Refresh your awareness! Tau actually protects neurons in Alzheimer's patients

*For medical professionals only

Neurofibrillary tangles caused by excessive phosphorylation of tau protein are one of the two main pathological features of Alzheimer's disease (AD), so excessive tau protein in neurons has been considered a risk factor for AD [1].

However, recent research published in Advances in Neurophysiology by Marie-Christine Galas of the University of Lille in France challenges this idea [2].

Using immunofluorescence, fluorescence-activated nucleus sorting and mononuclear sequencing, the research team found that neurons in the brains of AD patients will be activated to re-enter the active state of the cell cycle after being damaged by oxidative stress (normal neurons are in a quiescent state), and at this time, more dephosphorylated tau proteins will accumulate in the nucleus of neurons, confinement the cells to the S phase, thereby preventing neurons from crossing the S phase and apoptosis, which plays a certain protective role on neurons
。

This result shows that tau protein is not necessarily a killer, and may even play the role of protector at some times, giving us a deeper understanding
of the complex role of tau protein in AD pathological changes.

Screenshot of the first page of the paper

Theoretically, mature neurons are cells in a quiescent state (G0 phase), but scientists have found that under various stress conditions, they will also re-enter the G1 phase (pre-DNA synthesis), and after the G1/S phase (the S phase is the DAN synthesis phase), the cells either redifferentiate or continue to enter the S phase, but we know that mature neurons are not divisible in the body, so the ultimate fate of these cells is inevitable
.

At present, multiple evidence suggests that oxidative stress, pathological changes in tau protein, and neuronal cell cycle reactivation are associated with AD, and one theory suggests that oxidative stress-induced neuronal cell cycle reactivation is the upstream trigger of tau protein hyperphosphorylation [3], but the causal relationship of these factors remains unclear
.

To explore the link between neuronal cell cycle reactivation and different forms of tau protein in AD, the researchers stained cortical sections from AD patients (Braak pathological stage VI) and non-dementia control populations and found a positive correlation between neuronal intracellular phosphorylated tau protein and Ki67 expression (a marker of cell cycle activation status) in cells in the neurofibril tangled lesion area, but in some cells that did not develop neurofibrillary tangled lesions.
However, the more dephosphorylated tau protein in the nucleus, the stronger
the expression of Ki67.

At the same time, the expression of Ki67 and Tau1 (dephosphorylated tau protein) in neurons in the AD group was significantly increased
compared with the control brain.
Overall, in the AD group brain, Tau1 expression in Ki67⁺ neurons was also significantly increased
compared with Ki67-neurons.

AD Brain has a subset of neurons that specifically enter a cell cycle active state and is characterized by the dephosphorylation of tau protein in the nucleus

Together, these results indicate that there is a subpopulation of neurons in the AD brain that specifically enters a cell cycle active state, and the tau protein in its nucleus is in a dephosphorylated state (hereinafter referred to as ntau⁺ cycle active neurons).

Interestingly, the researchers found that these ^NTAU+ cycle active neurons tend to exist near amyloid plaques, basically within 100 μm of amyloid plaques, suggesting that amyloid plaques may play a role
in causing neuronal cell cycle reactivation.

Next, the researchers explored where the Ki67-positive cells were in the cell cycle (G1, S, G2 and M phases
).

Through cell-cycle-specific protein staining analysis, the researchers found that most of these cells were in the G1 and S phases, a very small number of cells were in the G2 phase, and no cells entered the M phase (mitosis phase).

This suggests that these ^NTAU+ cycle active neurons are blocked in the S phase
.

Active neurons in the ^NTAU+ cycle are blocked in the S phase

Since DNA synthesis has begun in the S phase, the researchers further analyzed the relationship
between intranuclear tau protein, increased DNA content, and cell cycle status through fluorescence-activated nuclear nuclear sorting and mononuclear sequencing.

The results showed that in the brains of AD patients, 1.
9-10.
7% of neurons had increased DNA content, compared with 1.
2-2.
3% in the control group brains (P < 0.
01).

At the same time, the increased DNA content did not double the original, suggesting that most neurons with increased DNA content had incomplete genome replication, and these neurons likely found themselves blocked in the S-phase
.

Most neurons with increased DNA content have incomplete genome replication

In addition, tau expression was almost detectable in the nuclei of neurons with increased DNA content in the brains of AD patients, but not in the nuclei of neurons with increased DNA content detected in the brains of the control group
.

These results reaffirm the aggregation of intranuclear dephosphorylated tau protein in subsets of neurons with increased DNA content, occurring only in the brains of AD patients, and that these neurons are blocked in the S phase
.

So why do neurons in AD patients have this ntau⁺ cycle active neuron?

Through further experiments, the researchers found that the level of DNA oxidative damage at active neurons in the ntau⁺ cycle was higher, and the higher the level of DNA oxidative damage, the stronger the expression of Tau1 in the nucleus, indicating that there was an association between DNA oxidative damage and changes in intranuclear tau protein content, which may be the cause of triggering neurons to re-enter the
cell cycle.

To confirm this, the researchers treated the cultured neurons with oxidative stress with drugs of different oxidative intensities, and found that oxidative stress can indeed re-enter the cell cycle of neurons, increasing the expression of Ki67 and Tau1 in the nucleus of neurons
.

Oxidative stress can indeed re-enter the cell cycle of neurons, with increased expression of Ki67 and Tau1 within the nucleus

More importantly, these neurons that re-entered the cell cycle did not undergo apoptosis, but stagnated in the S phase, suggesting that cell cycle reactivation and increased intranuclear tau may be a way
to urgently respond to DNA damage.

To confirm this hypothesis, the researchers downregulated the expression of tau in neurons in the brain of mouse embryos and then treated
them with oxidative stress.
The results found that although neurons can re-enter the cell cycle, most of them are in the G1 phase, and apoptosis is greatly increased, indicating that tau protein in the nucleus has no effect on oxidative stress-induced neurons to re-enter the G1 phase, but it can control the progression of the neuronal cell cycle to the S phase and stagnate, thereby "reining from the cliff"
.

The increased tau protein in the nucleus allows neurons that re-enter the cell cycle under oxidative stress to escape apoptosis

Overall, this study confirmed that there is a special subset of neurons in the brains of AD patients, which are re-entered into the cell cycle by oxidative stress, but they should have apoptosis and initiated an emergency self-rescue procedure, that is, the dephosphorylation of tau protein in the nucleus increases, so that the cells stagnate in the S phase and thus maintain survival
.

Theoretical schematic

This study shows that the role of tau protein in AD is far more complex than we think, but it also provides new insights
into the treatment of AD.

References

1.
Naseri NN, Wang H, Guo J, Sharma M, Luo W: The complexity of tau in Alzheimer's disease.
Neurosci Lett 2019, 705:183-194.

2.
Denechaud M, Geurs S, Comptdaer T, Begard S, Garcia-Nunez A, Pechereau LA, Bouillet T, Vermeiren Y, De Deyn PP, Perbet R et al: Tau promotes oxidative stress-associated cycling neurons in S phase as a pro-survival mechanism: possible implication for Alzheimer's disease.
Prog Neurobiol 2022:102386.

3.
Huang F, Wang M, Liu R, Wang JZ, Schadt E, Haroutunian V, Katsel P, Zhang B, Wang X: CDT2-controlled cell cycle reentry regulates the pathogenesis of Alzheimer's disease.
Alzheimers Dement 2019, 15(2):217-231.

The author of this article Zhu Junhao

Responsible editorDai Siyu