Phosphoinositides signaling modulates microglial actin remodeling and phagocytosis in Alzheimer’s disease

Abstract

Alzheimer’s disease is one of the neurodegenerative diseases, characterized by the accumulation of abnormal protein deposits, which disrupts signal transduction in neurons and other glia cells. The pathological protein in neurodegenerative diseases, Tau and amyloid-β contribute to the disrupted microglial signaling pathways, actin cytoskeleton, and cellular receptor expression. The important secondary messenger lipids i.e., phosphatidylinositols are largely affected by protein deposits of amyloid-β in Alzheimer’s disease. Phosphatidylinositols are the product of different phosphatidylinositol kinases and the state of phosphorylation at D3, D4, and D5 positions of inositol ring. Phosphatidylinositol 3,4,5-triphosphate (PI 3, 4, 5-P3) involves in phagocytic cup formation, cell polarization, whereas Phosphatidylinositol 4,5-bisphosphate (PI 4, 5-P2)-mediates the process of phagosomes formation and further its fusion with early endosome.. The necessary activation of actin-binding proteins such as Rac, WAVE complex, and ARP2/3 complex for the actin polymerization in the process of phagocytosis, migration is regulated and maintained by PI 3, 4, 5-P3 and PI 4, 5-P2. The ratio and types of fatty acid intake can influence the intracellular secondary lipid messengers along with the cellular content of phaphatidylcholine and phosphatidylethanolamine. The Amyloid-β deposits and extracellular Tau seeds disrupt phosphatidylinositides level and actin cytoskeletal network that hamper microglial-signaling pathways in AD. We hypothesize that being a lipid species intracellular levels of phosphatidylinositol would be regulated by dietary fatty acids. Further we are interested to understand phosphoinositide-based signaling cascades in phagocytosis and actin remodeling.

Astrocytic function is associated with both amyloid-β and tau pathology in non-dementedAPOE ϵ4carriers

“…For example, mIns plays an important role in various cellular processes as the structural basis for secondary messengers, including inositol triphosphates and phosphatidylinositol phosphate lipids 44 which are involved in phagocytosis. 45 Therefore, different levels of mIns could reflect a deficit in the clearing system of protein aggregates.…”

The PH Domain and C-Terminal polyD Motif of Phafin2 Exhibit a Unique Concurrence in Animals

“…Other predicted Phafin2-associated proteins are involved in functions outside of autophagy. For example, PIKFYVE participates in endosomal cargo transport, endomembrane homeostasis, and lysosomal trafficking [ 131 , 132 ]. This prediction is in line with early work on Phafin2’s function, in which the protein was associated with cargo trafficking and endosomal and lysosomal function [ 5 , 11 ].…”

The versatile regulation of K2P channels by polyanionic lipids of the phosphoinositide (PIP2) and fatty acid metabolism (LC-CoA)

“…Despite its expression in many regions of the CNS the specific role of THIK-1 channels is currently unknown with the exception of microglial cells, where THIK-1 activation was shown to be involved in microglial immune surveillance und inflammatory cytokine release (Madry et al, 2018). Interestingly, PIP 2 production in microglia has been reported to play a key role in immune response signalling (Nguyen et al, 2017; Desale and Chinnathambi, 2021), and thus, possibly involves PIP 2 activation of THIK-1.…”