Synaptic activity protects against AD and FTD-like pathology via autophagic-lysosomal degradation
| Autor: | Elena Alberdi, Thomas Vaccari, D Tampellini, Estibaliz Capetillo-Zarate, Carlos Matute, Elise Gondard, Amandeep Mann, S Marty, E E Baulieu, Andres M. Lozano, Y Akwa |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male Deep brain stimulation medicine.medical_treatment Deep Brain Stimulation Tau protein Hippocampus Stimulation Mice Transgenic tau Proteins Article 03 medical and health sciences Cellular and Molecular Neuroscience Mice 0302 clinical medicine Alzheimer Disease mental disorders medicine Autophagy Dementia Animals Humans Molecular Biology Amyloid beta-Peptides biology Chemistry Brain medicine.disease Psychiatry and Mental health Disease Models Animal 030104 developmental biology Neuroprotective Agents Tauopathies Frontotemporal Dementia Synapses biology.protein Female Alzheimer's disease Lysosomes Neuroscience 030217 neurology & neurosurgery Frontotemporal dementia |
| Zdroj: | Molecular psychiatry |
| ISSN: | 1476-5578 |
| Popis: | 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 (Aβ), 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 buildup 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. |
| Databáze: | OpenAIRE |
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