCance Center for Brain Health, Mass General Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA. Electronic address: Zhang.Can@mgh.harvard.edu.

PMID: 35728383
DOI: 10.1016/j.phymed.2022.154158

Abstract

Background: Based on the complex pathology of AD, a single chemical approach may not be sufficient to deal simultaneously with multiple pathways of amyloid-tau neuroinflammation. A polydrug approach which contains multiple bioactive components targeting multiple pathways in AD would be more appropriate. Here we focused on a Chinese medicine (HLXL), which contains 56 bioactive natural products identified in 11 medicinal plants and displays potent anti-inflammatory and immuno-modulatory activity.

Hypothesis/purpose: We investigated the neuroimmune and neuroinflammation mechanisms by which HLXL may attenuate AD neuropathology. Specifically, we investigated the effects of HLXL on the neuropathology of AD using both transgenic mouse models as well as microglial cell-based models.

Study design: The 5XFAD transgenic animals and microglial cell models were respectively treated with HLXL and Aβ42, and/or lipopolysaccharide (LPS), and then analyzed focusing on microglia mediated Aβ uptake and clearance, as well as pathway changes.

Methods: We showed that HLXL significantly reduced amyloid neuropathology by upregulation of microglia-mediated phagocytosis of Aβ both in vivo and in vitro. HLXL displayed multi-modal mechanisms regulating pathways of phagocytosis and energy metabolism.

Results: Our results may not only open a new avenue to support pharmacologic modulation of neuroinflammation and the neuroimmune system for AD intervention, but also identify HLXL as a promising natural medicine for AD.

Conclusion: It is conceivable that the traditional wisdom of natural medicine in combination with modern science and technology would be the best strategy in developing effective therapeutics for AD.

Keywords: Alzheimer's disease; HlXL; Innate immune response; Natural medicine; Neuroinflammation.

MeSH terms

Alzheimer Disease* / drug therapy
Alzheimer Disease* / metabolism
Amyloid beta-Peptides / metabolism
Amyloidosis*
Animals
Disease Models, Animal
Mice
Mice, Transgenic
Microglia
Neuroinflammatory Diseases
Phagocytosis

Substances

Amyloid beta-Peptides