Dementia’s Toughest Challenge: Why Finding a Cure Remains an Uphill Battle

The failure to find effective treatments for dementia has been a source of disappointment, despite numerous efforts. One area of focus has been the tau protein, which accumulates and forms tangles in the brain tissue of patients and is implicated in 75% of all dementia cases.

While drugs aimed at targeting tau have shown promise in mouse models, they have consistently failed to deliver positive results in clinical trials.

As such, there is a growing concern over the effectiveness of mouse models in studying tau accumulation and whether they can accurately predict clinical outcomes.

According to a recent work in Molecular Neurodegeneration, led by Kathrin Wenger, a Ph.D. student in the lab of Judith Steen, Ph.D., at Boston Children’s Hospital, one possible explanation for this is that the mouse models currently available for studying tau accumulation do not align with the tau pathology observed in humans experiencing late-stage dementia symptoms.

Wenger and team “don’t think these mice are the right models.”

Research conducted earlier in the Steen Lab, which is a part of the F.M. Kirby Neurobiology Center, discovered that the tau protein undergoes chemical modifications throughout the course of Alzheimer’s disease.

In the latest work, Wenger and her colleagues examined tau in its aggregated form in brain samples obtained from the two most commonly used mouse models – P301S and P301L. These models are based on genetic mutations of tau that have been identified in patients with frontotemporal dementia.

Wenger collaborated with the Proteomics Center at Boston Children’s to create a comprehensive map of modifications to tau protein at different stages of the disease. The team then compared their findings to samples of tau protein taken from individuals with Alzheimer’s disease, dementia, and P301L mutations.

According to Wenger, the team utilized a quantitative proteomics approach to take an unbiased look at all possible chemical modifications of tau over time and quantify them. Their technology is unique in its ability to comprehensively quantify modifications across a given protein, whereas other groups focus on only one or two previously suspected chemical modifications and lack the capability to quantify them.

The Steen team conducted rigorous experiments that demonstrated how tau accumulation in both mouse models is driven by the chemical process of phosphorylation. They found the same to be true in people with early stage Alzheimer’s disease or dementia with P301L tau mutations. However, they observed that in symptomatic human disease and late-stage human Alzheimer’s disease, the chemical processes of ubiquitination and acetylation of tau are crucial, and these were not accurately represented in the mouse models.

The researchers suggest that while the mouse models can be used for testing drugs that target tau modification in the early stages of dementia, they may not be suitable for symptomatic or later-stage disease when other modifications like ubiquitination and acetylation are important.

Additionally, the researchers emphasize the need for better models that account for the various factors, such as lifestyle, genetics, environment, and comorbidities like diabetes and infections, that can contribute to human dementia, particularly non-familial Alzheimer’s disease which comprises over 90% of all Alzheimer’s disease cases.

“We grow mice in optimal conditions, with healthy diets and no stressors or infections,” Steen adds. “But human Alzheimer’s disease is the product of multiple biological insults over a lifetime. We need a model that reflects insults people sustain over a lifetime.”

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