Astrocytic 4R tau expression drives astrocyte reactivity and dysfunction.

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• The protein tau and its isoforms are linked to neurodegenerative diseases, with 4-repeat (4R) tau deposition being common.
• The precise role of 4R tau in disease development is not fully understood.
• Previous studies showed 4R tau expression in mice increases seizure severity and tau phosphorylation.

Purpose of the Study:

• To investigate the role of specific tau isoforms in neurodegenerative disease pathogenesis.
• To explore the impact of altering the 3R to 4R tau ratio using antisense oligonucleotides (ASOs).

Main Methods:

• Developed ASOs to modify the 3R to 4R tau ratio in human tau-expressing (hTau) mice.
• Examined tau localization, gene expression, and astrocyte function in treated mice and primary/iPSC-derived astrocytes.
• Assessed neuronal activity in co-cultures with 4R tau-expressing astrocytes.

Main Results:

• ASO treatment led to 4R tau colocalization in reactive astrocytes and increased neurotoxic gene expression in hTau mice.
• Elevated 4R tau in astrocytes induced a neurotoxic genetic profile and impaired homeostatic functions.
• Neurons cultured with 4R tau-expressing astrocytes showed increased firing frequency and hypersynchrony, which was reversible by reducing tau levels.

Conclusions:

• Astrocytic 4R tau may mediate neuroinflammation and neuronal dysfunction through a novel pathway.
• Targeting 4R tau within astrocytes presents a potential therapeutic strategy for neurodegenerative diseases.