This hypothesis proposes that upregulating SULF1/SULF2 sulfatase activity provides dual neuroprotection by simultaneously blocking extracellular tau uptake and preserving intracellular cholinergic function. The molecular mechanism centers on SULF1/SULF2's ability to remove 6-O-sulfate groups from heparan sulfate proteoglycan chains, disrupting the high-affinity binding sites required for pathological tau aggregate uptake by cholinergic neurons. Cholinergic neurons in the nucleus basalis of Meynert and medial septal complex are particularly vulnerable targets due to their extensive axonal projections and high metabolic demands for acetylcholine synthesis. Under normal conditions, these neurons maintain robust anterograde transport of choline acetyltransferase (ChAT), vesicular acetylcholine transporter (VAChT), and high-affinity choline transporter (CHT1) to synaptic terminals while supporting retrograde transport of neurotrophic signaling complexes including BDNF-TrkB and NGF-TrkA.

This hypothesis proposes that upregulating SULF1/SULF2 sulfatase activity provides dual neuroprotection by simultaneously blocking extracellular tau uptake and preserving intracellular cholinergic function. The molecular mechanism centers on SULF1/SULF2's ability to remove 6-O-sulfate groups from heparan sulfate proteoglycan chains, disrupting the high-affinity binding sites required for pathological tau aggregate uptake by cholinergic neurons. Cholinergic neurons in the nucleus basalis of Meynert and medial septal complex are particularly vulnerable targets due to their extensive axonal projections and high metabolic demands for acetylcholine synthesis. Under normal conditions, these neurons maintain robust anterograde transport of choline acetyltransferase (ChAT), vesicular acetylcholine transporter (VAChT), and high-affinity choline transporter (CHT1) to synaptic terminals while supporting retrograde transport of neurotrophic signaling complexes including BDNF-TrkB and NGF-TrkA. However, the uptake of extracellular hyperphosphorylated tau aggregates via HSPG-mediated endocytosis initiates a cascade that disrupts microtubule stability and compromises both anterograde and retrograde axonal transport. By enhancing SULF1/SULF2 expression or enzymatic activity, the 6-O-sulfated HSPG binding motifs are enzymatically eliminated, preventing tau aggregate recognition and cellular entry. This protection preserves the microtubule network integrity essential for cholinergic neurotransmitter synthesis and transport, maintaining cholinergic innervation to hippocampal and cortical regions critical for memory formation and cognitive function.