A new molecular atlas of tau enables precision diagnostics and drug targeting across neurodegenerative diseases

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"Tau protein aggregation is a shared feature in over 20 neurodegenerative diseases (collectively referred to as "tauopathies"). New research led by Boston Children's Hospital challenges the current "one-size-fits-all" approach to diagnosing and treating these tauopathies. ...

analyzed brain tissue from 203 patients spanning several tauopathies, including Alzheimer's disease and chronic traumatic encephalopathy (CTE). They used a novel mass spectrometry tool called FLEXITau which enables absolute quantification of pathological tau species, measuring both the identities and abundances of disease-relevant chemical modifications. ...

that tau chemistry changes as the disease advances, and that the p217 Tau modification ranked as the most accurate diagnostic for Alzheimer's. p217 is now an FDA-approved diagnostic marker for Alzheimer's disease. ...

Using FLEXITau, the researchers identified 145 post-translational modifications and 195 cleavage sites across tau. Machine-learning models then ranked the molecular features that best distinguished each disease based on quantified chemical changes. ..."

From the highlights and abstract:

"Highlights

• Comprehensive mapping of tau identifies 145 PTMs and 195 cleavage sites in tauopathies

• Provides tau molar abundance and peptide modification stoichiometry in disease

• Machine learning classifies tauopathies using tau molecular features

• Identified disease-specific features are potential drug targets and diagnostics

Summary

In Alzheimer’s disease (AD), pathological tau protein shows a progressive accumulation of post-translational modifications (PTMs), reflecting disease severity, progression, and prion-like activity. Although many neurodegenerative diseases with dementia display tau aggregates, the pathological proteoforms of tau protein from each disease type remain unknown.

Here, using a quantitative mass spectrometry-based proteomics platform, FLEXITau, deep characterization of pathological tau protein isolated from the brains of 203 human subjects with AD, familial AD (fAD), chronic traumatic encephalopathy (CTE), corticobasal degeneration (CBD), Pick’s disease (PiD), progressive supranuclear palsy (PSP), dementia with Lewy bodies (DLB)—a non-tauopathy symptomatic control—and healthy controls (CTR) is performed. Unsupervised data analyses and supervised machine learning identify distinct molecular features of pathological tau for each disease, enabling molecular disease stratification.

This study identifies potential disease-specific biomarkers and therapeutic targets for tauopathies and provides critical quantitative information for pharmacokinetic modeling required for therapeutic and disease mechanism studies."

A new molecular atlas of tau enables precision diagnostics and drug targeting across neurodegenerative diseases

Molecular features of human pathological tau distinguish tauopathy-associated dementias (open access)

Graphical abstract

Figure 1 Workflow and quantification of pathological insoluble tau and isoforms across tauopathies and control human subjects