3D medical background with interconnecting green and grey lines. In foreground there is an illustration of a human head with a magnifying glass examining the brain depicting alzheimer's disease research.
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While new imaging and spinal fluid diagnostic techniques have improved the diagnosis of Alzheimer’s disease (AD), they are still only capable of a definitive diagnosis once a patient has a severe form of the disease, differentiating it from other neurodegenerative disorders. Now, a team of investigators from North Carolina Central University and Duke University have identified specific phosphorylated tau protein that can help differentiate AD from other tauopathies such as Pick’s disease (PiD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD).

According to the new research, published in ACS Chemical Neuroscience, the newly identified biomarker could help treating physicians diagnose AD at an earlier stage than is now possible, as a patient transitions to mild cognitive impairment (MCI).

“Many PTM (posttranslational modification) sites in tau protein have been identified, which include dozens of phosphorylation sites, and over a dozen each of acetylation sites and ubiquitination sites,” the researchers noted in their paper. “Based on the sequential accumulation model, different tau PTMs may occur at different AD stages, and specific combinations of PTMs were proposed to reflect progressive steps in the process of tau fibril formation and AD disease progression. Therefore, Tau PTM sites provided opportunities for antibody-based site-specific biomarker discovery, including biomarkers for early disease stages, which are urgently needed in clinical practice.”

Past research has focused on the tau protein and subtle changes in it that can lead to AD. Specific post-translational modifications of the protein can make it more likely clump which leads to the loss or neurons and cognitive decline. Researchers have already identified two such tau proteins—called p-tau181 and p-tau217—that are the result of phosphorylation at specific amino acids. In the new research, investigators Bin Xu, Jerry Wang, Ling Wu and colleagues sought to identify additional tau proteins that could be potentially serve as biomarkers to diagnose the disease at an earlier stage with the potential be developed as a diagnostic for AD.

“High-molecular-weight oligomers of tau (HMW-tau) in postmortem AD brains have been reported in two recent reports. However, there have been no reports of systematic screening using these AD-selective, HMW-tau aggregates as potential targets for AD diagnosis biomarker discovery,” the researchers wrote. “Our work independently discovered AD-specific, HMW-tau oligomers, and we further identified several site-specific phospho-tau-detectable HMW-tau aggregates as potential AD biomarkers.”

For their work, the researchers used post-mortem brain tissue from AD patients and those without the disease to help identify other p-tau biomarkers associated with tau aggregation in the brain. One biomarker in particular—p-tau198—showed it could discriminate AD from two other neurodegenerative diseases in which tau is known to clump. The team also noted that its asaays showed p-tau198 was as effective as p-tau181 and p-tau217. A significant finding was that both p-tau 198 and p-tau217 markers could be used to differentiate brain tissue of patients with mild cognitive impairment—one of the early signs of AD—from older subjects without impairment.

According to the team, their work and prior work into posttranslational modifications involving tauopathies has implications for not only providing an earlier diagnosis of AD, but of other neurodegenerative disease.

“Given that hyperphosphorylation is a common theme of PTM implicated in disease pathogenesis and progression in multiple amyloidogenic proteins including tau, α-synuclein, and TDP-43 in neurodegenerative diseases, we envision that our approach of biomarker discovery may be readily extended more broadly to other neurodegenerative disease diagnoses and translational detection applications,” the researchers concluded.

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