MCDB 6 UCSB Genetic Engineering Do Microbes Trigger Alzheimers Disease Paper •Should be TYPED and there is no length requirement as long as you summarize t

MCDB 6 UCSB Genetic Engineering Do Microbes Trigger Alzheimers Disease Paper •Should be TYPED and there is no length requirement as long as you summarize them well

•Each summary should be on a separate page (separate PDF document)

Suggestion: summary should include these 3 sections:

1. Aim/significance of paper/work

2. Methods/results

3. Conclusions/achievement

first article: https://deepak997398.blogspot.com/2020/05/genetic-…

also a video version for it:

second article: linked in the pdf Do Microbes Trigger Alzheimer’s Disease? | The Scientist Magazine®
https://www.the-scientist.com/features/do-microbes-trigger-alzheime…
Do Microbes Trigger Alzheimer’s Disease?
The once fringe idea is gaining traction among the scienti?c community.
Jill U. Adams
Aug 31, 2017
© ISTOCK.COM/KIRSTYPARGETER
I
n late 2011, Drexel University dermatology professor Herbert Allen was astounded to read a new
research paper documenting the presence of long, corkscrew-shape bacteria called spirochetes in
postmortem brains of patients with Alzheimer’s disease.1 Combing data from published reports, the
International Alzheimer Research Center’s Judith Miklossy and colleagues had found evidence of
spirochetes in 451 of 495 Alzheimer’s brains. In 25 percent of cases, researchers had identified the
spirochete as Borrelia burgdorferi, a causative agent of Lyme disease. Control brains did not contain the
spirochetes.
The study made Allen think back to 40 years earlier, when he was an intern at Johns Hopkins
University and had treated a patient diagnosed with neurosyphilis, a neurological syndrome that
included dementia and resulted from the invasion of the syphilis spirochete into the brain. “The
parallel between Lyme disease and syphilis had me intrigued,” he says.
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Allen had recently proposed a novel role for biofilms
—colonies of bacteria that adhere to surfaces and are
largely resistant to immune attack or antibiotics—in
eczema. He suggested that because biofilms block skin
ducts and trigger innate immune responses, they may
cause the stubborn skin condition. Allen knew of
recent work showing that Lyme spirochetes form
biofilms,2 which led him to wonder if biofilms might
also play a role in Alzheimer’s disease. When Allen
stained for biofilms in brains from deceased
Alzheimer’s patients, he found them in the same
hippocampal locations as amyloid plaques.3 Toll-like
receptor 2 (TLR2), a key player in innate immunity,
was also present in the same region of the Alzheimer’s
Hippocampal section of human brain with Alzheimer’s
disease that shows costaining of bio?lms and amyloid-?.
brains but not in the controls. He hypothesizes that
COURTESY OF HERBERT ALLEN
TLR2 is activated by the presence of bacteria, but is
locked out by the biofilm and damages the surrounding tissue instead.
Spirochetes, common members of the oral microbiome, belong to a small set of microbes that cross
the blood-brain barrier when they’re circulating in the blood, as they are during active Lyme
infections or after oral surgery. However, the bacteria are so slow to divide that it can take decades to
grow a biofilm. This time line is consistent with Alzheimer’s being a disease of old age, Allen reasons,
and is corroborated by syphilis cases in which the neuroinvasive effects of spirochetes might appear as
long as 50 years after primary infection.
Allen’s work contributes to the revival of a long-standing hypothesis concerning the development of
Alzheimer’s. For 30 years, a handful of researchers have been pursuing the idea that pathogenic
microbes may serve as triggers for the disease’s neuropathology. Most came across the connection
serendipitously, as Allen did, and some have made it their life’s work, in spite of scathing criticism and
related challenges in attracting funding and publishing results.
“There have been all these observations over time,”
says Miklossy. Although she says she’s been
dismissed as an “idiot” and denied funding, she
continues to pursue spirochetes as an instigating
factor in Alzheimer’s disease. “I’m a physician who
believes in the Hippocratic Oath,” she says. “We
have to do everything we can.”
And the Alzheimer’s field seems primed for a fresh
look at a theory that might account for the
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As early as the 1990s, three
laboratories in di?erent
countries, each studying
di?erent organisms, had
each implicated human
pathogens in the etiology of
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Do Microbes Trigger Alzheimer’s Disease? | The Scientist Magazine®
disease’s pathogenesis. Researchers still cannot say
