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Synaptic activity protects against AD and FTD-like pathology via autophagic-lysosomal degradation.
- Source :
-
Molecular psychiatry [Mol Psychiatry] 2018 Jun; Vol. 23 (6), pp. 1530-1540. Date of Electronic Publication: 2017 Jul 11. - Publication Year :
- 2018
-
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.
- Subjects :
- Amyloid beta-Peptides metabolism
Animals
Autophagy physiology
Brain metabolism
Deep Brain Stimulation methods
Disease Models, Animal
Female
Frontotemporal Dementia metabolism
Hippocampus pathology
Humans
Lysosomes metabolism
Male
Mice
Mice, Transgenic
Neuroprotective Agents metabolism
tau Proteins physiology
Alzheimer Disease metabolism
Synapses metabolism
Tauopathies metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5578
- Volume :
- 23
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Molecular psychiatry
- Publication Type :
- Academic Journal
- Accession number :
- 28696431
- Full Text :
- https://doi.org/10.1038/mp.2017.142