Sci Transl Med︱ A new mechanism to improve the pathology of Alzheimer's disease

Written by Wang Sizhen, edited by Wang Sizhen, Alzheimer's disease (AD) is a common neurodegenerative disease.

The accumulation of pathological tau protein in synapses has been identified as an early event of AD, and is closely related to the cognitive decline of AD patients [1].

Synaptic dysfunction and loss of synaptic spine are also associated with cognitive decline in AD [1].

Under normal physiological conditions, tau protein is mainly concentrated in the cytoplasm and axons of neurons, and does not exist in a large amount in synapses.
However, under disease conditions, due to the sorting error within neurons, the cross-neuronal For abnormalities in the transfer or clearance pathway, tau will accumulate in the postsynaptic compartment and presynaptic terminal [2].

Studies on mouse models of tau pathology have shown that hyperphosphorylation of tau can lead to mislocalization of tau on dendrites and dendritic spines [3].

 Interestingly, some studies claim that the accumulation of pathological tau in synapses is related to the accumulation of ubiquitinated proteins, which suggests an abnormality in the synaptic ubiquitin proteasome system (UPS) [4].

The UPS mechanism in the synapse is essential for the normal function of the synapse, such as synaptic protein turnover, synaptic plasticity and long-term memory formation [5].

In neurites, inhibiting protein degradation will lead to the wrong sorting of phosphorylated tau protein on dendrites and the loss of dendritic spines, while enhancing the protein degradation pathway will reduce the wrong selection of tau protein, which suggests that the protein degradation system is in the tau direction.
The distribution of dendrites and dendritic spines plays an important role [6].

The degradation of tau and other polyubiquitinated substrates is accomplished by the 26S proteasome, which is a protease that can degrade proteins into small peptides; the decrease in proteasome activity and its effects have also been observed in AD patients.
Conformation changes [7-9].

These data suggest that damage to proteasome activity may be a common mechanism in various neurodegenerative diseases.

In previous studies, related studies by Natura Myeku's laboratory at Columbia University Medical Center showed that the pure 26S proteasome in the brain of tau transgenic mice (rTg4510) has defects in degrading ubiquitinated proteins, while phosphodiesterase Inhibitors can enhance the activity of the proteasome through the cyclic activated protein kinase (cAMP)/cAMP-dependent protein kinase A (PKA), the cAMP/PKA signaling pathway, to hydrolyze tau, thereby alleviating the pathology of tau protein and improving cognitive function [ 8, 10].

However, activating or enhancing intracellular protein degradation through the proteasome or autophagy pathway may not be an ideal strategy for the treatment of AD.

Therefore, in the early stages of AD, targeting tau at specific locations in neurons may be a safer treatment strategy to prevent tau accumulation, spread, and cognitive decline.

   On May 26, 2021, Natura Myeku's laboratory published a new paper titled PAC1 receptor–mediated clearance of tau in postsynaptic compartments attenuates tau pathology in mouse brain in Science Translational Medicine, and found that PACAP1 receptor can reduce AD ​​mice Touch the amount of tau protein, relieve tau protein pathology, and improve the cognitive ability of mice.

 In this article, first of all, the authors found that with the progression of the disease in tau transgenic mice (rTg4510) (early, middle and later stages), the amount of pathological tau protein increased in neuron cell bodies, synapses, presynapses and postsynapses.
, Especially in the cell body; and compared to pre-synaptic, post-synaptic accumulation of a large number of different types of tau protein, such as tau monomer, high molecular weight tau (65 kDa), and mutant tau (AT8) (Figure 1 AC).

Similar results were also found in the cortex of the brain group of AD patients; at the same time, an increase in the level of K48-linked ubiquitin chains in similar mice was also observed in the patients’ postsynaptic, which suggested the most common proteasome degradation targeting signal ( Figure 1 DK).

 (Figure 1 AC) Pathological tau protein accumulation in the postsynaptic compartment of AD patients (picture quoted from: Schaler et al.
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2021; 13: eaba7394) (Figure 1D-K) Pathological tau Protein accumulation in the postsynaptic compartment of AD patients (picture quoted from: Schaler et al.
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2021; 13: eaba7394) Tau protein pathology has a basic feature, that is, tau protein with seed function It is preferentially transported through synapses, passing through adjacent brain regions [11-12].

Here, the author expressed the same amount of tau protein seeds extracted from mice at different disease stages in human embryonic kidney 293 DS1 cells, and found that compared with pre-synaptic tau seeds, post-synaptic tau seeds Tau seeds show high seed activity both in the early and late stages of the disease.

The same experiment was performed on the presynaptic and postsynaptic tau proteins isolated from the brain tissue of AD patients, and similar results were also observed.

These results indicate that the tau in the postsynaptic compartment has more seed activity and more spreading potential.

 Pituitary adenylate cyclase activating polypeptide (PACAP) type I receptor, referred to as PAC1R, is a Gs-G protein-coupled receptor mainly located on the postsynaptic membrane of neurons.
It can activate the proteasome activity and tau protein degradation mediated by the cAMP/PKA signaling pathway [13-14].

In the brain, after the ligand PACAP is released from the axon terminal, it acts by binding and activating the receptor PAC1R on the postsynaptic membrane [13-14].

Here, the authors infected tau particles in primary neurons of tau mutant (P301S) mice, and observed that neuronal dendrites exhibited tau seed activity and insoluble tau accumulation, and PAC1R treatment can reduce dendrites The tau seed activity and insoluble tau can also significantly reduce the total post-synaptic tau protein content (Figure 2).