with confidence which features of the disease, such
https://www.the-scientist.com/features/do-microbes-trigger-alzheime…
Alzheimer’s disease.
as neuroinflammation, tau tangles, and amyloid
plaques, are involved in disease progression and thus would make effective targets for treatment. So
far, most drugs that have made it to clinical testing have targeted the amyloid-? peptide, the main
component of the amyloid plaques that characterize Alzheimer’s brains. The idea is that a build-up of
amyloid-? causes the neuropathology and that removing amyloid-?—by decreasing its production,
impeding aggregation, or aiding removal of the molecule from the brain—will improve, or at least
stall, symptoms of dementia. But so far, researchers have come up empty-handed.
Last November, for example, a Phase 3 trial of Eli Lilly’s amyloid-targeting antibody solanezumab
revealed no improvement in patients in early stages of the disease. This costly and crushing failure
was followed up a few months later with another, when Merck halted its clinical trial of the smallmolecule drug verubecestat, which blocks the enzyme that yields amyloid-?, in patients with mild to
moderate disease. A trial using verubecestat in the earliest diagnosable stage of the disease is still
underway.
And these are just the latest in a string of experimental drugs for Alzheimer’s disease that have failed
to show any benefit in clinical trials. Some blame the trials themselves for these high-profile flops.
“The quality of the clinical trials has been low,” says John Hardy, a molecular neuroscientist at the
University College London, pointing out that a couple of the drugs didn’t even make it into the brain.4
But other researchers question the underlying theory.
In light of continued failures to develop effective drugs, some researchers, such as Harvard
neurobiologist Rudolph Tanzi, think it’s high time that more effort and funding go into alternative
theories of the disease. “Any hypothesis about Alzheimer’s disease must include amyloid plaques,
tangles, inflammation—and, I believe, infection.”
See “What Causes Alzheimer’s?”
A history of microbial links
Herpes simplex virus type 1 (HSV1) can acutely infect the brain and cause a rare but very serious
encephalitis. In the late 1980s, University of Manchester molecular virologist Ruth Itzhaki noticed that
the areas of the brain affected in HSV1 patients were the same as those damaged in patients with
Alzheimer’s disease. Knowing that herpes can lie latent in the body for long periods of time, she began
to wonder if there was a causal connection between the infection and the neurodegenerative disorder.
Itzhaki began looking for HSV1 DNA in the brains of Alzheimer’s patients—and found it. But the viral
DNA also turned up in the brains of age-matched controls. Using PCR, still a new technique at the
time, was fraught with difficulty, and Itzhaki’s findings were challenged as resulting from
contamination. Itzhaki repeated her work with great care and consistently found that two-thirds to
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Emerging evidence links bacterial or viral infection with the neuropathology of Alzheimer’s disease.
See full infographic: WEB | PDF
© KIMBERLY BATTISTA
three-quarters of elderly people harbor HSV1 in their brains, whether they had Alzheimer’s or not. So
she searched for a genetic difference that might explain why only some HSV1-infected individuals
develop dementia. Finally, in 1997, she reported that having both HSV1 in the brain and the
apolipoprotein E gene variant APOE4 accounted for 60 percent of the Alzheimer’s cases she
considered—much higher than either factor alone.5 But most Alzheimer’s researchers still dismissed
her work. Itzhaki says her detractors have been set in their ways—and perhaps too wedded to
scenarios involving plaques and tangles. “They don’t know anything about viruses,” she says, especially
the fact that herpes can linger in the body and brain. “If we say the virus causes this, they imagine the
scenario is fast. It’s incredibly naive.”
Around the same time, neuropathologist Miklossy, then at the University of Lausanne in Switzerland,
was detailing the brain damage caused by spirochetes—both in neurosyphilis and neuroborrelia, a
syndrome caused by Lyme bacteria. She happened upon a head trauma case with evidence of
bacterial invasion and plaque formation, and turned her attention to Alzheimer’s. She isolated
spirochetes from brain tissue in 14 Alzheimer’s patients but detected none in 13 age-matched controls.
In addition, monoclonal antibodies that target the amyloid precursor protein (APP)—which, when
cleaved, forms amyloid-?—cross-reacted with the spirochete species found, suggesting the bacteria
might be the source of the protein.6
