June 29, 2022

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α-synuclein oligomerization in cognitive impairment

α-synuclein oligomerization in cognitive impairment


α-synuclein oligomerization in cognitive impairment.  α-Syn oligomers have obvious damaging effects on many cellular processes, including cell membranes, mitochondria, endoplasmic reticulum function, neuroinflammation and synaptic transmission.

α-synuclein oligomerization in cognitive impairment


α-synuclein (α-Syn) is a soluble neuronal protein composed of 140 amino acid residues widely expressed in the presynaptic terminals, which regulates the homeostasis of neuronal cell membranes under physiological conditions , Control the transport of synaptic vesicles and the synthesis and regulation of dopamine. Soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNARE) protein complex is a key component of cell membrane fusion, which can mediate the directional transport of intracellular substances and maintain The normal operation of various life activities of the body. α-Syn interacts with SNARE in the presynaptic membrane to promote the formation of SNARE complex and maintain normal synaptic function.


Inflammation, oxidative stress, specific damage (excitatory toxicity, 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine) and other stimuli can cause α-Syn gene activation and make α The expression level of ‑Syn increases and abnormal aggregation occurs. The α-Syn that forms an oligomeric state further aggregates and develops into insoluble α-Syn fibers. “Oligomerization” refers to the aggregation of α-Syn, but the intermediate form of fibrous bodies has not yet formed. The most toxic α-Syn type is soluble oligomers.


1 Toxic mechanism of α-Syn oligomer

α-Syn exists in the degenerative areas of Parkinson’s disease (PD) patients or genetically modified mice, and has toxic effects. The mechanism of α-Syn oligomers inducing neurodegeneration may involve a variety of pathogenic processes.


1.1  Mitochondrial damage

Mitochondria are the “energy station” of cells and can regulate processes such as gene expression and cell apoptosis. In 2014, Plotegher et al. found that after α-Syn oligomers stimulate SH-SY5Y cells, the mitochondrial morphology is destroyed and the organelles are broken. In the PD mouse model overexpressing human A53T α-Syn, it was shown that the mitochondrial complex Ⅰ function was abnormal, and the mitochondrial complex Ⅰ activity was also found to be significantly reduced in the brains of PD patients. The mitochondrial-endoplasmic reticulum coupling structure has an important relationship with mitochondrion, mitochondrial dynamics and Ca2+ homeostasis. In α-Syn transgenic mice, it was found that the distance between the mitochondrial-endoplasmic reticulum coupling structure of neurons was increased, which in turn affected the release of endoplasmic reticulum Ca2+ and the production of ATP. α-Syn oligomers can induce mitochondrial toxicity, reduce the retention time of exogenous Ca2+, promote Ca2+-induced mitochondrial swelling and depolarization, and accelerate the release of cytochrome C. These studies suggest that α-Syn oligomers are related to mitochondrial dysfunction and may be related to the pathogenesis of PD.


1.2  Endoplasmic reticulum (ER) stress (endoplasmic reticulum stress, ERS)

ER is the site of protein modification, folding and Ca2+ storage. ERS will occur when the homeostasis of ER is imbalanced. The aggregation of α-Syn oligomers was found in the brain tissues of transgenic mice overexpressing A53T and PD patients, causing chronic ERS response and impaired ER protein function. Glucose-regulated protein 78 (Grp78) belongs to the stress protein family. When ERS occurs in cells, the expression of Grp78 is up-regulated, which improves the ability of ER to fold proteins and reduces the burden of ER. In animal experiments, it was found that by inhibiting the synthesis of oligomers in A30P α-Syn transgenic mice, the upregulation of Grp78 would be inhibited. Colla et al. found in PD mouse models and brain tissues of PD patients that α-Syn oligomers are related to ER membrane incompleteness, and the accumulation of oligomers in the brain stem is more obvious than in the cortex. These studies have emphasized that α-Syn oligomers may cause ERS and cause neurotoxicity.


1.3   impaired cell membrane integrity

The integrity of the membrane is essential for any type of cell to maintain normal function. α-Syn oligomers can cause membrane defects, accelerate membrane damage and change membrane properties. α-Syn has a high affinity with the outer mitochondrial membrane, especially the cardiolipin on the inner membrane. α-Syn oligomers can quickly combine with the mitochondrial membrane to destroy the mitochondrial morphology. Cell membrane integrity has an important effect on maintaining the stability of Ca2+ levels. Certain types of oligomers may disrupt cell homeostasis by forming pores in the cell membrane. The destruction of the outer lipid bilayer can increase cell permeability and promote the influx of extracellular ions. Inhibition of extracellular Ca2+ influx can reduce neuronal cell death caused by α-Syn oligomers. When α-Syn and phospholipid membrane vesicles incubate cells together, they can accelerate their aggregation on the cell membrane. This abnormal aggregation promoted by the membrane may disrupt the interaction between the central hydrophobic region of α-Syn and the membrane, exposing hydrophobicity. The region is related to the self-recombination of α-Syn, and preventing α-Syn oligomers from acting on the cell membrane can produce beneficial effects. These results suggest that maintaining the integrity of the membrane is essential, and α-Syn oligomers acting on the cell membrane can cause harmful effects. Appropriate intervention can reverse this harmful phenomenon.


