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THE ANTI-ASTHMATIC DRUG MONTELUKAST ALTERS MICROGLIA PHENOTYPE AND SYNUCLEOPATHY, AND RESTORES LEARNING AND MEMORY IN AN ANIMAL MODEL OF LEWY BODY DEMENTIA
Julia MarschallingerEmail the author Julia Marschallinger, Barbara Altendorfer, Nadine Pillichshammer, Garnweidner-Raith Julia, Edward Rockenstein, Eliezer Masliah, Ludwig Aigner
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DOI: http://dx.doi.org/10.1016/j.jalz.2017.06.233
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Background
Neurodegenerative diseases are associated with increased neuroinflammation. Leukotrienes are small lipid mediators of neuroinflammatory processes, and thus, leukotriene signaling might be a therapeutic target for neurodegenerative disease such as AD, PD, or Lewy body dementia (LBD).

Methods
6-month old PDGF-promoter-alpha-synuclein (PDGF-a-syn) D-line transgenic mice (abbreviated D-line), an animal model for LBD, were treated per oral gavage daily over a period of 42 days with montelukast (10 mg/kg), an approved leukotriene receptor antagonist for the treatment of asthma. Behavioral analyses (Morris Water Maze – learning and memory) of the animals were performed between days 28 and 40. After transcardial perfusion of the mice on day 42, histological analyses of the hippocampus (proliferation, cell survival, neuroinflammation, alpha-synuclein load) were assessed.

Results
We observed elevated levels of 5-LOX protein, the rate limiting enzyme in leukotriene production, in the hippocampus of 6 months old PDGF-promoter-alpha-synuclein (PDGF-a-syn) mice, an animal model for LBD. D-line animals exhibited elevated levels of neuroinflammation, and most importantly, had learning and memory deficits. Treatment of 6 months old D-line mice for 6 weeks with the leukotriene receptor antagonist Montelukast fully restored learning and memory to a level comparable to WT animals without having any adverse effects regardless of the phenotype. Montelukast significantly reduced microglia soma size (a typical morphological surrogate for microglia activation) and reduced the particle size of the phagosomal marker CD68 suggesting either a reduced microglial activity or a restoration of the phagocytic / lysosomal activity, which is otherwise disturbed in microglia of the aged and of the neurodegenerative brain. Moreover, the Montelukast treatment altered the synucleopathy in the D-line mice.

Conclusions
In summary, the leukotriene receptor antagonist Montelukast was highly efficient in restoring cognitive function in an animal model of LBD, most likely but not necessarily limited through its anti-inflammatory action on microglia. This work paves the road for a further development of Montelukast for the treatment neurodegenerative diseases.