Alzheimer’s disease (AD) is characterized by the accumulation of amyloid plaques and tau tangles in the brain. While recent therapies successfully reduced amyloid burden, their modest effects on cognition suggest that additional mechanisms contribute to neurodegeneration. Tau pathology is strongly associated with cognitive decline and disease progression, yet scientists still do not understand how normal tau transforms into the diverse pathological aggregates found in AD or why different forms of tau pathology emerge in different brain regions and disease states. Similar tau aggregates are also found in a group of related neurodegenerative disorders known as tauopathies, but the molecular features that distinguish these diseases remain poorly understood.
Drs. Zetterberg and Brinkmalm seek to define the molecular composition of tau aggregates across AD and other tauopathies. Their laboratory has developed a highly sensitive immunoprecipitation-mass spectrometry platform that can characterize tau protein fragments and post-translational modifications in unprecedented detail. Previous CureAlz-funded work using this approach identified distinct tau signatures across multiple neurodegenerative diseases and demonstrated that pathological tau species undergo specific truncations and chemical modifications as they aggregate. The team also developed methods to isolate individual tau tangles from human brain tissue, allowing them to examine the molecular composition of specific aggregate types rather than studying homogenized tissue alone.
Using these approaches, they generated preliminary evidence that tau composition differs across brain regions and disease stages. They found that tau accumulation occurs earlier in some vulnerable brain regions than others and identified specific modifications in the tau protein that increase with disease severity. They also demonstrated that tau can be detected and characterized from as few as 50 isolated tangles, revealing enrichment of phosphorylated and microtubule-binding region (MTBR) tau species within pathological aggregates. Additional early findings suggest that tau present in brain blood vessels and synaptic compartments may share molecular features with aggregated tau found in diseased brain tissue. Given this, they hypothesize that the molecular composition of tau changes as neurofibrillary tangles mature and that distinct forms of tau aggregates represent different pathological processes in the brain. They further hypothesize that specific tau fragments and modifications distinguish AD from other tauopathies and may serve as biomarkers of disease progression.
They will investigate this hypothesis using two aims. First, they will isolate and characterize tau aggregates at different stages of maturation and compare their molecular composition across AD and other tauopathies. Second, they will apply their mass spectrometry platform to multiple brain cohorts to identify disease-specific tau fragments, modifications, and co-pathologies across different brain regions, disease stages, and biological compartments.
If successful, this work will provide one of the most detailed molecular maps of tau pathology generated to date. By defining how tau changes during disease progression and identifying features unique to specific tauopathies, the study could reveal new biomarkers for monitoring disease progression and treatment response while improving our understanding of the mechanisms that drive neurodegeneration in AD and related disorders.
