Regional vulnerability and spreading of hyperphosphorylated tau in seeded mouse brain

Area of Science:

• Neuroscience
• Pathology
• Biomedical Imaging

Background:

• Hyperphosphorylated tau deposition is a hallmark of Alzheimer's disease (AD) and related tauopathies.
• Understanding tau propagation patterns is crucial for developing effective therapeutic strategies.
• Existing mouse models do not fully recapitulate the in vivo spreading of tau pathology observed in human AD.

Purpose of the Study:

• To map the three-dimensional (3D) progressive deposition of hyperphosphorylated tau in intact, cleared mouse brains.
• To compare tau spreading patterns in an aging P301L tau mouse model with those in AD patients.
• To establish a more faithful preclinical model for tauopathy research and drug validation.

Main Methods:

• Whole brain microscopy of intact, cleared mouse brains to visualize tau deposition.
• Stereotactic injection of synthetic or patient-derived tau fibrils into the CA1 region.
• Atlas-guided volumetric analysis to quantify tau spread and assess connectome dependency.
• Histological analysis of microglial morphology in response to tau seeding.
• Treatment with an anti-tau antibody (targeting the microtubule-binding domain) via intracranial and systemic administration.

Main Results:

• The natural spreading of hyperphosphorylated tau in aging P301L mice did not replicate AD patient patterns.
• Injection of tau fibrils into the CA1 region resulted in a more accurate tau spreading pattern.
• Tau deposition spread in a connectome-dependent manner but also extended beyond direct anatomical connections.
• Rod-like and swollen microglia were persistently detected in fibril-injected brains.
• Anti-tau antibody treatment reduced hyperphosphorylated tau load, particularly with intracranial co-administration.

Conclusions:

• Targeted seeding of tau fibrils provides a more relevant model for studying tauopathy progression.
• Whole-brain imaging and connectome analysis reveal complex tau spreading dynamics.
• This approach facilitates comprehensive assessment of regional vulnerability and serves as a valuable tool for preclinical drug validation in tauopathies.