Mechanical stimulation prevents impairment of axon growth and overcompensates microtubules destabilization in cellular models of Alzheimer's disease and related Tau pathologies

Alice Alessandra Galeotti¹Lorenzo Santucci¹Jennifer Klimek²Mohamed Aghyad Al Kabbani²Hans Zempel²Vittoria Raffa^1*

• ¹University of Pisa, Pisa, Italy
• ²University of Cologne, Cologne, North Rhine-Westphalia, Germany

Alzheimer's disease (AD) and related tauopathies such as Frontotemporal Dementia (FTD) or Traumatic Brain Injury (TBI) are neurodegenerative disorders characterized by progressive loss of memory and cognitive function. The main histopathological features of AD are amyloid-β plaques and Tau neurofibrillary tangles, suggestd to interfere with neuronal function and to cause microtubule (MT) destabilization. We recently demonstrated that low mechanical forces promote MT stabilization, which in turn promotes axon growth and neuronal maturation. As neurites may become dystrophic due to MT destabilization in tauopathies, we hypothesized that force-induced MT stabilization is neuroprotective in cell models subjected to tauopathy-like stress. We found that exposure of mouse primary neurons to Tau oligomers and neurons derived from human induced pluripotent stem cell (hiPSC) to amyloid-β oligomers resulted in neurotoxic effects such as axonal shortening, reduction in dendrite number and MT destabilization. We found that mechanical stimulation i) prevented delays in axonal extensions and dendrite sprouting, restoring axon outgrowth to physiological levels, and ii) compensated for axonal MT destabilization by increasing MT stability to levels higher than in control conditions. In summary, we here demonstrate that low mechanical force can be used as a neuroprotective extrinsic factor to prevent MT destabilization and axon degeneration caused by AD-like or tauopathies-like stressors.