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  • Alzheimer’s disease and other neurodegenerative disorders cause abnormal tau protein aggregation.
  • Until recently, researchers have mostly focused on the phosphorylated form of tau for diagnosing and treating Alzheimer’s disease.
  • A new study suggests that certain largely overlooked shorter or truncated fragments of the tau protein could also play a significant role in the formation of tau aggregates in Alzheimer’s disease.
  • These results suggest that these truncated tau proteins may play an important role in diagnosing and treating Alzheimer’s disease.

According to the conventional view, phosphorylated tau is the primary factor responsible for the formation of tau aggregates in Alzheimer’s disease (AD). A new study published in the journal Neuropathology and Applied Neurobiology suggests that two less-studied truncated tau proteins could contribute to the formation of tau aggregates in AD, independent of phosphorylated tau.

The potential role of these truncated tau proteins in the development of AD underscores the need to target these proteins to diagnose and treat this neurodegenerative disorder.

Alzheimer’s disease is characterized by the formation of aggregates of the tau protein in brain cells called neurofibrillary tangles. Although deposits of the amyloid β-protein are also found in AD brains, some scientists think that the tau protein aggregates are primarily responsible for the development of AD.

In addition to AD, abnormal tau aggregates are observed in other neurodegenerative disorders, collectively called tauopathies. There are two major types of tau protein — the 3-repeat (3R) and 4-repeat (4R) tau isoforms or variants. Based on the predominant isoform in the tau aggregates, these neurodegenerative disorders can be categorized as either 3R tauopathies or 4R tauopathies.

For instance, Pick’s disease (PiD) is a 3R tauopathy, whereas corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and argyrophilic grain disease (AGD) are examples of 4R tauopathies. Both the 3R and 4R tau isoforms are present in neurofibrillary tangles in AD.

After the tau protein is synthesized in the cell, it undergoes chemical modifications that influence its function. Phosphorylated tau, a modified form of this protein, has been considered to play a primary role in the formation of tau aggregates in Alzheimer’s disease and other tauopathies.

However, recent studiessuggest that tauopathies may also involve shorter or truncated forms of the tau protein. A class of enzymes called caspases can cut or cleave the full-length tau protein into truncated fragments of different sizes, which can then form tau aggregates.

For instance, the activated form of the enzyme caspase-6 cleaves the tau protein at a site called D421 (421st amino acid in the protein sequence) to create a fragment known to form aggregates.

Although an increase in the levels of activated caspase-6 in brain cells is associated with AD progression, whether a similar increase also occurs in other tauopathies is unknown.

Moreover, studies suggest that caspase-6 cleaves the tau protein at D402 and D13. There is some evidence to suggest that these fragments are present in tau aggregates in AD and may contribute to the progression of the disease.

In the present study, the authors further assessed the role of the D402 and D13 tau fragments in AD and other tauopathies.

To examine the presence of these truncated tau fragments in various tauopathies, the researchers used post-mortem brain samples from individuals with AD, PiD, and 4R tauopathies (CBD, PSP, and AGD).

The researchers used a technique called immunofluorescence staining to microscopically detect and visualize the expression of caspase-6, phosphorylated tau, and the D402 and D13 truncated tau fragments in brain cells. They found that the number of brain cells expressing activated caspase-6 and the truncated tau fragments was considerably higher in AD and PiD than in 4R-tauopathies, such as PSP and CBD.

Notably, these truncated tau fragments can be detected in the cerebrospinal fluid. Thus, these truncated tau proteins could serve as biomarkers for AD and PiD diagnosis and help distinguish individuals with AD and Pick’s disease from those with 4R-tauopathies.

Although the levels of phosphorylated tau differed among the AD and other tauopathies, the magnitude of differences in truncated tau levels was more profound. In other words, the present study suggests that the truncated tau fragments could serve as more sensitive biomarkers than phosphorylated tau.

Medical News Today spoke with the study’s co-author, Dr. Michelle Arkin, a professor of pharmaceutical chemistry at the University of California San Francisco (UCSF).

“This is the first study to quantitatively demonstrate that whereas phosphorylation is associated with all tauopathies, the truncated tau fragments we detected were only observed in PiD and AD,” said Dr. Arkin. “Thus, truncation could provide new diagnostics for AD and PiD versus other tauopathies.”

The researchers found that about half of the brain cells expressed both the truncated tau fragments and phosphorylated tau in the brains of AD and PiD patients. The rest of the cells were positive for truncated tau fragments but not phosphorylated tau.

Contrary to the view that phosphorylated tau plays a predominant role in the formation of aggregates in AD, these results suggest that truncated tau fragments could independently contribute to the development of AD and PiD. Thus drugs that could prevent the synthesis of these tau fragments, such as caspase-6 inhibitors, could be necessary for the treatment of these neurodegenerative diseases.

The study’s co-author, Dr. Lea Grinberg, a neuropathologist at UCSF, provided MNT with the following explanation of the study’s findings:

“[Our results suggest] that when we measure phosphorylated tau as a proxy of tau pathology in AD, we are missing almost half of the story. Any in vivo measure using phosphorylated tau only to monitor AD (progression and clinical trial results) is missing a lot. Furthermore, we are not detecting well which class of neurons are the most vulnerable, so we cannot create the right strategies to protect them. Importantly, caspase-6 inhibitors are available and experimental work shows that inhibiting caspase 6 activation decreases tau pathology. Thus, caspase-6 inhibitors could be an effective therapy for AD.”

Dr. Grinberg