Neonatal infection leads to increased susceptibility to Aβ oligomer-induced brain inflammation, synapse loss and cognitive impairment in mice

• Published in: Cell death & disease Vol. 10; no. 4; p. 323
• Main Authors: Frost, Paula S., Barros-Aragão, Fernanda, da Silva, Rachel T., Venancio, Aline, Matias, Isadora, Lyra e Silva, Natalia M., Kincheski, Grasielle C., Pimentel-Coelho, Pedro M., De Felice, Fernanda G., Gomes, Flávia C. A., Ferreira, Sergio T., Figueiredo, Claudia P., Clarke, Julia R.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11-04-2019; Springer Nature B.V
• Subjects: 13/1; 38; 631/250/255/1318; 631/378/371; 64/60; 82/51; Adolescents; Alzheimer's disease; Amyloid beta-Peptides; Animals; Animals, Newborn; Antibodies; Biochemistry; Biomedical and Life Sciences; Brain - growth & development; Brain - immunology; Brain - microbiology; Cell Biology; Cell Culture; Cells, Cultured; Cognitive ability; Cognitive Dysfunction - chemically induced; Cognitive Dysfunction - microbiology; Developmental stages; Disease; Disease Susceptibility - etiology; E coli; Encephalitis - microbiology; Environmental effects; Escherichia coli Infections - complications; Female; Immunology; Infants; Infections; Inflammation; Life Sciences; Low-birth-weight; Male; Mice; Microglia - cytology; Microglia - drug effects; Microglia - metabolism; Microglial cells; Minocycline; Neonates; Neurodegenerative diseases; Neurotoxins; Pattern recognition; Rodents; Synapses - drug effects; Synapses - metabolism; Synapses - pathology; Time Factors; Toxicity
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-019-1529-x

Harmful environmental stimuli during critical stages of development can profoundly affect behavior and susceptibility to diseases. Alzheimer disease (AD) is the most frequent neurodegenerative disease, and evidence suggest that inflammatory conditions act cumulatively, contributing to disease onset. Here we investigated whether infection early in life can contribute to synapse damage and cognitive impairment induced by amyloid-β oligomers (AβOs), neurotoxins found in AD brains. To this end, wild-type mice were subjected to neonatal (post-natal day 4) infection by
Escherichia coli
(1 × 10
4
CFU/g), the main cause of infection in low-birth-weight premature infants in the US.
E. coli
infection caused a transient inflammatory response in the mouse brain starting shortly after infection. Although infected mice performed normally in behavioral tasks in adulthood, they showed increased susceptibility to synapse damage and memory impairment induced by low doses of AβOs (1 pmol; intracerebroventricular) in the novel object recognition paradigm. Using in vitro and in vivo approaches, we show that microglial cells from
E. coli
-infected mice undergo exacerbated activation when exposed to low doses of AβOs. In addition, treatment of infected pups with minocycline, an antibiotic that inhibits microglial pro-inflammatory polarization, normalized microglial response to AβOs and restored normal susceptibility of mice to oligomer-induced cognitive impairment. Interestingly, mice infected with by
E. coli
(1 × 10
4
CFU/g) during adolescence (post-natal day 21) or adulthood (post-natal day 60) showed normal cognitive performance even in the presence of AβOs (1 pmol), suggesting that only infections at critical stages of development may lead to increased susceptibility to amyloid-β-induced toxicity. Altogether, our findings suggest that neonatal infections can modulate microglial response to AβOs into adulthood, thus contributing to amyloid-β-induced synapse damage and cognitive impairment.