Break through common sense!

▎The content team editor of WuXi AppTec.
Leslie Norins, who is also an immunologist and entrepreneur, declared three years ago that if any scientist could prove that "germs cause Alzheimer's disease", he would receive a $1 million bonus.

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As soon as this remark came out, a single stone caused a thousand waves of waves, and the pathogenic mechanism of Alzheimer's disease once again aroused heated discussion
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Although the current mainstream theory believes that the root cause of Alzheimer's disease is amyloid deposition, in recent years, the "infection theory" has gradually attracted the attention of the scientific community
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This theory suggests that the root cause of Alzheimer's disease is more likely to be a microbial infection
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Image source: 123RF The two theories seem incompatible, because the former believes that the deposition of amyloid will further induce inflammatory reactions, promote the production of Tau protein tangles, and ultimately damage and kill neurons
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However, supporters of the "infection theory" point out that some people do not have Alzheimer's disease but still have amyloid deposits in their brains.
These cases seem to be more consistent with microbial infections
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"Academic Jingwei" related report: "Nature" hot discussion: the root cause of Alzheimer's disease is.
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microbial infection? Today, a study in "Nature-Communications" adds to the "infection theory".
Researchers from the German Neurodegenerative Disease Research Center have discovered that glycoproteins on the surface of the virus may promote the spread of protein aggregates
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Research has focused on a relatively novel direction: the propagation process of proteopathic seeds
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The seeds here refer to pathological protein deposition.
They can not only recruit monomeric pathological proteins in infected cells to grow into aggregates, but also spread to them by means of extracellular vesicles or direct contact between cells.
Unaffected cells
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This process seems to be a repetition of a tsunami of error proteins in the patient's brain
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Normally, the pathological proteins that can be transported by extracellular vesicles are very limited
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But if the virus exists, the situation will be reversed
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Because the glycoprotein on the virus can play a role in helping cells to bond and enhance the connection between cells
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For example, the vesicular stomatitis virus glycoprotein VSV-G is believed to promote the transport outside the vesicle and help the cargo to be transported to the receiving cell.
VSV-G can bind to the LDL receptor expressed on the surface of almost all cells
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In the test of the new research, Professor Ina M.
Vorberg and colleagues found that VSV-G can significantly increase the spread of prions between cells.
Prions are a mutant prion protein that can "infect" normal prions during transmission.
, And cause massive death of nerve cells
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▲VSV-G can significantly enhance the spread of protein aggregates (red) (picture source: reference [1]) The special cell line constructed by the research shows that compared with the group transfected with the empty vector, when the donor cells are transfected After VSV-G, the proportion of prion aggregates in recipient cells will increase significantly
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The mutant VSV-G, which does not possess cell binding capacity, also cannot promote the spread of aggregates
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Specifically, in addition to enhancing cell-to-cell contact, VSV-G also affects extracellular vesicles, delivering prion protein aggregates with less effort
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Moreover, extracellular vesicles can be said to be a necessary condition for the spread of protein aggregates.
Once they are lost, the transmission efficiency of VSV-G will drop a lot.

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The study also analyzed Tau protein aggregates, and the results, like prions, the expression of VSV-G can also help the spread of Tau protein between cells
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Even more frightening is that the spreading process mediated by viral glycoproteins can occur between different cell lines
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For example, prion-infected neuroma blasts can spread protein aggregates to fibroblasts
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It is worth noting that the spike protein on the surface of the new coronavirus can also achieve the function of spreading disease-causing seeds of the protein
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In the research design, donor cells expressing spike protein can significantly spread Tau protein aggregates to cell lines expressing ACE2 receptor (the natural binding region of spike protein)
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Is the amyloid theory or the infection theory correct? This question may cause further discussion, but there is an idea worthy of our consideration: amyloid is not only a harmful substance, it also has an important role in clearing infection
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Age or genetic factors will break the balance of this system, and the accumulation of too much amyloid will eventually lead to problems
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Perhaps the combination of the two theories is the final answer to the pathogenesis of many neurodegenerative diseases
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Reference: [1]Shu Liu, et al, Highly efficient intercellular spreading of protein misfolding mediated by viral ligand-receptor interactions.
Nat com 2021, DOI:10.
1038/s41467-021-25855-2[2] Are infections seeding some cases of Alzheimer's disease? Retrieved November 4, 2020, from https:// Hur, J.
, Frost, GR, Wu, X.
et al.
( 2020) The innate immunity protein IFITM3 modulates γ-secretase in Alzheimer's disease.
Nature.
https://doi.
org/10.
1038/s41586-020-2681-2[4] Stephen S.
Dominy et al.
, (2019) Porphyromonas gingivalis in Alzheimer's disease brains: Evidence for disease causation and treatment with small-molecule inhibitors, Science Advances, DOI: 10.
1126/sciadv.
aau3333[5] Ben Readhead et al.
, (2018), Multiscale Analysis of Independent Alzheimer's Cohorts Finds Disruption of Molecular , Genetic,and Clinical Networks by Human Herpesvirus, Neuron, DOI: 10.
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