2-Hydroxypropyl-beta-cyclodextrin exacerbates tau pathology in a mouse model of tauopathy: implication of the pathological role of cholesteryl ester

초록

Abnormal accumulation of tau aggregates is a pathological hallmark of Alzheimer’s disease (AD) and other tauopathies. In AD, the sequential spreading of tau aggregation throughout the brain is strongly correlated with disease progression. Accumulating evidence suggests that intracellular aggregation and trans-cellular propagation of pathological tau are key pathological events underlying the spreading of tau pathology. Accumulating evidence strongly suggest that the disruption of lipid homeostasis is closely linked to AD pathologies, in particular dysregulation of cholesterol. Several evidence reported that cyclodextrin (CD), a cyclic oligosaccharide compounds widely used cholesterol depleting agent, reduces amyloid beta plaque in AD mouse model and insoluble alpha synuclein in cell model. Although increasing evidence suggests the pathological link between cholesterol metabolism and tauopathy, the detail mechanisms remain elusive. In the current study, we investigated the effect of cholesterol on tauopathy in PS19 transgenic mice expressing P301S mutant human tau by injecting 2-Hydroxypropyl-beta-cyclodextrin (HP-CD). Unexpectedly, HP-CD dramatically promoted pathological tau accumulation and neurodegeneration in the hippocampus. We further showed that the changes in cholesterol level in the various organs including blood plasma, liver, and brain. Interestingly, cholesteryl ester (CE) was increased by HP-CD in liver and brain cytosol. Recently, it has been reported that CE is accumulated in the brains of AD patients and AD mouse models, and CE increases tau phosphorylation. Based on these results, we hypothesized that increased cytoplasmic CE might exacerbate tau pathology. To confirm this hypothesis, we tested the effect of K604, the Acat1 inhibitor, in a seed-dependent tau aggregation cell model. Here, we found that K604 decreased tau aggregation and both Thioflavin S and AT8-positive cells in neuronal cell of tauopathy. Our data suggest that CE is a strong modulator of tauopathy.