Aβ is generally considered a rogue peptide, but recent research is building a case that it may have a secret identity as an antimicrobial superhero. Confronted with an unwelcome bacteria or fungus, the peptide quickly forms amyloid fibrils that ensnare the invader. Is this response to pathogens relevant to the development of Alzheimer’s disease? The idea is controversial, but new data from two complementary papers make it more plausible. First, a gene-expression network analysis led by Joel Dudley at Mount Sinai, New York, reported human herpesviruses 6 and 7 to be more abundant in AD than control brains, and linked these viruses to upregulation of many genes involved in amyloidosis (Jun 2018 news). Now, researchers led by Rudolph Tanzi and Robert Moir at Massachusetts General Hospital, Charlestown, offer a mechanism to explain this association. In the July 11 Neuron, they report that herpes simplex virus 1 (HSV-1) and human herpesvirus activate Aβ’s superpower, just as bacteria and fungi do. The viruses sparked rapid amyloidosis in mouse and cellular models of AD; this response protected neurons from infection and helped AD mice live longer after a viral challenge. The work is available on BioRxiv, and Neuron has lifted its embargo on the manuscript.
- Aβ42 protects neurons and mice from infection by herpes viruses.
- The peptide binds viral particles and rapidly fibrillizes, forming sticky nets.
- As a result, viral infections bring on amyloidosis in AD models within 48 hours.
The amyloid hypothesis of AD holds that amyloidosis kicks off downstream pathologies, such as tau tangles and neuroinflammation, which lead to dementia.
“When you take the two papers together, they provide a complete picture of how herpes virus may accelerate and enhance the progression of AD,” Moir told Alzforum. “Viral seeding of plaque can be regarded as a prequel to the amyloid hypothesis,” he and Tanzi wrote to Alzforum (full comment below).
Moir acknowledged that it remains uncertain whether the virus by itself can initiate the disease. Even if it does, infection likely represents but one possible trigger for Alzheimer’s pathology, he stressed. Other cases may be purely genetic, caused by overproduction or poor clearance of the peptide. Howard Federoff at the University of California, Irvine, said the data bolster the theory that Alzheimer’s disease is actually many diseases. “There may be disparate triggers that lie upstream of a common pathway of Aβ induction and fibrillization,” Federoff suggested.
Others called the data exciting. “The concept that Aβ fibrils can act as pathogen nets—ensnaring and then trapping herpesviruses—is remarkable and unanticipated,” Terrence Town at the University of Southern California, Los Angeles, wrote to Alzforum (full comment below). “This paper properly highlights the anti-infective nature of Aβ amyloid,” wrote Brian Balin, Philadelphia College of Osteopathic Medicine, Pennsylvania, and Alan Hudson, Wayne State University School of Medicine, Detroit (full comment below).
The idea that infections might stimulate AD has been around since at least the 1990s, championed by researchers such as Balin and Ruth Itzhaki at the University of Manchester, U.K. (e.g., July 2004 webinar). It received a boost when Tanzi, Moir, and colleagues proposed that Aβ functions as an antimicrobial peptide, shutting down bacterial and fungal replication in vitro (Apr 2009 conference news; Mar 2010 news).
The MGH researchers subsequently showed that the peptide formed sticky nets that ensnared pathogenic yeast and bacteria in animal and cell culture models, helping the cell or host organism to survive (May 2016 news). Alas, few other labs jumped in to study the topic, though some researchers have reported analogous findings in Parkinson’s, turning up evidence that α-synuclein, too, functions as an antimicrobial (May 2017 news; Jul 2017 news; Apr 2018 news).
Yeast and bacteria are not that common in human brain. Herpes viruses are. Some studies claim that nearly everyone carries these viruses, usually since early childhood, and they often reach the central nervous system (Jamieson et al., 1991). Herpes viruses are found in 90 percent of amyloid plaques, and active infections have been linked to AD risk (Wozniak et al., 2009; Letenneur et al., 2008; Feb 2011 webinar). “Herpes virus is the No. 1 pathogen associated with AD,” Moir noted.
To test Aβ’s response to these pathogens, first author William Eimer injected a lethal dose of HSV1 into the hippocampi of five- to six-week-old 5xFAD mice and controls. At this age, plaques have not yet formed, but Aβ levels are high. The AD mice survived longer, with half of them still alive after two days, when nearly all controls had already succumbed to the infection.
Moreover, in the AD mice, amyloid plaques popped up within 48 hours of virus injection, surrounding viral particles (see image above). Plaques did not form in sham-injected 5xFAD mice, nor in wild-type controls injected with virus. In a separate experiment, the researchers injected young 5xFAD mice with non-lethal doses of HSV1 and saw advanced amyloidosis in their cortices three weeks later. The data suggest that a low-level viral infection in the brain can still accelerate amyloid formation, the authors noted.
Snare that Virus. Aβ42 rapidly cocoons viral particles, forming fibrils after 15 minutes (left), nets after 30 (middle), and impenetrable clumps after two hours (right). [Courtesy of Neuron, Eimer et al.]
How might viruses do this? Eimer and colleagues report that Aβ42 oligomers bind to HSV1 through glycoprotein B, a component of the viral envelope that helps viruses enter host cells. Antibodies to this glycoprotein competitively inhibited Aβ binding, but did not entirely eliminate it, suggesting the peptide may bind other moieties as well. After Aβ42 oligomers bound glycoprotein B, they immediately began to fibrillize. Within minutes, viral particles in vitro sported long fibril tails (see image above). Moir noted that this accoutrement would prevent viruses from penetrating cells, effectively neutralizing the infection. Fibrillization itself continues, however. Within an hour, viral particles were linked by a sticky net of Aβ strands. After two hours, gobs of amyloid completely sequestered the viruses and began to break down viral envelopes, destroying the microbes.
