Synaptic activity protects against AD and FTD-like pathology via autophagic-lysosomal degradation - Sorbonne Université Access content directly
Journal Articles Molecular Psychiatry Year : 2017

Synaptic activity protects against AD and FTD-like pathology via autophagic-lysosomal degradation

Abstract

Changes in synaptic excitability and reduced brain metabolism are among the earliest detectable alterations associated with the development of Alzheimer's disease (AD). Stimulation of synaptic activity has been shown to be protective in models of AD beta-amyloidosis. Remarkably, deep brain stimulation (DBS) provides beneficial effects in AD patients, and represents an important therapeutic approach against AD and other forms of dementia. While several studies have explored the effect of synaptic activation on beta-amyloid, little is known about Tau protein. In this study, we investigated the effect of synaptic stimulation on Tau pathology and synapses in in vivo and in vitro models of AD and frontotemporal dementia (FTD). We found that chronic DBS or chemically induced synaptic stimulation reduced accumulation of pathological forms of Tau and protected synapses, while chronic inhibition of synaptic activity worsened Tau pathology and caused detrimental effects on pre- and post-synaptic markers, suggesting that synapses are affected. Interestingly, degradation via the proteasomal system was not involved in the reduction of pathological Tau during stimulation. In contrast, chronic synaptic activation promoted clearance of Tau oligomers by autophagosomes and lysosomes. Chronic inhibition of synaptic activity resulted in opposite outcomes, with build-up of Tau oligomers in enlarged auto-lysosomes. Our data indicate that synaptic activity counteracts the negative effects of Tau in AD and FTD by acting on autophagy, providing a rationale for therapeutic use of DBS and synaptic stimulation in tauopathies.

Dates and versions

hal-04559209 , version 1 (25-04-2024)

Identifiers

Cite

Y Akwa, E Gondard, A Mann, E Capetillo-Zarate, E Alberdi, et al.. Synaptic activity protects against AD and FTD-like pathology via autophagic-lysosomal degradation. Molecular Psychiatry, 2017, 23 (6), pp.1530-1540. ⟨10.1038/mp.2017.142⟩. ⟨hal-04559209⟩
4 View
0 Download

Altmetric

Share

Gmail Facebook X LinkedIn More