Objective:

To systematically analyze neuropathologic features and gene expression profiles in brain tissues from families carrying MAPT mutations (V337M, P301L, L284L) to determine distinct neuropathologic signatures associated with these mutations.

Approach:

• Study Cohort: Analyzed brain tissues from 19 donors across eight families with confirmed MAPT mutations, following clinical evaluations at the University of Washington Alzheimer's Disease Research Center.
• Genetic Testing: Confirmed pathogenic MAPT mutations through DNA extraction and genotyping.
• Brain Sampling and Tissue Preparation: Collected and processed brain tissues from various regions known to contribute to FTLD features, following approved protocols.
• Histochemistry and Immunohistochemistry: Performed immunohistochemistry on paraffin-embedded tissues using optimized staining protocols.

Key Findings:

• More than 60 pathogenic MAPT variants identified, primarily clustered in exons 9 to 13 and introns of exon 10.
• Mutations V337M and P301L can alter tau protein function through changes in amino-acid sequence or splicing of exon 10.
• Distinct neuropathologic patterns observed across the V337M, P301L, and L284L MAPT mutations, indicating mutation-specific effects.

Interpretation:

The study provides insights into the neuropathological features associated with specific MAPT mutations in FTLD-tau.

Limitations:

• Few studies have systematically examined neuropathologic features across multiple individuals with MAPT mutations, limiting generalizability.
• The focus on familial cases may not fully represent the variability seen in sporadic FTLD-tau.

Conclusion:

Understanding mutation-specific neuropathologic features is essential for elucidating tau biology.