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Review

Microglia-Mediated Neuroinflammation Through Phosphatidylinositol 3-Kinase Signaling Causes Cognitive Dysfunction

by
Mohammad Nazmul Hasan Maziz
1,
Srikumar Chakravarthi
2,
Thidar Aung
3,
Phone Myint Htoo
4,
Wana Hla Shwe
5,
Sergey Gupalo
6,
Manglesh Waran Udayah
1,
Hardev Singh
1,
Mohammed Shahjahan Kabir
4,
Rajesh Thangarajan
4 and
Maheedhar Kodali
7,*
1
School of Medicine, Perdana University, Damansara Heights, Kuala Lumpur 50490, Malaysia
2
Faculty of Medicine, Nursing and Health Sciences, SEGi University, Kota Damansara Campus, Petaling Jaya 47810, Selangor, Malaysia
3
Department of Pathology, Manipal University College Malaysia, Persimpangan Batu Hampar, Bukit Baru, Melaka 75150, Malaysia
4
International Medical School, Management and Science University, Shah Alam 40100, Selangor, Malaysia
5
Faculty of Medicine and Health Sciences, UCSI University, Springhill, Port Dickson 71010, Negeri Sembilan, Malaysia
6
Saint James School of Medicine Anguilla, 6X75+64G A-1, Albert Lake Dr, The Quarter 2640, Anguilla
7
Department of Cell Biology and Genetics, Texas A&M Health Science Center, College of Medicine, College Station, TX 77843, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2025, 26(15), 7212; https://doi.org/10.3390/ijms26157212
Submission received: 12 June 2025 / Revised: 16 July 2025 / Accepted: 21 July 2025 / Published: 25 July 2025
(This article belongs to the Special Issue Therapeutics and Pathophysiology of Cognitive Dysfunction)
Review Reports Versions Notes

Abstract

Microglia, as the immune guardians of the central nervous system (CNS), have the ability to maintain neural homeostasis, respond to environmental changes, and remodel the synaptic landscape. However, persistent microglial activation can lead to chronic neuroinflammation, which can alter neuronal signaling pathways, resulting in accelerated cognitive decline. Phosphoinositol 3-kinase (PI3K) has emerged as a critical driver, connecting inflammation to neurodegeneration, serving as the nexus of numerous intracellular processes that govern microglial activation. This review focuses on the relationship between PI3K signaling and microglial activation, which might lead to cognitive impairment, inflammation, or even neurodegeneration. The review delves into the components of the PI3K signaling cascade, isoforms, and receptors of PI3K, as well as the downstream effects of PI3K signaling, including its effectors such as protein kinase B (Akt) and mammalian target of rapamycin (mTOR) and the negative regulator phosphatase and tensin homolog (PTEN). Experiments have shown that the overproduction of certain cytokines, coupled with abnormal oxidative stress, is a consequence of poor PI3K regulation, resulting in excessive synapse pruning and, consequently, impacting learning and memory functions. The review also highlights the implications of autonomously activated microglia exhibiting M1/M2 polarization driven by PI3K on hippocampal, cortical, and subcortical circuits. Conclusions from behavioral studies, electrophysiology, and neuroimaging linking cognitive performance and PI3K activity were evaluated, along with new approaches to therapy using selective inhibitors or gene editing. The review concludes by highlighting important knowledge gaps, including the specific effects of different isoforms, the risks associated with long-term pathway modulation, and the limitations of translational potential, underscoring the crucial role of PI3K in mitigating cognitive impairment driven by neuroinflammation.
Keywords: microglia; PI3K signaling; neuroinflammation; cognitive dysfunction; cytokine release; synaptic plasticity; Akt-mTOR pathway; neurodegeneration microglia; PI3K signaling; neuroinflammation; cognitive dysfunction; cytokine release; synaptic plasticity; Akt-mTOR pathway; neurodegeneration

Share and Cite

MDPI and ACS Style

Maziz, M.N.H.; Chakravarthi, S.; Aung, T.; Htoo, P.M.; Shwe, W.H.; Gupalo, S.; Udayah, M.W.; Singh, H.; Kabir, M.S.; Thangarajan, R.; et al. Microglia-Mediated Neuroinflammation Through Phosphatidylinositol 3-Kinase Signaling Causes Cognitive Dysfunction. Int. J. Mol. Sci. 2025, 26, 7212. https://doi.org/10.3390/ijms26157212

AMA Style

Maziz MNH, Chakravarthi S, Aung T, Htoo PM, Shwe WH, Gupalo S, Udayah MW, Singh H, Kabir MS, Thangarajan R, et al. Microglia-Mediated Neuroinflammation Through Phosphatidylinositol 3-Kinase Signaling Causes Cognitive Dysfunction. International Journal of Molecular Sciences. 2025; 26(15):7212. https://doi.org/10.3390/ijms26157212

Chicago/Turabian Style

Maziz, Mohammad Nazmul Hasan, Srikumar Chakravarthi, Thidar Aung, Phone Myint Htoo, Wana Hla Shwe, Sergey Gupalo, Manglesh Waran Udayah, Hardev Singh, Mohammed Shahjahan Kabir, Rajesh Thangarajan, and et al. 2025. "Microglia-Mediated Neuroinflammation Through Phosphatidylinositol 3-Kinase Signaling Causes Cognitive Dysfunction" International Journal of Molecular Sciences 26, no. 15: 7212. https://doi.org/10.3390/ijms26157212

APA Style

Maziz, M. N. H., Chakravarthi, S., Aung, T., Htoo, P. M., Shwe, W. H., Gupalo, S., Udayah, M. W., Singh, H., Kabir, M. S., Thangarajan, R., & Kodali, M. (2025). Microglia-Mediated Neuroinflammation Through Phosphatidylinositol 3-Kinase Signaling Causes Cognitive Dysfunction. International Journal of Molecular Sciences, 26(15), 7212. https://doi.org/10.3390/ijms26157212

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