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Intranasally administered S100A9 amyloids induced cellular stress, amyloid seeding and behavioral impairment in aged mice

Iashchishyn, Igor A., Gruden, Marina, Moskalenko, Roman, Davydova, Tatiana, Wang, Chao, Sewell, Robert D.E. and Morozova-Roche, Ludmilla A 2018. Intranasally administered S100A9 amyloids induced cellular stress, amyloid seeding and behavioral impairment in aged mice. ACS Chemical Neuroscience 9 (6) , pp. 1338-1348. 10.1021/acschemneuro.7b00512

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Amyloid formation and neuroinflammation are major features of Alzheimer’s disease pathology. Proinflammatory mediator S100A9 was shown to act as a link between the amyloid and neuroinflammatory cascades in Alzheimer’s disease, leading together with Aβ to plaque formation, neuronal loss and memory impairment. In order to examine if S100A9 alone in its native and amyloid states can induce neuronal stress and memory impairment, we have administered S100A9 species intranasally to aged mice. Single and sequential immunohistochemistry and passive avoidance behavioral test were conducted to evaluate the consequences. Administered S100A9 species induced widespread cellular stress responses in cerebral structures, including frontal lobe, hippocampus and cerebellum. These were manifested by increased levels of S100A9, Bax, and to a lesser extent activated caspase-3 immunopositive cells. Upon administration of S100A9 fibrils, the amyloid oligomerization was observed in the brain tissues, which can further exacerbate cellular stress. The cellular stress responses correlated with significantly increased training and decreased retention latencies measured in the passive avoidance test for the S100A9 treated animal groups. Remarkably, the effect size in the behavioral tests was moderate already in the group treated with native S100A9, while the effect sizes were large in the groups administered S100A9 amyloid oligomers or fibrils. The findings demonstrate the brain susceptibility to neurotoxic damage of S100A9 species leading to behavioral and memory impairments. Intranasal administration of S100A9 species proved to be an effective method to study amyloid induced brain dysfunctions, and S100A9 itself may be postulated as a target to allay early stage neurodegenerative and neuroinflammatory processes

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Publisher: American Chemical Society
ISSN: 1948-7193
Date of First Compliant Deposit: 11 April 2018
Date of Acceptance: 4 April 2018
Last Modified: 03 Jul 2019 11:08

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