Prenatal immune activation and adult Poly(I:C) re-challenge promote neuroimmune priming and AD-related behavioural, cellular and molecular alterations in wild-type mice.

Overview

1. Department of Experimental Neurosciences, Istituto di Ricovero e Cura a Carattere Scientifico (IRCSS) Santa Lucia Foundation, Rome, Italy
2. Institute of Translational Pharmacology, National Research Council, Rome, Italy
3. European Brain Research Institute (EBRI), Rome, Italy
4. Laboratory of Experimental Neuropsychobiology, Scientific Institute for Research, Hospitalization, and Healthcare Istituto di Ricovero e Cura a Carattere Scientifico (IRCSS) Santa Lucia Foundation, Rome, Italy
5. National Research Council (CNR), Institute for Complex System (ISC), Rome, Italy

Abstract

Objective: Alzheimer’s Disease (AD) is neurodegenerative disorder characterized by deposition of Aβ plaques, tau-positive neurofibrillary tangles, neuroinflammation and clinical dementia. Epidemiological and experimental evidence suggest that peripheral immune inflammation is a risk factor for age-related neurodegeneration but whether its sustained activation is sufficient to drive behavioural, molecular and cellular changes consistent with AD-associated neurodegenerative vulnerability remains unclear. Here we investigated whether prenatal immune stimulation followed by an adult systemic re-challenge with Polyinosinic-polycytidylic acid (Poly(I:C)) induces persistent cognitive/motivational/social deficits and hippocampal neurodegeneration in wild-type mice, consistent with long-lasting neuroimmune priming mechanism(s).

Methods: Pregnant C57Bl/6J dams received intravenously Poly(I:C) at gestational day 17 and male offspring received intraperitoneal Poly(I:C) at 9 months (single- or double-hit design) and were analyzed at 12 months. Recognition memory, working memory, reward-related learning, and social interaction were assessed followed by hippocampal Western blotting and immunofluorescence.

Results: Poly(I:C)-exposed mice exhibited impaired recognition and working memory, reduced palatable food-induced conditioned place preference, and blunted social investigation. These behavioral abnormalities were accompanied by increased amyloidogenic APP processing (BACE1/PSEN1 upregulation and β-CTF accumulation), tau dysregulation (AT8 hyperphosphorylation), microglial activation (Iba1/CD68 upregulation and process retraction), synaptic alterations (α-synuclein reduction), and bioenergetic impairment (reduced mitochondrial and glycolytic markers) in the hippocampus.

Conclusion: Overall, these findings indicate that repeated prenatal and postnatal peripheral activation of innate immunity may act as a contributing factor to neurodegenerative phenotype with features relevant to AD-related susceptibility, paving the way for the development of next-generation therapeutical interventions affecting systemic-to-brain inflammatory signaling.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• portal.brain-map.org/anatomy, at Allen Brain Map; found in the text, “Immunofluorescence assays and analyses”

Data availability statement

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 2, 28 September 2026

• Funding: added Ministero della Salute: RF-2021-12374301

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, pages, dates, 8 authors, 8 keywords, 13 MeSH terms, 111 references.

Cite

This paper

Giacovazzo, G., Latina, V., Yurtsever, Z. N., Piccolino, I., Iannuzzi, F., Bossù, P., Amadoro, G., & Coccurello, R. (2026). Prenatal immune activation and adult Poly(I:C) re-challenge promote neuroimmune priming and AD-related behavioural, cellular and molecular alterations in wild-type mice. Frontiers in immunology, 17, 1845312. https://doi.org/10.3389/fimmu.2026.1845312

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