Diving into the role of tau in Alzheimer’s disease
Alzheimer’s disease (AD) is a prevalent neurodegenerative disorder associated with significant cognitive decline. At the molecular level, AD is characterised by the abnormal accumulation of amyloid beta peptide(opens in new window) plaques and neurofibrillary tangles formed by the tau protein(opens in new window). These tangles disrupt normal neuronal function, impairing communication between brain neurons and eventually causing their death. Tau is a protein that plays a crucial role in the normal functioning of neurons in the brain as it helps maintain cellular stability and structure. The dissemination of pathological tau follows a prion-like mechanism(opens in new window), wherein an atypical strain of tau enters a recipient cell and promotes the misfolding and clustering of the native tau protein, a phenomenon known as seeding. AD manifests with different clinical presentations, which are closely tied to the spread or ‘seeding’ of misfolded, aggregated tau.
Optimised assays for measuring tau aggregation
Undertaken with the support of the Marie Skłodowska-Curie Actions(opens in new window) (MSCA) programme, the DIVE into AD project worked under the hypothesis that different strains of tau are accountable for the diverse manifestations of AD and could potentially influence the rate of progression, gender-related distinctions, and clinical presentation. The team set out to develop sensitive tools to measure tau seeding in biological samples. “These tools will enhance our understanding of AD and aid in designing targeted therapies for the benefit of society,” explains MSCA research fellow Aurélien Lathuilière. Lathuilière and colleagues optimised existing assays for detecting the aggregated species of pathological tau protein that have the capacity to propagate in the brain. They generated a clonal cell line that overexpresses a fragment of tau protein tightly linked to AD neurofibrillary tangles. Through Förster resonance energy transfer(opens in new window), it was possible to generate a sensitive tool for detecting seeding tau species and improving the specificity of AD pathology. Moreover, this led to the identification of other molecular players responsible for tau uptake, degradation and seeding.
Could tau serve as a prognostic biomarker for Alzheimer’s disease?
DIVE into AD deeply characterised the various tau species present in post-mortem brain samples of AD patients. They discovered that the levels of seeding competent tau correlated with the rate of disease progression. The team is currently in the process of adapting this approach to measure tau seeding competency in the cerebrospinal fluid of AD patients. “This could lead to a novel prognostic marker for AD,” emphasises Lathuilière. Moreover, researchers discovered that when pathological tau species meet a tau template that is structurally similar, their propensity to aggregate increases. This finding opens the way to the detection of disease-specific aggregates. Collectively, the DIVE into AD project corroborated previous findings that brain deposition of tau correlates with human cognition and neurodegeneration. The discovery of distinct tau strains exhibiting varying seeding capabilities will help comprehend the variable AD clinical presentation and enable the prediction of individual patient outcomes. This has the potential to significantly reshape the design and analysis of clinical trials and pave the path for personalised medicine approaches tailored to patients with specific tau characteristics.
