Characterization of the brain lipidome associated with frontotemporal lobar degeneration MAPT P301S mutation

Mutations in microtubule-associated protein Tau (MAPT), the gene that codes for the protein Tau, cause frontotemporal lobar degeneration (FTLD) with phenotypes ranging from behavioral changes to cognitive impairment and parkinsonism. Recently, lipid changes have been heavily implicated in synucleinopathies and secondary tauopathies such as Alzheimer's disease. Whether mutations in MAPT or accumulation of hyperphosphorylated Tau (pTau) can contribute to lipid changes in primary tauopathies is unknown. Here, we examine the effect of the FTLD-associated mutation MAPT P301S on brain lipid metabolism in a Tau transgenic mouse model. We find that the MAPT P301S mutation drives increased levels of diglycerides and hexosylceramides and lactosylceramides while reducing triglycerides, specifically those triglyceride species containing monounsaturated fatty acids, but does not affect cholesterol metabolism prior to pTau accumulation. Strikingly, with increasing accumulation of pTau, neutral lipids such as cholesteryl esters and triglycerides start to accumulate in the brain of mutant mice, as also reported in the Alzheimer's disease and FTLD brain. Furthermore, with increasing buildup of pTau, we observe decreased cholesterol synthesis and turnover to 24S-hydroxycholesterol. Overall our data indicates that the MAPT P301S mutation and accumulation of pTau are associated with distinct brain lipidomes in vivo.