Akt at the crossroads of microglial function: a double-edged sword in Alzheimer's disease neuroinflammation

Alzheimer's disease (AD) pathology is increasingly understood to be driven by complex neuroinflammatory processes, with microglia-the resident immune cells of the brain playing a pivotal role. The PI3K/Akt signaling pathway serves as a critical intracellular hub, orchestrating the diverse and often opposing functions of microglia. This review synthesizes current insights into the multifaceted role of Akt signaling in modulating microglial activity in the context of AD. We explore the dualistic nature of Akt, which can promote pro-inflammatory neurotoxicity through pathways such as NF-κB while simultaneously mediating neuroprotective functions, including anti-inflammatory resolution, amyloid-β (Aβ) phagocytosis, and regulation of key clearance receptors like triggering receptor expressed on myeloid cells 2 (TREM2). Additionally, we examine how the Akt/mTOR axis governs microglial immunometabolism, facilitating the transition between glycolytic, pro-inflammatory states and oxidative phosphorylation-driven, phagocytic phenotypes. Emerging therapeutic strategies are discussed, including natural compounds, pharmacological agents, indirect modulation via the gut-brain axis and physical brain stimulation, as well as advanced nanotechnology platforms designed to target this pathway in microglia with precision. Finally, we address key challenges such as isoform specificity, therapeutic timing, and translational relevance, and outline future perspectives aimed at achieving "precision immunomodulation" of the Akt pathway. Such fine-tuning of microglial function represents a promising yet complex avenue for developing effective therapies to combat AD.