Figure 1.

Molecular mechanisms underlying neurovascular tau toxicity in AD and other tauopathies. Neuronal transmission through (1) tunneling nanotubes (TNTs), (2) exosomes, (3) ectosomes, or (4) plasma membrane may account for extracellular tau, which can be internalized by neighboring neurons via (5) low-density lipoprotein receptor (LRP), (6) clathrin-mediated endocytosis, (7) micropinocytosis by heparin sulfate proteoglycans, or (1) TNTs. Tau is also detected in brain interstitial fluids, cerebrospinal fluid (CSF) and in blood, reflecting the intensity of neurodegeneration. Inside the neuron, hyperphosphorylated tau promotes microtubules disassembly, aggregates into oligomers and paired helical filaments (PHF) which, in turn, accumulate, leading to neurofibrillary tangles (NFT) deposition. Phosphorylated tau can interact with mitochondrial proteins, such as Drp1, triggering excessive mitochondrial fission and mitochondrial dysfunction, including elevated ROS production, Ca²⁺ homeostasis dysregulation, decreased ATP production, and ultimately caspase activation. Caspase-3 cleaved tau facilitates tau phosphorylation and self-aggregation, further exacerbating tau pathology. Tau can propagate to astrocytes and microglia, and be internalized via micropinocytosis and CX3CR1, respectively. In astrocytes, the accumulation of tau fibrils around the nucleus confers the characteristic tufted phenotype. Tau pathological species, through astrocytic end-feet and interstitial fluids, may spread to endothelial cells and pericytes, inducing blood brain barrier (BBB) disruption and permeability to blood-borne components, including peripheral blood monocyte-derived macrophages (PB-MoM), immunoglubulins (IgGs and IgMs), and α2-macroglobulin (α2M). Moreover, the presence of tau within glial cells induces the secretion of several pro-inflammatory cytokines and chemokines, such as IL-1β,−6, - 8,−10, IFNγ, and MCP-1, initiating a high inflammatory state, which contributes to BBB integrity loss.