 Figure 2 PACAP treatment can alleviate tau seed activity and insoluble tau accumulation in primary neurons in vitro (MC1 labeled conformational tau protein, MAP2 labeled neuronal dendrites) (picture quoted from: Schaler et al.
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2021; 13: eaba7394) Previous results showed that enhancing the activity of PKA proteasome can promote the clearance of tau protein [8].

The phosphorylated tau at serine 214 (pS204 tau) is a marker of activating cAMP/PKA signal transduction (in short, if the level of pS204 tau is high, the signaling pathway is activated).

Here, the authors found that pS214 tau protein was enriched in cytoplasm and presynaptic expression, while the PACAP treatment group significantly up-regulated the pS214 tau protein content in the cytoplasmic component of mouse neurons, suggesting PKA-dependent tau protein phosphorylation Occurs after PACAP treatment; the pS214 tau protein in the large presynaptic mice after PACAP treatment was significantly reduced, suggesting that PACAP treatment did not activate the presynaptic PKA.

The authors also found that PACAP treatment can significantly down-regulate mouse cytoplasm, pre-synaptic and post-synaptic proteasome-specific ubiquitination protein levels, and can also significantly down-regulate the level of post-synaptic receptor PAC1R.

These results comprehensively suggest that PACA treatment can improve the tau protein pathology of mouse neuronal synapses.

 Figure 3 PACAP treatment can alleviate tau protein lesions in rTg4510 mice (picture quoted from: Schaler et al.
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2021; 13: eaba7394) At the same time, the results also show that PACA treatment can significantly enhance mouse synapses The 26S proteasome activity and its substrate degradation rate, the phosphorylation level of the serine and threonine sites of the synaptic 26S proteasome also increased, and this phosphorylation is specific to the PKA signal (Figure 3).
The results suggest that PACA treatment can increase the activity of the postsynaptic proteasome by activating the PKA signaling pathway, and promote the hydrolysis of tau, thereby exerting a neuroprotective effect.

Indeed, further results show that PACA treatment can alleviate the tau protein lesions in the cortex and hippocampus of mice, which is reflected in the reduction of total tau protein, tau phosphorylated at multiple sites, and insoluble tau.

Finally, Morris water maze test and new object recognition test showed that PACAP treatment can significantly improve the spatial (learning) memory and declarative (situational) memory of the hippocampus of mice with early tau protein disease (rTg4510).

These behavioral tests show that after receiving PACAP treatment, the tau protein pathology and memory ability of the mice have been improved.

Figure 4 Work summary diagram: the mechanism of tau protein clearance in the postsynaptic compartment of neurons (picture quoted from: Schaler et al.
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2021; 13: eaba7394) Conclusion and discussion of the article by the researcher through the use of sub-cells The separation method demonstrated the biochemical properties of tau protein in the presynaptic and postsynaptic compartments of the brains of rTg4510 mice and AD patients after death (Figure 4).

 The postsynaptic compartment appears to contain pathological tau protein, which may make the neuronal synapse structure susceptible to the toxicity of tau protein.

The researchers used PACAP to target PAC1R to eliminate tau protein in the postsynaptic compartment of the mouse brain by increasing PKA signaling and enhancing proteasome activity (Figure 4).

In PACAP-treated mice, the increase in proteasome activity in the postsynaptic compartment was associated with a pathological decrease in tau protein and an increase in cognitive ability (Figure 4).

In addition, this study also suggests that PKA phosphorylation of the proteasome is a better way to target the 26S proteasome enzyme activity.
However, as an effector molecule of cAMP, PKA has a wide range of substrate proteins, which may be a long-term treatment for AD and other protein toxicity.
Diseases that need attention.

  Of course, there are still some unsolved problems in this study.
For example, although PACAP treatment improves the cognitive ability of mice, PACAP has neurogenic, anti-apoptotic and neuroprotective properties, however, its metabolic instability limits For its clinical application, it is necessary to develop PACAP derivatives or chemically modified small molecules to increase the stability of the enzyme while maintaining the selectivity and potency of PAC1R.

 In conclusion, research suggests that this method of targeted activation of PAC1R may be a potential strategy to prevent the accumulation of toxic tau protein and treat AD and other tau protein pathologies.

 Original link: https://stm.
sciencemag.
org/content/13/595/eaba7394 Selected articles from previous issues [1] Alzheimer's Dementia︱ The latest scientific hypothesis! JNK is a therapeutic target for neurodegenerative diseases [2] Nat Neurosci︱ for the first time! Neuronal ApoE affects the new mechanism of AD pathology by influencing immune response genes [3] Interpretation of Nature︱ how impaired meningeal lymphatic function affects the response of microglia And anti-Aβ immunotherapy [4] Cell Death Dis︱Yi Sheng's research group reported that leukemia inhibitory factor regulates the effect of Schwann cell phenotype on peripheral nerve injury and repair [5] Nat Neurosci︱GWAS analysis reveals obvious causality with depression The new gene of relationship (new protein) Recommended high-quality scientific research training courses [1] "Scientific Research Image Processing and Mapping" off-line: June 26-27, Shanghai; July 10-11, Beijing [2] Patch Clamp and Light Genetic and Calcium Imaging Technology Seminar (June 26-27, two days and one night) References (slide up and down to view) [1] MK Chen, AP Mecca, M.
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Lu, JW McDonald, HR Michalak, NB Nabulsi, AFT Arnsten, Y.
Huang, RE Carson, CH van Dyck, Assessing synaptic density in Alzheimer disease with synaptic vesicle glycoprotein 2A positron emission tomographic imaging .
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