1.4  Synaptic dysfunction

Neurons can perform their biological functions through synapses. α-Syn oligomers can bind to the small synaptophysin, which is a component of the SNARE complex necessary for synaptic vesicle fusion, to prevent the composition of the SNARE complex, which in turn leads to reduced neurotransmitter release, neuronal dysfunction and death. α-Syn oligomers can also reduce the stability of microtubules, disrupt the interaction between actin and microtubules to reduce axon transport, destroy the transport function of synaptic vesicles, and inhibit the polymerization of tubulin. Some researchers speculate that α-Syn may be a new type of microtubule motility enzyme that can promote tubulin nucleation or microtubule mutation. Danzer et al. found that α-Syn oligomers may disrupt the function of synaptic vesicles, again leading to reduced neurotransmitter release and increased cell membrane permeability, causing Ca2+ influx and excitotoxicity. These studies indicate that α-Syn oligomers may mediate early synaptic-related pathological processes by damaging the function of synaptic vesicles in the central nervous system.


1.5   glial cells and inflammation

Astrocytes and microglia play an important role in maintaining neuronal homeostasis and participating in clearing pathological protein aggregation. α-Syn oligomer activates glial cells by activating the Toll-like receptor 2 pathway, triggers central inflammatory response, destroys synaptic function and promotes neuronal death, leading to memory impairment. Astrocytes can take up α-Syn oligomers and degrade them through the proteasome pathway. However, when the amount of α-Syn taken up by astrocytes exceeds the amount of lysosomal degradation, new oligomers and fibers are formed in the astrocytes, which will aggravate the pathological process and promote neuronal death. In addition, the microglia isolated from adult mice or elderly patients have significantly lower phagocytic capacity of α-Syn oligomers than those isolated from young mice or patients, and they are affected by α-Syn oligomers. ‑Syn oligomers will secrete more TNF‑α when damaged. Therefore, further research on the effect of glial cells on α-Syn oligomers is of great significance for the development of its potential role in the treatment of synucleinopathies.


2 Research progress of α-Syn in perioperative cognitive dysfunction

Postoperative delirium (POD) is a major type of perioperative neurocognitive impairment, and its pathogenesis has many hypotheses. Clinical studies have observed that in the tissue samples of patients undergoing subtotal gastrectomy with POD, the positive expression rate of nerve plexus α-Syn and the degree of phosphorylation are significantly higher than those of surgical patients without POD, suggesting that α-Syn may be Is the cause of POD.

The researchers also found that elderly patients with preoperative PD non-motor system symptoms (such as rapid eye movement sleep disorder, olfactory disorder, daytime sleepiness, and insomnia) have a higher incidence of POD after spinal surgery. PD Non-motor system symptoms are closely related to α-Syn deposition. Researchers speculate that having PD non-motor system symptoms is a risk factor for POD. In addition, cognitive disorders associated with POD and α-Syn abnormalities [such as Parkinson’s disease dementia (PDD) and dementia with lewy bodies (DLB)] have similar clinical features, such as inattention , Hallucinations, confusion and sleep-wake cycle changes. The above study is consistent with the results of the POD mouse model.

In mice with delirium-like neurobehavioral manifestations after laparotomy, the expression of α-Syn in the mouse cortex was significantly up-regulated after 12 hours of surgical anesthesia, and was earlier than their behavioral abnormalities. Appeared. These evidences suggest that the abnormal expression or pathological changes of α-Syn may be related to the changes in postoperative cognitive function.


3 α-Syn in Alzheimer’s disease (Alzheimer’s disease, AD) related cognitive impairment research progress

AD is a common neurodegenerative disease and the most common type of dementia. Its main pathological changes are the formation of intracellular neurofibrillary tangles and extracellular amyloid β-protein (Aβ) Deposited age spots. However, 30%-40% of AD patients show other symptoms of protein pathology, that is, lewy bodies (LB) and Lewy neurites formed by intracellular α-Syn deposition. Patients with LB AD have a faster and more severe decline in cognitive function than patients with pure AD. The researchers also found the same phenomenon in mice.

