Structural variation in amyloid beta and tau filaments from distinct Alzheimer's disease clinical subtypes

Introduction:
Alzheimer’s disease (AD) exhibits substantial clinical heterogeneity, with subtypes such as rapidly progressive AD and posterior cortical atrophy displaying unique symptom profiles. Recent studies employing solid-state NMR, seeding, and biophysical assays suggest that both amyloid beta (Aβ) and Tau filaments adopt distinct conformations in these subtypes compared to typical slow-progressing AD. Elucidating the atomic structures of these filaments may offer crucial insights into subtype-specific pathogenic mechanisms.

Objectives:
This study aims to resolve the atomic structures of Aβ and Tau filaments from the brains of patients with different AD subtypes and to investigate the prion-like seeding potential of these conformers in knock-in mouse models expressing human Tau and Aβ.

Methods:
Aβ and Tau filaments were extracted from post-mortem brain tissue using a modified protocol. Filament yield was increased by introducing Collagenase and Pronase digestion, validated by negative-stain transmission electron microscopy (TEM). Cryo-EM screening will assess extract suitability for high-resolution data acquisition to determine atomic structures. Prion-like seeding will be evaluated by inoculating knock-in AD mouse models with brain homogenates from distinct subtypes, followed by comparative structural analysis of filaments from inoculated and control animals to probe templating mechanisms.

Results/Discussion:
Enzymatic digestion has enhanced filament recovery from post-mortem brain tissue, as evidenced by negative-stain TEM imaging. Cryo-EM screening is to follow, with the expectation of advancing towards structural resolution of subtype-specific Aβ and Tau filaments.

Conclusion:
This work will clarify structural variation in Aβ and Tau filaments among AD subtypes and its implications for prion-like templating and disease progression.