Cholesterol determines the cytosolic entry and seeded aggregation of tau

Tuck, Benjamin J.; Miller, Lauren V. C.; Katsinelos, Taxiarchis; Smith, Annabel E; Wilson, Emily; Keeling, Sophie; Cheng, Sheue-yann; Vaysburd, Marina; Knox, Claire; Tredgett, Lucy; Metzakopian, Emmanouil; James, Leo C.; McEwan, William A.

doi:10.1016/j.celrep.2022.110776

Cited by 28 publications

(35 citation statements)

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“…Cholesterol in the plasma membrane is the main constituent of lipid rafts [ 67 ], which suggests that ApoE may regulate lipid raft-dependent endocytosis [ 68 , 69 ] and supports our finding. A recent study demonstrated that cholesterol supplementation reduces the entry of tau aggregates and almost completely blocks seeded aggregation [ 70 ], which is also similar to our observation.…”

Section: Discussionsupporting

confidence: 92%

Neuronal ApoE Regulates the Cell-to-Cell Transmission of α-Synuclein

Kang

Kim

Noh

et al. 2022

IJMS

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The presence of protein inclusions, called Lewy bodies (LBs) and Lewy neurites (LNs), in the brain is the main feature of Parkinson’s disease (PD). Recent evidence that the prion-like propagation of α-synuclein (α-syn), as a major component of LBs and LNs, plays an important role in the progression of PD has gained much attention, although the molecular mechanism remains unclear. In this study, we evaluated whether neuronal ApoE regulates the cell-to-cell transmission of α-syn and explored its molecular mechanism using in vitro and in vivo model systems. We demonstrate that neuronal ApoE deficiency attenuates both α-syn uptake and release by downregulating LRP-1 and LDLR expression and enhancing chaperone-mediated autophagy activity, respectively, thereby contributing to α-syn propagation. In addition, we observed that α-syn propagation was attenuated in ApoE knockout mice injected with pre-formed mouse α-syn fibrils. This study will help our understanding of the molecular mechanisms underlying α-syn propagation.

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Section: Discussionsupporting

confidence: 92%

Neuronal ApoE Regulates the Cell-to-Cell Transmission of α-Synuclein

Kang

Kim

Noh

et al. 2022

IJMS

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“…Even before amyloid beta deposits appear in the brain, endocytic pathway abnormalities such as Rab5-positive early endosome enlargement, phagocytic vacuole accumulation and defects in lysosomes have been described (Cataldo et al, 2004; Cataldo et al, 2000; Kunkle et al, 2017). Indeed, a recent report indicates that cholesterol depletion, in association with vesicle trafficking defects, promotes cytosolic entry of tau aggregates (Tuck et al, 2022). Our results add a new mechanistic consideration to the role of vesicle trafficking as mediator of tauopathy via effects on cytoplasmic seeding.…”

Section: Discussionmentioning

confidence: 99%

Tau seeds translocate across the cell membrane to initiate aggregation

Dodd

LaCroix

Valdez

et al. 2022

Preprint

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Neurodegenerative tauopathies, including Alzheimer’s disease and related disorders, are caused by intracellular aggregation of tau protein in ordered assemblies. Experimental evidence suggests that tau assemblies propagate pathology across brain networks. Tau seeds enter cells through endocytosis but must access the cytoplasm to serve as templates for their own replication. The mechanism by which this occurs is unknown. To study tau uptake, we began with a whole-genome CRISPR knockout screen, which indicated a requirement vacuolar H+ ATPase (v-ATPase) components. Treatment with Bafilomycin A1, an inhibitor of the v-ATPase, also reduced tau entry. We next tested direct modifiers of endolysosomal trafficking. Dominant-negative Rab5a expression uniquely decreased tau uptake, as did temporary cold temperature during tau exposure, consistent with a primary role of endocytosis in tau uptake. However, despite reducing tau uptake, these interventions all paradoxically increased intracellular seeding. Consequently, we generated giant plasma membrane vesicles (GPMVs), which cannot undergo endocytosis, and observed that tau fibrils and monomer translocated into the vesicles, in addition to TAT peptide, whereas transferrin and albumin did not. In every case, tau required binding to heparan sulfate proteoglycans (HSPGs) for cell uptake, seeding, or GPMV entry. These findings are most consistent with direct translocation of tau seeds across the lipid bilayer, a novel mechanism of entry into the cytoplasm.

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“…One interesting possibility is that the formation of tau oligomers from mutant tau might damage membranes ( Flach et al., 2012 ), and increased cholesterol biosynthesis might be a compensatory response. According to a recent report ( Tuck et al., 2022 ), such elevated membrane cholesterol might in turn protect neurons from tau spread, while cholesteryl esters, on the other hand, play a role in the formation of pathological tau ( van der Kant et al., 2019 ), highlighting the multifaceted role of cholesterol in neurodegeneration. It is also conceivable that cholesterol biosynthesis is increased by toxic tau species via stress signaling.…”

Section: Discussionmentioning

confidence: 99%