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Neurological disorders impact around one billion individuals globally (15 % approx.), with significant implications for disability and mortality with their impact in Australia currently amounts to 6.8 million deaths annually. Heparan sulfate proteoglycans (HSPGs) are complex extracellular molecules implicated in promoting Tau fibril formation resulting in Tau tangles, a hallmark of Alzheimer's disease (AD). HSPG-Tau protein interactions contribute to various AD stages via aggregation, toxicity, and clearance, largely via interactions with the glypican 1 and syndecan 3 core proteins. The tunnelling nanotubes (TNTs) pathway is emerging as a facilitator of intercellular molecule transport, including Tau and Amyloid β proteins, across extensive distances. While current TNT-associated evidence primarily stems from cancer models, their role in Tau propagation and its effects on recipient cells remain unclear. This review explores the interplay of TNTs, HSPGs, and AD-related factors and proposes that HSPGs influence TNT formation in neurodegenerative conditions such as AD. [Display omitted] • HSPGs in Neural Dynamics: Syndecan 1, 4, and glypican 4 regulate healthy and diseased neural cells. • HSPGs in Protein Aggregation: Implicated in Tau fibrils/seeds and senile tangles/seeds formation. • TNTs as Pathological Bridges: Facilitate spread of Tau tangles/seeds and amyloid plaques/seeds. • HSPGs Regulate TNT Formation: Syndecan 1 and 4 influence TNT formation via Wnt and AKT pathways. • Therapeutic Potential: Targeting HSPGs and/or TNTs offers new Alzheimer's treatments. [ABSTRACT FROM AUTHOR]