Unraveling novel mechanisms of ATP-Binding cassette (ABC) transporter in insulin Resistance-induced amyloidogenesis.

Insulin resistance (IR) impairs glucose uptake and metabolism, whereas amyloidogenesis, the formation of abnormal protein aggregation, forming insoluble fibrils called amyloids, which are linked with numerous neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD), Huntington disease's (HD), Parkinson's disease (PD) and Prion's disease. This review explores how IR promotes amyloidogenesis by disrupting cholesterol homeostasis and enhancing Amyloid beta (Aβ) production and aggregation. Specifically, we examine the role of ATP-binding cassette (ABC) transporters in cholesterol homeostasis along with their impact on insulin signaling pathways, highlights how their dysregulation can lead to IR, a significant contributor to the development of amyloidogenesis, a key factor in causing NDDs. We explore the novel molecular mechanisms linking IR and Aβ aggregation, focusing on the interplay between ABC transporters and Amyloid precursor protein (APP) processing. Furthermore, we also explore emerging evidence linking ABC transporters to oxidative stress, inflammation and mitochondrial dysfunction critical factors in the development of amyloidogenesis. Additionally, this review also discusses potential therapeutic strategies targeting ABC transporters to mitigate IR and reduce amyloid burden by various mechanisms including Insulin receptors/IRS-1 signaling, Phosphatidylinositol3kinase-Protein kinase-B (PI3K/AKT), Mitogen-activated protein kinases (MAPK), c-Jun N-terminal kinase (JNK), Glycogen synthase kinase 3 (GSK3), mammalian Target of Rapamycin (mTOR), Insulin-Degrading Enzyme (IDE), Advanced glycation end products (AGEs), Glucose transporters (GLUTs), Apolipoprotein E (ApoE), Peroxisome proliferator-activated receptors (PPARs), Adiponectin, Mitochondrial dysfunctioning, AMP-activated protein kinase (AMPK) Wingless-related integration site/beta-catenin (Wnt/β-catenin) and Sirtuin1 (SIRT1). These insights provide new possibilities for developing targeted therapies against neurodegenerative diseases associated with IR and amyloid accumulation.