Soluble pathogenic tau transmission to astrocytes drives acute oxidative damage, cellular senescence, and neurovascular uncoupling in a model of Alzheimers tauopathy
We previously found that soluble pathogenic tau aggregates (tau oligomers) enter brain microvascular endothelial cells and induce cellular senescence and microvascular dysfunction in a tauopathy mouse model. This study shows that soluble pathogenic tau is also transmitted to astrocytes, where it induces mitochondrial dysfunction, mediates senescence, and impairs neurovascular coupling responses.…
Soluble pathogenic tau aggregates, also known as tau oligomers, have been found to enter brain microvascular endothelial cells and induce cellular senescence and microvascular dysfunction in a tauopathy mouse model. This study reveals that soluble pathogenic tau can also be transmitted to astrocytes, leading to mitochondrial dysfunction, senescence, and impaired neurovascular coupling responses.
Upon examination of cortex tissue from hTau mice, single-cell RNA sequencing showed astrocytes as one of the most significantly altered cell types, displaying decreased expression of electron transport chain genes and increased expression of stress-induced and inflammatory markers. These alterations were also observed in hTau mouse brain and astrocyte-enriched fractions.
Soluble tau aggregates entered primary human astrocytes through a process sensitive to heparin, causing microtubule destabilization, ATP depletion, and mitochondrial ROS accumulation. This progression ultimately resulted in cell cycle arrest-associated markers. Mitigating mitochondrial ROS with Mito TEMPO reduced the secretion of SASP cytokines in astrocytes both in vitro and in vivo.
Coculturing neurons with astrocytes displaying tau-induced senescence led to a non-cell-autonomous decrease in dendritic spine density, branch number, and dendritic area. The proteins tau and SASP-associated cytokines IL-1β and IL-6 contributed to various aspects of the neuronal structural phenotype.
Interestingly, targeting astrocytes with SOD2 overexpression attenuated the hTau-related deficit in evoked cerebral blood flow responses; however, the improvement in response magnitude and duration did not reach statistical significance compared to hTau mice expressing GFP. These findings suggest that astrocyte senescence may serve as a mechanism linking astrocyte tau uptake, mitochondrial stress, and neuronal structural impairment.
The study emphasizes the importance of further exploring mitochondrial antioxidant defense in tau-associated astrocyte dysfunction.
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