Équipe Philippe MARIN

We hypothesize that circadian BT variations regulate Aβ and tau secretion, reuptake and clearance. This project aims to unravel the vicious cycle linking thermoregulatory deficits, sleep disturbances, and glymphatic dysfunction to the propagation of Aβ and tau. Understanding these connections will enable to propose innovative therapeutic strategies. The following specific objectives will be pursued:

• Aim 1. Determine whether sleep–wake body temperature (BT) variation regulate tau reuptake.
  Define how sleep–wake BT fluctuation (35–38°C) regulate neuronal reuptake and cell-to-cell propagation of tau (role of Syndecan-3).
• Aim 2. Determine whether sleep–wake BT variations regulate Aβ propagation.
  Determine how BT modulates Aβ production and reuptake (role of Syndecan-3), and its propagation using in vitro, in vivo, and clinical correlative readouts.
• Aim 3. Test whether genetic inhibition of SDC3 prevents the propagation of amyloid and tau pathologies in mouse models of AD subjected to sleep deprivation.
  Test whether genetic SDC3 inhibition (KO/siRNA) blocks tau and Aβ secretion/uptake/propagation and rescues cognition in mice exposed to chronic sleep deprivation; quantify ISF/CSF tau/Aβ and pathology.
• Aim 4. Determine whether BT influences the glymphatic clearance of Aβ and tau.
  Define how BT modulates glymphatic clearance of tau/Aβ (AQP4 expression/polarization, microdialysis ISF↔CSF/plasma flux). Evaluate controlled heat exposures as a non-pharmacological strategy, and probe consequences of AQP4 inhibition on sleep, thermoregulation, and pathology.