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Minocycline attenuates Aβ oligomers-induced pro-inflammatory phenotype in primary microglia while enhancing Aβ
Ismail Amr El-Shimy1, Ola Ahmed Heikal2, Nabila Hamdi1
1Department of Pharmacology and Toxicology, Faculty of Pharmacy and Biotechnology, The German University in Cairo, New Cairo City, Cairo, Egypt.
Abstract:
Microglia, the brain innate immune cells, are activated in response to amyloid beta (Aβ) resulting in neuroinflammation in AD brains. Recently, two phenotypes have been described for microglia: the pro-inflammatory classical and the anti-inflammatory alternative. Changes in microglia phenotype that control their phagocytic function are yet to be determined. The highly neurotoxic Aβ oligomers (oAβ) formed at an early disease stage induce pro-inflammatory microglia activation releasing neurotoxic mediators and contributing to neurodegeneration. A novel strategy for AD treatment is to attenuate microglia-induced inflammation while maintaining efficient Aβ clearance. Minocycline effectively crosses the blood-brain barrier and has widely reported neuroprotective effects. Yet, its exact mechanism of neuroprotection and its effects on microglia are still unknown. The aim of this study is to investigate the effect of minocycline on the phagocytic uptake of fAβ by primary microglia in relation to their activation state in an inflammatory milieu generated by oAβ or LPS. The study shows that minocycline is able to attenuate oAβ-induced neuroinflammatory response of microglia by inhibiting their pro-inflammatory phenotype activation. In addition, a significant enhancement of fAβ phagocytosis by minocycline- treated microglia is reported for the first time, providing novel insight into its neuroprotective role in AD.
Insights
Minocycline reduces neuroinflammation by inhibiting pro-inflammatory microglia activation in Alzheimer's disease (AD). It also enhances amyloid-beta (Aβ) clearance, offering a novel therapeutic strategy for AD.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Microglia, the brain's immune cells, become pro-inflammatory in Alzheimer's disease (AD) due to amyloid-beta (Aβ) exposure, contributing to neurodegeneration.
- Minocycline is a potential therapeutic agent for AD, but its precise neuroprotective mechanisms, particularly its effects on microglia, remain unclear.
Purpose of the Study:
- To investigate how minocycline affects microglia's phagocytic activity and activation state in an inflammatory environment relevant to AD.
- To determine if minocycline can modulate the pro-inflammatory response of microglia to amyloid-beta oligomers (oAβ) and lipopolysaccharide (LPS).
Main Methods:
- Primary microglia were cultured and exposed to inflammatory stimuli (oAβ or LPS) with or without minocycline.
- Microglia activation states and phagocytic uptake of fibrillar Aβ (fAβ) were analyzed.
Main Results:
- Minocycline significantly attenuated the oAβ-induced pro-inflammatory activation of microglia.
- For the first time, this study demonstrated that minocycline enhances the phagocytic uptake of fAβ by microglia.
- Minocycline treatment shifted microglia away from a pro-inflammatory phenotype.
Conclusions:
- Minocycline exhibits neuroprotective effects in AD by reducing neuroinflammation and enhancing Aβ clearance.
- Minocycline's ability to modulate microglia phenotype and function offers a promising therapeutic avenue for Alzheimer's disease.
