The Leukotriene Receptor Antagonist Montelukast Reduces Alpha-Synuclein Load and Restores Memory in an Animal Model of D
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ORIGINAL ARTICLE
The Leukotriene Receptor Antagonist Montelukast Reduces Alpha-Synuclein Load and Restores Memory in an Animal Model of Dementia with Lewy Bodies Julia Marschallinger 1,2 & Barbara Altendorfer 1,2 & Edward Rockenstein 3 & Miriam Holztrattner 1,2 & Julia Garnweidner-Raith 1,2 & Nadine Pillichshammer 1,2 & Iris Leister 1,2 & Birgit Hutter-Paier 4 & Katharina Strempfl 1,2,4 & Michael S. Unger 1,2 & Mansoor Chishty 5 & Thomas Felder 6 & Mary Johnson 7 & Johannes Attems 7 & Eliezer Masliah 3 & Ludwig Aigner 1,2,8
# The Author(s) 2020
Abstract Dementia with Lewy bodies (DLB) represents a huge medical need as it accounts for up to 30% of all dementia cases, and there is no cure available. The underyling spectrum of pathology is complex and creates a challenge for targeted molecular therapies. We here tested the hypothesis that leukotrienes are involved in the pathology of DLB and that blocking leukotrienes through Montelukast, a leukotriene receptor antagonist and approved anti-asthmatic drug, might alleviate pathology and restore cognitive functions. Expression of 5-lipoxygenase, the rate-limiting enzyme for leukotriene production, was indeed elevated in brains with DLB. Treatment of cognitively deficient human alpha-synuclein overexpressing transgenic mice with Montelukast restored memory. Montelukast treatment resulted in modulation of beclin-1 expression, a marker for autophagy, and in a reduction in the human alpha-synulcein load in the transgenic mice. Reducing the protein aggregation load in neurodegenerative diseases might be a novel model of action of Montelukast. Moreover, this work presents leukotriene signaling as a potential drug target for DLB and shows that Montelukast might be a promising drug candidate for future DLB therapy development. Key Words Leukotrienes . autophagy . alpha-synulcein . Montelukast . neuroinflammation . dementia . cognition
Julia Marschallinger and Barbara Altendorfer contributed equally to this work. * Ludwig Aigner [email protected] 1
Institute of Molecular Regenerative Medicine, Paracelsus Medical University, Salzburg, Austria
2
Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI-TReCS), Paracelsus Medical University, Salzburg, Austria
3
Department of Neuroscience, School of Medicine, University of California San Diego, San Diego, USA
4
QPS Austria GmbH, Neuropharmacology, Grambach, Austria
5
Pharmidex, London W1S 1RR, UK
6
Department of Laboratory Medicine, Paracelsus Medical University, Salzburg, Austria
7
Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK
8
Austrian Cluster for Tissue Regeneration, Vienna, Austria
Introduction Dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD) are age-related chronic neurodegenerative syndromes with the common features of cognitive decline, parkinsonian motor symptoms, and with an underlying pathology of alpha-synuclein aggregated in neuronal inclusions, so called Lewy bodies [1, 2]. The two syndromes are roofed under the term Lewy body dementias (LB
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