HEИндивидуална стипендия2024–2026

sleepyTau · A function for sleep-dependent tau dynamics

„Хоризонт Европа“ — Действия „Мария Склодовска-Кюри“

Период: 2024-04-01 → 2026-03-31
Финансиране от ЕС: 191 760 €
Участници: 1
Схема: HORIZON-TMA-MSCA-PF-EF

Линиите свързват координатора с партньорите.

Накратко на български

Свързаността между съня и протеина Тау се проучва чрез влиянието на охлаждането на мозъка върху неговото натрупване. Разбирането на този механизъм помага да се разбере как недостигът на сън допринася за развитието на деменция и болестта Алцхаймер.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

A function for sleep-dependent tau dynamics

Over 55 million people worldwide are living with dementia, with 10 million new diagnoses each year. The disease places an enormous burden on patients, caregivers, and healthcare systems. Dementia is multifactorial, arising from a combination of genetic and environmental factors, and one well-established environmental risk factor is poor or insufficient sleep. Accumulation of abnormal forms of the Tau protein are often found in the brain of people who are living with dementia. Tau normally stabilizes the internal skeleton of cells in the brain (neurons), but when Tau becomes excessively phosphorylated, it detaches, clumps together, and forms toxic tangles inside neurons. This toxic tangling together is a hallmark of Alzheimer's Disease, the majority of dementia cases. Sleep and Tau have a bidirectional relationship. Acute sleep loss raises extracellular Tau levels in both mice and humans, and chronic sleep deprivation accelerates Tau pathology. Paradoxically, sleep itself also triggers Tau phosphorylation. Part of the explanation may lie in brain temperature: the brain cools during sleep, and such a change in brain temperature can induce Tau phosphorylation. This project investigates whether sleep-driven brain cooling is a key mechanism linking sleep to Tau biology. Not only does sleep shape Tau dynamics, but Tau pathology is linked to disrupted sleep: it reduces deep (NREM) sleep quality and increases sleep fragmentation, as shown in both human brain imaging studies and mouse models. Tau phosphorylation also affects the brain's capacity for synaptic plasticity. Sleep loss impairs long-term potentiation (LTP), the strengthening of synaptic connections in the hippocampus, the brain's memory hub. Interestingly, pathology associated changes in Tau phosphorylation produce similar effects. This project therefore tests the central hypothesis that sleep, via its cooling effect on the brain, modulates Tau phosphorylation in a way that shapes hippocampal synaptic plasticity. Understanding the physiological role of pTau during sleep may reveal how this fundamental process tips into a disease hallmark.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

Dysfunction of protein Tau is the main cause of dementia. Dementia associates with synaptic failure and sleep disturbances, but their connection remains elusive. In dementia, Tau becomes hyperphosphorylated (p-Tau) causing synaptic loss. Temperature fluctuations also associate with Tau phosphorylation, for example in hibernating animals. Intriguingly, my work demonstrates that brain temperature decreases during sleep, and further evidence suggests there are Tau-sites phosphorylated during sleep. My hypothesis is that sleep (and temperature)-induced Tau phosphorylation drives synaptic plasticity changes during sleep. To investigate this, I will map the dynamic changes in p-Tau during sleep and then delve into the mechanisms by mimicking brain temperature changes that naturally occur during sleep in human-induced neurons and mouse primary neurons. Employing genome engineering, I will interfere with p-Tau during sleep in mice in vivo and evaluate its impact on sleep, sleep-dependent synaptic plasticity and hippocampal long-term potentiation. This research challenges the notion that p-Tau solely drives disease progression, exploring a physiological function for p-Tau in regulating synaptic plasticity during sleep. The result of this project can challenge our understanding of Tau's function and open a new therapeutic avenue: the development of sleep-wake mechanisms to reverse the pathological p-Tau state observed in dementia. With my host lab's prior track record of uncovering critical insights into Tau-induced synaptic dysfunction, it stands as the perfect platform to tackle these questions. Additionally, I find myself in an ideal position, armed with exciting preliminary data that bolsters the validity of this proposal, and a robust technical and scientific background that empowers me to embark on this ambitious research journey. The plan I propose brings us closer to breakthroughs in effective dementia treatments.

Оригинален текст от CORDIS (на английски).

Участници

VIB VZW · ZWIJNAARDE - GENTКоординаторБелгия