. A 3D human brain-like tissue model of herpes-induced Alzheimer's disease. Sci Adv. 2020 May;6(19):eaay8828. Epub 2020 May 6 PubMed.


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  1. Using a new, three-dimensional bioengineered human brain model, Cairns et al. report that HSV-1 infection induces pathological changes reminiscent of those observed in Alzheimer’s disease. This study is consistent with our previous publication, which showed that HSV-1 infection accelerates AD pathology by directly promoting Aβ aggregation in mice and in a three-dimensional human neural cell culture model of AD (Choi et al., 2014; Eimer et al., 2018). In the new study, Cairns et al. show that HSV-1 infection induces multiple AD-like pathological features including multicellular, dense Aβ fibrillar plaque-like formations (PLFs), phospho-tau accumulation, cellular death, astrogliosis, and pro-inflammatory cytokines. Most importantly, this is achieved in naïve human neural cells devoid of FAD mutations or Aβ overexpression. These data support the role of endogenous Aβ as an antimicrobial peptide, consistent with the Antimicrobial Protection Hypothesis of AD first proposed by our group (Soscia et al., 2010; Kumar et al., 2016; Eimer et al., 2018; Moir et al., 2018). 

    While the use of naïve neural cells in a three-dimensional model brings us closer to physiological conditions, we would caution that it may be too early to conclude that the three-dimensional naïve human neural cells with acute HSV-1 infection reported here constitute a validated model for “herpes-induced sporadic AD.” First, it is not clear that the multicellular, dense Aβ PLFs in this model represent actual Aβ plaques observed in AD patients. Second, increases in phospho-tau levels cannot be directly translated into evidence for neurofibrillary tangles/paired helical filaments without biochemical and histochemical validation. The new three-dimensional model includes elevated levels of pro-inflammatory cytokines and astrogliosis in the HSV-1 infected cultures, which are proposed to mimic “neuroinflammation” in AD. However, it is important to point out that these three-dimensional cultures do not contain microglia; thus, they do not recapitulate AD-related neuroinflammation. This is in contrast to our previous report of a human triculture (neural-microglial-astrocyte) three-dimensional cell model of AD (Park et al., 2018). Finally, it is important to note that the three-dimensional iPSC-derived neural cells used in this new model are probably fetal in status and may, therefore, not accurately recapitulate adult brain physiology following HSV-1 infection. Yet, it is very interesting that the combination of HSV-1 and naïve neurons were able to engender these pathological features.

    Regarding the proposed mechanism of pathogenesis in the new model, the authors appear to favor HSV-1 inducing increased production of Ab42, together with increased levels of presenilin 1 (PS1) mRNA levels following HSV-1 infection. MSD analysis revealed moderate increases in levels of Ab42, but not Ab40, following HSV-1 infection. It is important to point out that increased PSEN1 transcription would not, alone, provide evidence of increased or altered PS1/γ-secretase activity. Importantly, the PS1/γ-secretase complex is composed of multiple subunits including PS1, APH1, PEN2 and Nicastrin. Moreover, APP and BACE1 mRNA levels were significantly decreased, suggesting that Aβ levels should be decreased. Thus, it is unlikely that Aβ accumulation in this model is actually due to effects of HSV1 on Aβ production.

    In accordance with our Antimicrobial Protection Hypothesis of AD, we propose that the Aβ accumulations observed in this new three-dimensional model were most likely not solely due to Aβ production, but may have been induced by microbial “seeding” of Aβ into beta-amyloid by HSV-1. This would be consistent with the role of Aβ as an antimicrobial peptide (Kumar et al. 2016; Eimer et al. 2018). In brief, we previously showed that upon binding to microbes, Aβ is rapidly “seeded" to form amyloid fibrils, leading to extracellular traps consisting of Aβ. These traps (amyloid deposits) then immobilize microbes to protect host cells, a classic property of antimicrobial peptides (Kumar et al., 2016Eimer et al., 2018). 

    In summary, the pathological features observed in this new three-dimensional cell model are consistent with our previous findings (Eimer et al., 2018), and also suggest that HSV-1 may have the ability to nucleate endogenous Aβ derived from naive human neurons, into Aβ deposits, consistent with the role of Aβ42 as an antimicrobial peptide (Moir et al., 2018). Thus, while the authors chose to focus on HSV-1 effects on Aβ production, the new three-dimensional model provides further evidence for a role of Aβ as an antimicrobial peptide, under more physiological conditions, free of Aβ overexpression, i.e., HSV-1 induces “seeding” of endogenous Aβ (in its role as an antimicrobial peptide) from naive neurons leading to Aβ oligomers/fibrils, phospho-tau, and astrogliosis. As such, these findings have broad implications for the ability of HSV-1 and other microbes to rapidly nucleate beta-amyloid deposition, perhaps even in the presence of only physiological levels of Aβ, further supporting the Antimicrobial Protection Hypothesis of AD (Moir et al., 2018). 


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    View all comments by Rudy Tanzi
  2. If you add any microbes with β-sheet proteins at their surface (not only virus) in this three-dimensional culture system, you will be able to see Aβ plaque formation within two to four hours. This supports the new Alzheimer's disease concept that this syndrome can be caused by microbiome dysbiosis, and expansion of the microbes across the blood-brain barrier. Plaque formation is simply the evidence of this invasion, as the brain's innate immune system tries to tag and engulf the microbes with antimicrobial peptides, amongst other mechanisms.

    View all comments by Frank Bernier

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  1. Herpes Simplex Virus Triggers Amyloidosis in 3D Neural Cultures