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O2‐05‐01: CEREBROSPINAL FLUID SYNAPTIC VESICLE GLYCOPROTEIN 2A IN ALZHEIMER'S DISEASE
Author(s) -
Ashton Nicholas J.,
Höglund Kina,
Leuzy Antoine,
Heurling Kerstin,
Hugon Jacques,
Dumurgier Julien,
Cognat Emmanuel,
Paquet Claire,
Hansson Oskar,
Schöll Michael,
Zetterberg Henrik,
Blennow Kaj
Publication year - 2019
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2019.06.4475
Subject(s) - cerebrospinal fluid , medicine , cohort , neurogranin , alzheimer's disease , pathology , oncology , hippocampus , neuroscience , disease , psychology , biology , biochemistry , protein kinase c , enzyme
AD, the initiating factors of AD remain unclear. Recent studies suggest a strong link between AD and systemic infection. Likewise, supporting evidence from our lab show distinct alterations in the microbiota of AD mice compared to control mice. These findings suggest microbes may be implicated in AD pathogenesis. Therefore, we hypothesized that sepsis would exacerbate neurodegeneration and neuroinflammation in brain regions affected by AD. Methods: We employed the APPSwDI/Nos2(CVN-AD) mouse model of AD combined with an experimental model of sepsis, cecal ligation and puncture (CLP), to investigate this hypothesis. Cognitive, neuroinflammatory, and histopathological outcomes were compared between AD and AD female mice (8-10 months old). Sickness behavior was assessed with a murine modified sepsis score (MMSS) accompanied by behavioral assays to evaluate: spatial learning and memory (two-day radial arm water mazeRAWM), non-spatial learning and memory (passive avoidance), nociception (hot plate), locomotion (open field and rotarod), and depression (forced swim test). Animals were euthanized and organs harvested on day 21. The brains and spleens were analyzed for CD45+ cells populations by flow cytometry; brains were also immunostained for GFAP (astrocyte) and Iba-1 (microglia). Results: Our results revealed significant deficits in spatial memory in AD compared to AD in the RAWM (p1⁄40.001); however, non-spatial memory was not altered. Forced swim testing demonstrated a worsened refusal to escape or shift behavior from mobility to immobility in AD compared to AD (p1⁄40.01). The latency to respond to thermal stimuli was increased in AD compared to AD (p1⁄40.0073) but locomotion was not altered between the two groups. Isolated CD45+ cell populations revealed an elevated CD4(+)FoxP3(+)CD25(-) T regulatory cell population in AD compared to AD (p1⁄40.04), but not compared to AD. A parallel analysis of CD45+ spleen cells showed that CD19(+) B-cell populations were decreased in AD compared to AD (p1⁄40.03). Lastly, immunohistochemistry showed significant increases in astrocyte and microglial activation in the entorhinal cortex of AD compared AD. Conclusions: Taken together, our current results suggest that sepsis induces chronic immunosuppression and cognitive impairment in AD mice.