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bioRxiv · 10.1101/2024.05.20.594921

Intercellular adhesion molecule-1 reprograms microglia to improve cognitive functions by inhibiting ERK/STAT3 signalling pathway in a model of Alzheimer's disease

Goswami, S.·Biswas, S. C.
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Abstract

BackgroundMicrogliosis is one of the early hallmarks of Alzheimers disease (AD) that plays a crucial role in AD-associated neuroinflammation. However, strategies to harness microglial activation without affecting its homeostatic function are currently lacking. Our recent finding revealed astrocyte secreted cytokine Intercellular adhesion molecule 1 (ICAM-1) improves memory and cognitive impairment in 5xFAD mice model of AD. Here, we investigated the possible mechanism of ICAM-1 that involves modification of microglial activation state and function. MethodsWe treated primary microglia cultures with amyloid-{beta} (A{beta}) in presence or absence of ICAM-1 and then assessed microglial inflammatory activation and phagocytic clearance of A{beta} by western blotting and confocal imaging. We further treated 5xFAD mice with ICAM-1 intraperitoneally and ICAM-1 antagonist lifitegrast intranasally to assess the beneficial effect of ICAM-1 on A{beta} mediated microgliosis, synaptic protein expressions and cognitive deficits. ResultsHere we report that, ICAM-1 inhibits microglial inflammatory activation by inhibiting ERK-STAT3 pathway which is indispensable for microglial inflammation. Moreover, ICAM-1 was found to potentiate microglia to engulf and eliminate A{beta} in primary culture and reduced A{beta} plaque load and associated microglial activation in 5xFAD mice hippocampus. This reduced plaque levels and associated microgliosis in turn refurbished synaptic protein expressions and improved cognition and memory in these mice. Interestingly, ICAM-1 mediated microglial modification along with cognitive improvement was partially lost when ICAM-1-LFA-1 interaction was inhibited. ConclusionTaken together these findings delineate the importance of ERK/STAT3 pathway in A{beta} mediated microglial inflammation and the modulatory role of ICAM-1 in microglial activation and phagocytosis in order to improve clearance of A{beta} and associated memory and cognitive impairments.

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Goswami, S., Biswas, S. C.. 2024-05-20. Intercellular adhesion molecule-1 reprograms microglia to improve cognitive functions by inhibiting ERK/STAT3 signalling pathway in a model of Alzheimer's disease. https://doi.org/10.1101/2024.05.20.594921

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