Although Miklossy says she received some positive reactions to her findings when she published them
in 1993, she, like Itzhaki, also faced her fair share of skepticism. The critiques included comments that
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the work was “foolish, unorthodox, and crazy,” she adds.
Meanwhile, in the U.S., a third line of evidence linking Alzheimer’s to microbial infection began to
emerge. While serving on a fraud investigation committee, Alan Hudson, a microbiologist then at
MCP-Hahnemann School of Medicine in Philadelphia, met Brian Balin, who studied
neuropathological processes at the Philadelphia College of Osteopathic Medicine. Soon, Balin began
to send Hudson Alzheimer’s brain tissue to test for intracellular bacteria in the Chlamydia genus. Some
samples tested positive for C. pneumoniae: specifically, the bacteria resided in microglia and astrocytes
in regions of the brain associated with Alzheimer’s neuropathology, such as the hippocampus and
other limbic system areas. Hudson had a second technician repeat the tests before he called Balin to
unblind the samples. The negatives were from control brains; the positives all had advanced
Alzheimer’s disease.7 “We were floored,” Hudson says.
The paper that Balin, Hudson, and colleagues wrote to announce the findings received worldwide
press coverage, says Hudson, now professor emeritus at Wayne State University School of Medicine.
But when the authors went to the Alzheimer’s disease meeting, he says, “nobody talked to us.”
Thus, as early as the 1990s, three laboratories in different countries, each studying different organisms,
had each implicated human pathogens in the etiology of Alzheimer’s disease. But the suggestion that
Alzheimer’s might have some microbial infection component was still well outside of the theoretical
mainstream.
New century, new mechanisms
Last year, Itzhaki, Miklossy, Hudson, and Balin, along with 29 other scientists, published a review in
the Journal of Alzheimer’s Disease to lay out the evidence implicating a causal role for microbes in the
disease.8 The paper opens with a plea: “We are researchers and clinicians working on Alzheimer’s
disease . . . and we write to express our concern that one particular aspect of the disease has been
neglected.”
George Perry, editor of the journal and an Alzheimer’s researcher at the University of Texas at San
Antonio, not only agreed to publish the article, he signed on as an author too. “The Journal of
Alzheimer’s Disease promotes all sorts of different ideas,” he says. “We don’t care about popularity.”
And, slowly but surely, Alzheimer’s researchers finally seem to be giving the pathogen hypothesis a
good, hard look. Harvard’s Tanzi, one of the newer microbial theorists, has been a prominent figure in
the Alzheimer’s field for decades. He contributed to the 1987 discovery of APP, the first Alzheimer’s
disease gene. Recently, Tanzi and his colleagues showed that amyloid-? inhibits the in vitro growth of
pathogenic bacteria, including Candida albicans, E. coli, and Staphylococcus aureus, suggesting the
Alzheimer’s-linked peptide was acting as an antimicrobial.9 Tanzi’s working hypothesis is that
microbes trigger an innate immune response, in which amyloid-? plays a key role. The peptide
surrounds the site of infection to shield healthy tissue from the invaders. Too much clumping,
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Transgenic mice (top row) whose brains were injected with Salmonella expressed high levels of amyloid-? in those same regions
48 hours later.
REPRINTED WITH PERMISSION FROM D.K.V. KUMAR ET AL., SCI TRANSL MED, 8:340RA72, 2016.
however, can cause problems of its own—the very processes by which plaques trigger neuronal death.
A subsequent study by Tanzi’s group found that amyloid-? binds to microbes and links together with
more amyloid-? to entrap the invaders and keep them from interacting with host cells. Indeed, in a
transgenic mouse model of Alzheimer’s disease, Salmonella infection seeded amyloid plaques in the
brain.10 “The plaques are generated in the hippocampus and temporal cortex—the regions most
susceptible to blood-brain barrier breach,” Tanzi says, suggesting that those areas are where pathogens
would first gain entry. “It makes perfect sense to me.”
Tanzi is well aware of the work by Miklossy and others and the criticism that they’ve received.
Expecting to get their own dose of criticism, Tanzi says, “we wanted to do everything right, do every
control. We spent eight years on this paper.” But to his surprise, the backlash didn’t come. “To our
delight, the field looked at what we did,” he says—a sign, perhaps, that the Alzheimer’s research
community is finally ready to consider the microbe theory.
Proponents of this idea still face skepticism, however. Elaine Bearer, a molecular neurobiologist at the
