Tau-Driven Neurovascular-Metabolic Coupling in Alzheimer's Disease: Shared Signalling Hubs Linking Blood-Brain Barrier Breakdown and Cerebral Insulin Resistance

Alzheimer's disease (AD) is increasingly recognized as a disorder in which tau pathology, vascular dysfunction, and metabolic impairment are not separate events but rather interconnected components of a single, self-reinforcing cascade. Tau, long studied for its role in neurofibrillary pathology, is now recognized as an active driver of damage at the neurovascular unit, the interface where endothelial cells, pericytes, and astrocytes maintain the blood-brain barrier (BBB) and regulate the transport and signaling of insulin into the brain. Critically, the injury induced by tau appears to be mediated through a small number of shared signaling hubs that couple vascular breakdown to metabolic failure.Two such hubs are emerging as central. Recent studies indicate that pathogenic forms of tau activate RhoA/ROCK signaling, leading to alterations in endothelial cell mechanics and disruption of the blood–brain barrier (BBB). The same pathway also impairs insulin signaling by promoting the serine phosphorylation of IRS-1, a hallmark of insulin resistance. In parallel, cytosolic phospholipase A2 (cPLA2) directly links tau pathology to cerebral insulin resistance while also disrupting the BBB and promoting neuroinflammation. In both cases, a single tau-triggered mechanism simultaneously affects both the vascular and metabolic pathways rather than influencing only one process.This convergence reframes the problem. BBB breakdown, neuroinflammation, and cerebral insulin resistance can be viewed as downstream consequences of tau-driven signaling at the neurovascular unit, each feeding back to exacerbate tau pathology in a vicious cycle. Yet the biochemical, biomechanical, and molecular mechanisms underlying this coupling remain incompletely understood, and their translation into actionable therapeutic targets is still at an early stage. Understanding the shared signaling hubs that connect these processes offers a route to interventions capable of targeting multiple arms of the disease simultaneously rather than isolated pathological features.This Research Topic aims to define the convergent, tau-driven mechanisms that couple BBB breakdown to cerebral insulin resistance in AD and to translate these insights into novel therapeutic targets. Rather than treating tau pathology, vascular dysfunction, and metabolic impairment as separate problems, we seek work that identifies the shared signalling hubs and biomechanical processes linking them at the neurovascular unit. We particularly welcome studies that dissect mechanisms such as pathogenic forms of tau-driven RhoA/ROCK signalling in endothelial damage and IRS-1 disruption, cPLA2- and lipid signalling-mediated crosstalk between tau pathology and insulin resistance, and the feedback loops through which vascular and metabolic dysfunction amplify tau pathology. Contributions that identify and validate targets acting across multiple disease pathways, establish screening platforms and disease models that capture this coupling, and evaluate candidate interventions are strongly encouraged. By integrating mechanistic discoveries across the vascular, metabolic, and cytoskeletal domains, this collection seeks to define the next phase of therapeutic screening for Alzheimer's disease.We invite contributions spanning molecular, cellular, biomechanical, and translational research on the tau-driven coupling of neurovascular and metabolic dysfunction in Alzheimer's disease. Topics of interest include, but are not limited to:• Shared signaling hubs (e.g., RhoA/ROCK and cPLA2) linking tau pathology to vascular and metabolic dysfunction• Oligomeric tau-driven RhoA/ROCK signaling in endothelial damage and BBB breakdown• cPLA2- and lipid signaling-mediated mechanisms linking tau pathology and cerebral insulin resistance• IRS-1 disruption and the mechanisms of cerebral insulin resistance downstream of tau • Biomechanical forces and cytoskeletal signaling in maintaining neurovascular unit integrity • Feedback loops through which BBB breakdown and metabolic dysfunction amplify tau pathology• Neuroinflammation at the tau–vascular–metabolic interface• Discovery and validation of therapeutic targets acting across multiple disease pathways• Cellular, molecular, and animal models that capture tau-driven neurovascular-metabolic coupling• Screening platforms, biomarkers, and candidate interventions targeting shared disease driversWe encourage a wide range of submissions, including original research, methods papers, brief research reports, data reports, systematic reviews, mini reviews, and perspectives. Topic editors: Faruk Hossen, M.Sc., PhD., Grzegorz Walkiewicz, Chao Zheng, Roberto Guzman-Hernandez Source: https://www.frontiersin.org/research-topics/86193/tau-driven-neurovascular-metabolic-coupling-in-alzheimers-disease-shared-signalling-hubs-linking-blood-brain-barrier-breakdown-and-cerebral-insulin-resistance