Neuronal expression of pathological tau accelerates oligodendrocyte progenitor cell differentiation

Area of Science:

• Neuroscience
• Cell Biology
• Pathology

Background:

• Oligodendrocyte progenitor cell (OPC) differentiation is crucial for remyelination in multiple sclerosis (MS).
• Pathological tau, hyperphosphorylated and aggregated, is found in MS lesions and linked to axonal degeneration.
• The impact of tau-induced axonal damage on OPC differentiation and remyelination potential remains unclear.

Purpose of the Study:

• To investigate the influence of pathological tau on OPC differentiation and remyelination following demyelination.
• To explore the mechanisms behind tau's effect on OPCs in vivo and in vitro.

Main Methods:

• Utilized human P301S tau transgenic mice (P301S-htau) and wild-type (Wt) littermates.
• Assessed OPC differentiation in vivo after focal white matter demyelination.
• Conducted in vitro differentiation assays using OPCs isolated from P301S-htau and Wt mice.
• Analyzed axonal integrity, microgliosis, and inflammatory markers (IL-1β, TNFα).

Main Results:

• P301S-htau mice exhibited atrophic axons and microgliosis with elevated IL-1β and TNFα.
• OPCs differentiated more efficiently in P301S-htau mice following in vivo demyelination.
• In vitro, OPCs from P301S-htau mice showed enhanced differentiation capacity.
• Despite increased OPC differentiation, remyelination was limited by higher axonal susceptibility to degeneration in P301S-htau mice.
• Enhanced OPC differentiation was attributed to microenvironmental priming, not transgene expression in OPCs.

Conclusions:

• Damaged axons, influenced by pathological tau, may signal to OPCs, promoting their differentiation.
• This microenvironmental priming enhances OPC differentiation capacity, suggesting an intrinsic attempt at axonal rescue via remyelination.
• While OPCs are primed for differentiation, the overall remyelination outcome is compromised by increased axonal vulnerability in the pathological tau environment.