The role of sulfatide in the development of tauopathy in the context of ADRD

Alzheimer’s disease (AD) and its related dementias (ADRD) are the most common type of dementia in the aging population without effective therapy to delay its onset and/or progression. Sulfatide (ST), a key myelin lipid component, is specifically synthesized in oligodendrocytes (OLGs) in the CNS by cerebroside sulfotransferase (CST). Our previous/preliminary studies have revealed a causal association between ST loss and increased Tau phosphorylation (pTau). We showed that: 1. ST levels are markedly reduced at very early stages of AD and under multiple AD risk conditions; 2. brain ST is transported by apoE particles in an isoform-dependent manner (the lowest in the brains of apoE4 carriers); 3. the degree of pTau is inversely correlated with ST mass in human apoE knockin (KI) mice; 4. Aβ accelerates ST loss, whereas the loss of hydroxy-containing ST (OH-ST) is more rapid than non-OH-ST (NOH-ST) in all examined AD models; 5. ST loss in CST constitutive (CST-/-) and conditional (CSTfl/fl/Plp1-CreERT, referred to as CST cKO) knockout mice leads to increased pTau at multiple sites and abnormal accumulation within OLG cell bodies; 6. Mapt (highly expressed not only in neurons, but also in OLGs) and multiple genes encoding tau kinases are markedly upregulated in OLGs of CST cKO mice as uncovered by snRNAseq; 7. Fa2h (coding for fatty acid 2-hydroxylase) is drastically upregulated in CST KO mice and AD brains, while myelinating glial FA2H cKO mice display a marked loss of total ST and depleted OH-ST; and 8. expression of multiple myelin and lipid metabolism genes is significantly altered in OLGs of CST cKO mice. These lines of evidence led us to hypothesize that ST loss leads to increased pTau and tauopathy in OLGs, and accelerates tau seeding, spreading, and aggregation in ADRD. Further, it has been well established that lipid rafts in OLGs play a crucial role in cellular cytoskeleton stability and integrity to regulate myelin formation and maintenance, and sphingolipids are essential components of lipid rafts. Previous studies reported that the upregulation of Mapt and altered expression of the genes involved in myelin lipid synthesis and metabolism are manifest in OLGs of AD subjects as revealed by snRNAseq. These studies, along with our new findings led us to hypothesize that disruption of OLG lipid rafts induced by ST loss is a key driver of increased pTau and then tauopathy in OLGs in ADRD. Our Specific Aims to test the hypotheses include (1) To extensively investigate if ST deficiency leads to increased human tau phosphorylation, accumulation, and aggregation in OLGs; (2) To systematically determine the role of OLG tau and ST content in tau seeding, spreading, and aggregation; (3) To identify whether ST deficiency-induced disruption of OLG lipid rafts is a key driver of increased pTau and tauopathy in OLGs; and (4) To determine if restoring brain ST content ameliorates tauopathy in the context of ADRD. This proposal is the first to address the knowledge gap of when, where, and how enhanced pTau occurs following ST loss. The rigor of this proposal is built upon our new findings, and various novel animal models. If our hypothesis is borne out, this work will provide a novel path to develop drug strategies for treatment of AD.