Tau protein profiling in tauopathies: a human brain study.
Juan Lantero-Rodriguez1,2, Elena Camporesi1,2, Laia Montoliu-Gaya1,2
1Department of Psychiatry & Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
Molecular Neurodegeneration
|July 18, 2024
Summary
This study reveals distinct tau protein profiles in various tauopathies, finding that Alzheimer's disease (AD) shows significantly higher levels of tau phosphorylation and aggregation compared to other tauopathies like PSP, PiD, and CBD.
Area of Science:
- Neuroscience
- Biochemistry
- Pathology
Background:
- Tauopathies, including Alzheimer's disease (AD), are characterized by abnormal tau protein accumulation.
- Cerebrospinal fluid (CSF) tau biomarkers are specific for AD but not all tauopathies (e.g., PSP, PiD, CBD).
- Understanding tau proteoform differences across tauopathies is crucial for diagnosis and treatment.
Purpose of the Study:
- To develop and apply a multiplex assay for quantifying tau proteoforms in different tauopathies.
- To compare non-phosphorylated and phosphorylated tau peptide profiles across AD, PSP, PiD, CBD, and control brain tissues.
- To identify unique tau pathology signatures distinguishing AD from other tauopathies.
Main Methods:
- Developed a multiplex assay combining immunoprecipitation and high-resolution mass spectrometry.
- Analyzed soluble and insoluble brain tissue fractions from autopsy-confirmed tauopathy cases (AD, PSP, PiD, CBD) and controls.
- Quantified tau isoforms, non-phosphorylated tau peptides (especially MTBR-containing), and 23 different phosphorylated peptides.
Main Results:
- Non-phosphorylated tau profiles differed across tauopathies, with AD showing 12-72 times higher levels of MTBR-containing aggregates in insoluble fractions.
- Tau isoform distribution varied: 3R tau predominated in PiD, while 4R tau was more abundant in CBD and PSP (insoluble fractions).
- All investigated phosphorylated peptides increased in AD insoluble fractions; doubly and triply phosphorylated peptides also increased in AD soluble fractions, unlike other tauopathies.
Conclusions:
- Abnormal tau phosphorylation and aggregation occur in non-AD tauopathies but are significantly more pronounced in Alzheimer's disease.
- The developed multiplex assay effectively differentiates tau proteoform profiles across various tauopathies.
- Distinct tau phosphorylation and aggregation patterns, particularly in AD, highlight potential diagnostic and therapeutic targets.
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