Age-dependent changes in synaptic plasticity enhance tau oligomerization in the mouse hippocampus

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• Phosphorylated tau aggregation is a key target for tauopathies like Alzheimer's disease, but the aggregation mechanism remains unclear.
• Tau phosphorylation influences AMPA receptor trafficking, which is associated with synaptic long-term depression (LTD).

Purpose of the Study:

• To investigate the effect of LTD-inducing low-frequency stimulation (LFS) on pathological tau aggregate formation in adult and aged wild-type mice.
• To explore the role of the autophagy-lysosomal pathway (ALP) in age-dependent tau aggregation.

Main Methods:

• Biochemical analysis of tau aggregates (sarkosyl-insoluble oligomers).
• Electrophysiological recordings to assess LTD and ALP contribution.
• Analysis of LC3 ratio (autophagosome formation indicator).
• Pharmacological inhibition/prevention of autophagy and lysosomal function.

Main Results:

• LFS induced sarkosyl-insoluble tau oligomers in aged, but not adult, mouse hippocampi.
• Aging increased the ALP's contribution to LFS-induced LTD.
• LFS potentiated the ALP in aged hippocampi, indicated by increased LC3 type II.
• Inhibiting autophagosome formation reduced LFS-induced tau oligomerization.
• Lysosomal dysfunction enhanced LFS-induced tau oligomer formation, promoting fibrillar aggregates.

Conclusions:

• The autophagy-lysosomal pathway (ALP) plays a critical role in the age-dependent, LFS-induced oligomerization of tau.
• LFS-induced LTD in aged neurons involves an enhanced ALP, contributing to pathological tau aggregate formation.
• Lysosomal dysfunction exacerbates tau aggregation, suggesting therapeutic targets for tauopathies.