While most people have HSV1 in their peripheral nervous system, the virus does not always get into the brain. Human herpesvirus 6 (HHV-6) is much more common there, with some estimates putting it at close to 100 percent prevalence. The authors could not test this virus in mice because mice resist HHV-6 infection due to genetic differences in a cellular receptor between mice and humans. Instead, the authors added HHV-6A to three-week-old, three-dimensional neural cell cultures that model aspects of Alzheimer’s pathology (Oct 2014 news). These cultures normally do not form amyloid plaques before six weeks, but 48 hours after addition of HHV-6A, they were peppered with fibrillar deposits. As with HSV-1, Aβ42 bound to glycoprotein B in HHV-6A’s viral envelope and rapidly fibrillized.
Charlotte Warren-Gash at the London School of Hygiene and Tropical Medicine considers the case for Aβ acting as an antimicrobial peptide convincing, but cautioned the findings may have little relevance for AD. She noted that only a small proportion of people experience HSV-1 outbreaks. “During latency—the commonest state—there is very little viral gene expression. … Reactivating herpes viruses may be just one of a range of factors that can accelerate some part of the aging process, but disentangling their effects from those of other environmental, social, and lifestyle factors remains a formidable challenge,” she wrote to Alzforum (full comment below).
Moir agrees that viruses are likely to play a role in only a subset of AD cases. People have differing susceptibilities to viral infection, with some never experiencing outbreaks, and others having them regularly. A combination of genetic and environmental factors may affect how active viral infections are in a given person, he suggested. In particular, the ApoE4 allele seems to supercharge the immune response, improving survival in pathogen-rich environments early in life (Vasunilashorn et al., 2011; Fujioka et al., 2013; Gale et al., 2014; van Exel et al., 2017). Late in life, this aggressiveness may become a liability if the brain overreacts to recurrent viral outbreaks by producing too much amyloid, Moir speculated.
“Immune responses are a double-edged sword. Amyloidosis may be analogous to a fever—a protective host response that can get out of hand and cause damage,” he suggested. This excess of amyloid can lead to inflammation, Moir noted. Other research suggests that this neuroinflammation, not plaques or tangles, is responsible for neuronal death and dementia (Perez-Nievas et al., 2013).
Federoff said an interaction between ApoE4 and the immune response would not surprise him. In previous research on human ApoE knock-in mice infected with HSV-1, he found that those carrying the E4 allele had trouble suppressing viral activity, with their infections less likely to enter latency (Miller and Federoff, 2008). It is unclear how this finding relates to ApoE4’s proinflammatory effects.
As further evidence of a link between viruses and AD, Moir points to a Taiwanese population study of more than 33,000 adults, which found that recent HSV-1 infections conferred a 2.5-fold increased risk of developing dementia. This risk dropped back to baseline for those treated with antiviral medication (Tzeng et al., 2018). “That’s nice evidence that antiviral drugs are effective in reducing your risk for AD,” Moir said. The challenge will be to identify the people who might benefit from such treatment, he added. Federoff wondered whether Dudley’s recent transcriptome data might provide potential biomarkers for active CNS viral infections.
Another new paper, currently available as a preprint on BioRxiv, adds genetic evidence for HSV-1 playing a role in AD. Researchers led by Robert Graham at Genentech, South San Francisco, identified the functional variant linked to a protective GWAS hit as being a missense mutation in the paired immunoglobulin-like type 2 receptor alpha (PILRA). PILRA is a microglia receptor that dampens inflammation.
To examine the effects of the G78R missense variant, first author Nisha Rathore transfected the variant and the normal protein into a kidney cell line. Rathore and colleagues found that G78R weakened binding to several endogenous ligands. Because the virus HSV-1 uses PILRA to enter cells, the authors tested this as well, and found the missense variant reduced its binding by half.
Graham and colleagues wondered if the G78R variant might protect carriers from viral infection. They isolated monocyte-derived macrophages from five people homozygous for the variant, and five homozygous for the normal gene. When the cells were exposed to HSV-1, those carrying the variant resisted infection, accumulating five- to 10-fold less HSV-1 DNA than controls. The results suggest that resistance to HSV-1 infection could help protect against Alzheimer’s, the authors noted.
While several studies now strengthen the case for viral infections as a risk factor for AD, Moir sees little utility in treating people who already have the disease with antivirals. “Aβ is like the match that sets fire to the underbrush, sparking tau tangles, which then start a forest fire of neuroinflammation,” he said.—Madolyn Bowman Rogers
- Aberrant Networks in Alzheimer’s Tied to Herpes Viruses
- Prague: Aβ Rehabilitated as an Antimicrobial Protein?
- Paper Alert: Aβ’s Day Job—Slayer of Microbes?
- Like a Tiny Spider-Man, Aβ May Fight Infection by Cocooning Microbes
- Olfactory System Model Explores Antimicrobial Role for α-Synuclein
- Put ’Em Up: Does α-Synuclein Help Fight Microbes in the Gut?
- Do Immune Responses Promote, or Prevent, Parkinson’s Disease?
- Alzheimer’s in a Dish? Aβ Stokes Tau Pathology in Third Dimension
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