Will Tau protein be an effective target for the treatment of Alzheimer’s disease?
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Will Tau protein be an effective target for the treatment of Alzheimer’s disease?
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“Molecular Psychiatry”: Will Tau protein be an effective target for the treatment of Alzheimer’s disease?
When it comes to the development of new drugs for Alzheimer’s disease (AD), the name of “Tiankeng” is not in vain.
From 1998 to 2021, 198 AD new drugs worldwide have failed clinically, and the clinical success rate is only 2%. This failed to dampen the determination of scientists to overcome AD.
According to the report of the Alzheimer’s Disease Drug Research Foundation (ADDF), as of 2021, there are still 118 treatments under development, of which the highest proportion is targeting misfolded proteins. therapy.
Amyloid β (Aβ) and tau protein are the two most concerned pathological proteins in AD pathology.
In contrast, Aβ has attracted more attention. However, in recent years, Aβ drugs have failed repeatedly, and the complexity of related theories has gradually emerged. The role of tau protein in disease progression has also returned to the academic field of vision.
So, can tau protein be a target for the treatment of AD?
Recently, the journal “Molecular Psychiatry” published a review summarizing new AD drugs aimed at regulating tau protein hyperphosphorylation.
This article also takes this opportunity to sort out new tau protein drugs that deserve attention.
What is Tau protin?
Tau protein is a protein with various physiological functions. Interestingly, it is an intrinsically disordered protein (DIP) and does not have a fixed three-dimensional structure, which endows it with extremely flexible conformation and diverse Function.
But on the other hand, the multiple regulatory factors of tau protein conformation also give it more room for “errors”.
When these regulatory mechanisms fail, misfolded proteins begin to accumulate, and diseases occur.
Phosphorylation of tau protein is one of the most studied post-translational modifications (PTM), and tau protein has abundant phosphorylation sites, and there are even 85 phosphorylation sites in the longest human tau protein subtype 2N4R.
Normally, there are 2-3 phosphate molecules per tau molecule in healthy individuals, but in AD, this number is very different.
The phosphorylated form present in 2N4R, red is the phosphorylation site commonly found in pathology
Aberrant phosphorylation is sufficient to promote tau filament formation. Under cryo-electron microscopy, tau filaments can be observed to have unique conformations, and different tauopathies have unique conformations and specific phosphorylation features.
These structures suggest a possible causal relationship between dysregulated tau phosphorylation and different tauopathies.
Therefore, targeting the phosphorylation of tau protein has also become a potential means for the treatment of AD, including two types of available targets, protein kinase (PK) and protein phosphatase 2A (PP2A).
PKI and PP2AI in AD Clinic
At present, some PKs that drive AD-related phosphorylation epitopes have been identified, as shown in the table below.
AD-associated phosphorylation sites and corresponding protein kinases
Many drugs have been tested in preclinical research, but not many have entered clinical trials, including lithium salts, tideglusib, saracatinib, nilotinib, etc.
PP2A belongs to the phosphoprotein phosphatases (PPPs), the major phosphatases in the brain, accounting for more than 70% of the total tau phosphatase activity.
PP2A can act on almost all phosphorylation sites of tau. Studies have shown that the activity of PP2A in the AD cortex and hippocampus is significantly reduced.
There are many drugs with PP2A activation effect, but only sodium selenate has a clear mechanism of action and has been tested in clinical trials.
Tideglusib is a small molecule GSK3β inhibitor. In the phase 2 clinical study, the cognitive improvement of tideglusib was not observed (including ADAS-Cog, MMSE, word fluency test, ADCS-ADL, NPI and other scales), in addition, Aβ42, total tau, There was no change in pTau181, and the test was declared a failure.
Lithium is a commonly used psychiatric drug, and the results of three clinical trials for the treatment of AD have been published.
However, it is not optimistic that lithium salts failed to show neuroprotective activity and improvement in cognitive or psychometric scores, and did not affect CSF Aβ42, pTau181, pTau231, and total tau levels.
Saracatinib and nilotinib are small molecule inhibitors of Fyn and Bcr-Abl, respectively. In Phase 1b and Phase 2 clinical trials, saracatinib failed to show statistically significant efficacy.
Nilotinib had some effect on cerebrospinal fluid and frontal cortex amyloid levels in phase 2 clinical trials, but no effect on tau was observed.
In a phase 2a clinical study, no improvement in cognition was observed with sodium selenate, but the analysis showed that the degree of white matter degeneration was lower in the sodium selenate treatment group than in the placebo group.
In addition, patients with higher levels of selenium in their blood and cerebrospinal fluid showed less cognitive decline. Due to insufficient clinical evidence, it cannot be considered that enhancing phosphatase activity is beneficial for the treatment of AD.
Drug star targeting tau
In addition to the drug accidents mentioned above, tau protein and several other drugs have entered Phase 2 or Phase 3 clinical trials, and are expected to achieve good results in the next few years.
LMTX (TRx0237) is a small molecule tau protein aggregation inhibitor that can prevent tau protein aggregation or degrade existing aggregates.
None of the three clinical studies that have been completed so far have yielded positive results, and there is still one phase 1/3 clinical study in progress.
AADvac1 is a tau fragment peptide vaccine. In the phase 2 clinical study, 95% of the subjects successfully produced antibodies
. The results showed that AADvac1 can significantly slow down the growth of blood NfL.
The CSF pTau217 in the treatment group decreased significantly, and pTau181 and total tau tended to decrease, but no effect on cognition was observed. benefits.
In younger participants, better indicator improvements were observed.
ACI-35 is a liposome-based vaccine that targets the pathological conformation of the partially phosphorylated tau protein.
In the phase 2 clinical trial of the vaccine, the three dose groups all produced effective antibody responses, and the antibodies could last for more than one year.
Bepranemab is a humanized IgG4 monoclonal antibody that binds to the central region of tau protein; semorinemab is an IgG4 antibody against extracellular tau to limit inflammatory microglial activation. Both have entered clinical phase 2.
With the emergence of various new markers, the focus of AD clinical research design in the new era began to point to the precise selection of the subject population and the search for indicators of disease improvement.
Obviously, to target tau protein, it is necessary to find patients whose neurodegeneration is mainly driven by tau pathology, and the inclusion criteria of the trial should include tau/phosphorylated tau markers in cerebrospinal fluid/blood, and complete longitudinal monitoring during clinical trials .
In addition, it is necessary to determine the standard of disease improvement, the window of intervention, and the selection of clinical endpoints.
Before all this, it is necessary to rigorously clarify the pharmacological mechanism in preclinical research, so that clinical transformation can be carried out smoothly.
References:
[1] https://www.nature.com/articles/s41380-023-02113-z
Will Tau protein be an effective target for the treatment of Alzheimer’s disease?
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