They observed non-transgenic mice of different ages, 3×Tg‑AD mice, A53T α‑Syn transgenic mice and DLB‑AD transgenic mice, and found that they were at 2 and 4 months old. The cognitive function of 3×Tg‑AD and DLB‑AD mice was significantly reduced, but the difference in the reduction level was not statistically significant; the cognitive impairment of 6-month-old DLB‑AD mice was more serious than that of 3×Tg‑AD mice. The difference in severity is more pronounced at 9 months of age. Clinical study of 84 elderly patients, AD patients who have not yet developed pathological changes of LB, the expression level of soluble α-Syn protein in cerebral cortex tissue cells is higher than that of non-cognitive impairment (NCI) and those with moderate cognitive impairment. The disordered patients were up-regulated about 2.24 times and 1.69 times, respectively, which was consistent with the changes in α-Syn levels. The SNCA gene expression level in AD group was up-regulated by about 1.67 times compared with NCI group.

It was also found in basic research that transgenic mice overexpressing wild-type soluble α-Syn showed the same level of cognitive impairment as AD transgenic mice (J20) in the Barnes circular maze behavior test, which was relatively common. The cognitive function of wild-type mice of the same age was significantly decreased. The research team also found that soluble α-Syn monomers can be overexpressed under abnormal conditions and aggregate into soluble toxic oligomers, inhibiting the transcription factor cAMP response element binding protein (cAMP response element binding, CREB) and nuclear related Receptor factor 1 (nuclear receptor related factor 1, Nurr1) activity causes it to lose control of the synaptophysin gene promoter activity and reduce the expression of SYN-related proteins (SYN1 and SYN2). SYN participates in the regulation of synaptic transmission efficiency, and Synaptic remodeling is closely related to cognition, which leads to memory impairment. In addition, more and more studies have found that α-Syn, Tau and Aβ molecules can interact with each other and affect each other’s expression levels. These studies have shown that α-Syn oligomers may be related to AD-related cognitive impairment.


4 The research progress of α-Syn in PD-related cognitive impairment

DLB and PDD are synucleinopathies with PD symptoms and dementia as the main clinical manifestations. They are currently considered to be the second most common neurodegenerative dementia after AD. Unfortunately, there is currently no effective treatment for PDD and DLB. Synucleinopathy-associated dementia is related to the abnormal accumulation of α-Syn in the cortex and hippocampus. Adamowicz et al. studied 95 DLB patients and found that the pathological changes of α-Syn were mainly in the hippocampal CA2 area and the entorhinal cortex.

The CA1 area had the least pathological changes, but the CA1 area had the best correlation with memory. α‑amino‑3‑hydroxy‑5‑methyl‑4‑isoxazole propionic acid receptor (amino‑3‑hydroxy‑5‑methylisoxazole‑4‑propionic acid receptor, AMPAR) is an ionotropic glutamate receptor Subtypes, which mediate the transmission of excitatory transmitters in the central nervous system, are composed of one or more of the four subunits of GluR (receptor of glutamic acid) 1~4 combined into a tetrameric structure in different ways, of which GluR 2 Subunits are an important part of participating in the formation of AMPAR. AMPAR and the induction and maintenance of synaptic plasticity play an important role.

The abnormality of AMPAR can make synaptic plasticity abnormal and cause cognitive function damage. A53T α-Syn transgenic mice rely on tau phosphorylation to down-regulate GluR 2 subunits, increase Ca2+ permeability, post-synaptic dysfunction and abnormal synaptic plasticity, leading to memory and cognitive dysfunction. Studies have found that the acidic C-terminus of α-Syn can interact with the basic central area of ​​Tau, inhibiting its function of stabilizing microtubules, and abnormal accumulation of Tau overexpression leads to neuronal dysfunction.

The latest study also found that the fibrous form of α-Syn (preformed fibrils, PFF) is injected into the muscular layer of the pylorus and duodenum, which is rich in vagus nerves, and the pathogenic α-Syn is transmitted to the brain through the intestine-brain axis. Behavioral tests such as water maze showed that the cognitive function of mice after PFF injection was significantly lower than that of the PBS injection group, and the expression of hippocampal nucleoprotein was significantly reduced, and the phosphorylation of α-Syn serine 129 was significantly up-regulated.

After the vagus nerve was cut, there was no significant difference in cognitive function and other symptoms between the PFF injection group and the PBS injection group, indicating that pathological α-Syn may spread through the gut-brain axis and cause related neurodegeneration and behavioral defects. The above studies have shown that pathological α-Syn may be related to the pathogenesis of DLB ​​and PDD.


5 Conclusion and outlook

In summary, α-Syn oligomers have obvious damaging effects on many cellular processes, including cell membranes, mitochondria, endoplasmic reticulum function, neuroinflammation, and synaptic transmission.

In addition, more and more evidence supports that α-Syn oligomerization plays an important role in the multifactorial causes of neurodegenerative disease-related dementia and postoperative cognitive dysfunction.

Future research needs to fully clarify the role of oligomers with diverse structures on specific pathways. The technology to detect and differentiate different types of α-Syn oligomers will also be the key, which may be used to treat pathological α-Syn-related neurodegenerative diseases. And provide new ideas for postoperative cognitive impairment.




(source:internet, reference only)

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