Caspase activation precedes and leads to tangles

Area of Science:

• Neuroscience
• Molecular Biology
• Pathology

Background:

• Post-mortem studies link neurofibrillary tangles (NFTs) to neuronal death in Alzheimer's disease (AD) and frontotemporal dementia.
• NFTs are associated with caspase activation and apoptosis, suggesting tangles cause neurodegeneration.

Purpose of the Study:

• To investigate the temporal relationship between caspase activation and NFT formation in vivo.
• To elucidate the role of caspase-cleaved tau in initiating tau pathology and neurodegeneration.

Main Methods:

• In vivo multiphoton imaging in living tau transgenic mice (Tg4510 strain).
• Observation of caspase activation and NFT formation.
• Introduction of wild-type 4-repeat tau (tau-4R) and caspase-cleaved tau constructs in wild-type mice.

Main Results:

• Caspase activation precedes NFT formation by hours to days.
• New NFTs form within a day, and neurons survive with suppressed caspase activity.
• Caspase activation, tau truncation, and aggregation were triggered by tau-4R introduction.
• Caspase-cleaved tau mimetic induced aggregates, tangle epitopes, and endogenous tau recruitment.

Conclusions:

• A novel model proposes caspase activation initiates tau cleavage, leading to NFT formation.
• NFTs may be 'off pathway' to acute neuronal death, with tangle-bearing neurons being long-lived.
• Soluble tau species, rather than fibrillar tau, are likely the primary toxic agents in neurodegeneration.