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Receptor for advanced glycation end products mediates meningitis‐triggered amyloid‐β accumulation and cognitive impairment
Author(s) -
Barichello Tatiana,
Generoso Jaqueline S,
Giridharan Vijayasree V,
Collodel Allan,
Dominguini Diogo,
Petronilho Fabricia,
DalPizzol Felipe
Publication year - 2020
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 - 10.1002/alz.047199
Subject(s) - meningitis , medicine , rage (emotion) , glial fibrillary acidic protein , streptococcus pneumoniae , immunology , receptor expression , cerebrospinal fluid , anesthesia , receptor , neuroscience , biology , surgery , antibiotics , immunohistochemistry , microbiology and biotechnology
Background Pneumococcal meningitis is a life‐threatening infection of the central nervous system (CNS), and half of the survivors of meningitis suffer from neurological sequelae. We hypothesized that pneumococcal meningitis causes CNS inflammation via the disruption of the blood‐brain barrier (BBB) and by increasing the expression of the receptor for advanced glycation end products (RAGE) in the brain, which then causes glial cell activation and cognitive impairment, triggering similar Alzheimer's disease pathology. Method To test our hypothesis, sixty‐day‐old male Wistar rats were subjected to meningitis by receiving an intracisternal injection of Streptococcus pneumoniae or artificial cerebrospinal fluid (aCSF) as a control group and were treated with a high‐affinity RAGE‐specific inhibitor (FPS‐ZM1) in saline or placebo. Rats also received ceftriaxone 100 mg/kg, i.p., bid, and fluid replacements. We evaluate the blood‐brain barrier at 12, 18, and 24 hours after meningitis induction or aCSF. At ten days after the meningitis induction, we evaluate behavioral tasks, including open field, novel object recognition task, and Morris water maze. After the behavioral tasks, the brain of the animals was removed to evaluate RAGE, amyloid‐beta (Aβ1‐42), and glial cells activation. Result We demonstrated that experimental pneumococcal meningitis triggered BBB disruption at 12, 18, and 24 hours after meningitis induction, and FPS‐ZM1 treatment significantly suppressed BBB disruption. Ten days after meningitis induction, surviving animals were free from infection, but they presented increased levels of TNF‐α and IL‐1β in the prefrontal cortex (PFC); high expression levels of RAGE and Aβ1‐42, high levels of microglial cell activation in the prefrontal cortex (PFC) and hippocampus, and memory impairment, as evaluated by the open field, novel object recognition task, and Morris water maze behavioral tasks. Conclusion Pneumococcal meningitis can increase the RAGE and Aβ1‐42 in the brain of the animals. Targeting RAGE inhibition was able to reduce cytokine levels, decrease the expression of RAGE and Aβ1‐42, inhibit microglial cell activation, and improve cognitive deficits in meningitis survivor rats.