A role of tau‐induced astrocyte dysfunction and senescence in AD
Haneen Makhlouf, Angela O Dorigatti, Stacy A Hussong, Viviana Perez, Rakez Kayed, Veronica Galvan- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
- Geriatrics and Gerontology
- Neurology (clinical)
- Developmental Neuroscience
- Health Policy
- Epidemiology
Abstract
Background
Under certain conditions and during aging, cellular stress and damage can trigger cellular senescence, an irreversible state of cell cycle arrest accompanied by the expression of proinflammatory mediators known collectively as the “senescent‐associated secretory phenotype” (SASP). In Alzheimer’s disease (AD), neuronal tau becomes hyperphosphorylated and misfolded, forming pathogenic soluble aggregates (tau oligomers) and destabilizing the microtubule cytoskeleton. Pathogenic soluble tau is released from neurons during neuronal activation and is transmitted in a prion‐like fashion to postsynaptic cells. In addition to neurons, tau is expressed in a variety of brain cell types including astrocytes. In the present study, we tested the central hypothesis that soluble pathogenic tau can be transmitted to astrocytes and that tau transmission to astrocytes induces cytoskeleton destabilization and cellular dysfunction, contributing to the progression of AD.
Methods
To test the molecular consequences of tau transmission, we treated primary human astrocytes with purified tau oligomers. We used advanced biochemical tools, immunocytochemistry, and live‐cell microscopy to measure cell and nuclear size, cell cycle arrest, and SASP activation. We also co cultured human astrocytes undergoing tau‐induced senescence with primary mouse or non‐human primate neurons to determine the functional impact of senescent astrocytes on neurons, then utilized immunocytochemistry and 3D image analyses to measure parameters of dendrite and spine morphology.
Results
We found that pathogenic soluble tau is readily transmitted to primary human astrocytes, and that pathogenic tau transmission triggers phosphorylation of endogenous astrocyte tau, leading to the destabilization of the microtubule cytoskeleton. Further, we found that transmission of pathogenic tau to astrocytes potently upregulated multiple markers of cellular senescence, demonstrating for the first time tau‐induced astrocyte senescence. Density of dendritic spines and dendritic area were pronouncedly decreased in neurons co‐cultured with astrocytes undergoing tau‐induced senescence.
Conclusion
We showed transmission of pathogenic tau to human astrocytes and that this event triggers astrocyte senescence in mouse models of AD tauopathy. Our data suggest that senescent astrocytes may be critical mediators of neuronal dysfunction in AD tauopathy.