University of New Mexico Health Sciences Center, received mixed responses when she began
publishing and presenting her work linking HSV1 to Alzheimer’s neuropathology. As is a familiar story
by now, Bearer had stumbled onto the microbe theory serendipitously.
Her main research interest is how molecular motors pick up cargo in the giant squid axon, and she
uses HSV1 as experimental cargo because it’s known to travel in both directions along axonal transport
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There are several hypotheses to explain the apparent connection between infection and Alzheimer’s neurodegeneration
pathology.
See full infographic: WEB | PDF
© KIMBERLY BATTISTA
routes. During infection, HSV1 travels from sensory nerve endings to nerve cell bodies where the virus
can hole up. When activated, HSV1 travels back out to synapses, reinfects epithelial cells, and voilà—
cold-sore recurrence.
In 2006, Bearer found that HSV1 uses APP to attach to axonal transport machinery.11 And as a result,
HSV1 redistributes APP within the neuron, she says. That means APP can pile up in ways that don’t
happen in uninfected cells. More recently, Bearer showed that “the virus does something to APP,” she
says. “In epithelial cells, it induces a 25-fold increase in the protein,” suggesting synthesis of the
protein also responds to infection.12
Bearer has also produced evidence that HSV1 is trapped in amyloid plaques in human brains. (She has
presented this work, but not published it.) This mirrors Tanzi’s findings of Salmonella within amyloid
plaques in an animal model, and those of Allen, who found bacterial biofilms colocalized with
amyloid-? in human brain tissue.
Despite the increase in evidence supporting the microbial theory of Alzheimer’s disease, however,
funding for such research remains difficult to procure. And scientists working in this area also
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continue to face skepticism from the Alzheimer’s research community. University College London’s
Hardy, squarely in the amyloid hypothesis camp, is aware of the work of Itzhaki, Tanzi, and some of
the others, but he says he’s still “not convinced.”
Hardy’s main objections are twofold: the idea that microbes cause Alzheimer’s neuropathology
doesn’t fully explain the hereditary aspects of the disease, and it doesn’t explain the characteristic
anatomical distribution of plaques and tangles in diseased brains. He thinks distribution would be
more widespread in the brain with blood-borne disease. “It just doesn’t ring right,” he says. “It doesn’t
fit the epidemiology, the neuropathology, or the genetics.” To get him to change his tune, Hardy says,
he’d need to see more experimental evidence “to show some element of cause and effect: infect mice,
infect primates, and show disease.”
The microbe theorists freely admit that their proposed microbial triggers are not the only cause of
Alzheimer’s disease. In Itzhaki’s case, some 40 percent of cases are not explained by HSV1 infection.
Of course, the idea that Alzheimer’s might be linked to infection isn’t limited to any one pathogen; the
hypothesis is simply that, following infection, certain pathogens gain access to brain, where immune
responses result in the accumulation of amyloid-?, leading to plaque formation. In the meantime,
with Alzheimer’s patients representing a huge unmet medical need, and experimental drugs often
failing in late-stage trials, even Hardy admits that there are more questions than answers at this point
in terms of the causative factors in Alzheimer’s. “The pathology is a mess. The brain has been diseased
for a long time by the time we see it,” Hardy says. “We’re looking at the end product and trying to
determine how it got that way.”
Perry agrees: “Most of the resources in this field are spent on a few biomarkers. All the evidence shows
that amyloid is important. But causality and centrality are two different things.”
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References
1. J. Miklossy, “Alzheimer’s disease – a neurospirochetosis. Analysis of the evidence following
Koch’s and Hill’s criteria,” J Neuroinflamm, 8:90, 2011.
2. E. Sapi et al., “Characterization of biofilm formation by Borrelia burgdorferi in vitro,” PLOS
ONE, 7:e48277, 2012.
3. H.B. Allen et al., “Alzheimer’s disease: A novel hypothesis integrating spirochetes, biofilm, and
the immune system,” J Neuroinfect Dis, 7:200, 2016.
4. E. Karran, J. Hardy, “A critique of the drug discovery and phase 3 clinical programs targeting the
amyloid hypothesis for Alzheimer disease,” Ann Neurol, 76:185-205, 2014.
5. R.F. Itzhaki et al., “Herpes simplex virus type 1 in brain and risk of Alzheimer’s disease,” Lancet,
349:241-44, 1997.
6. J. Miklossy, “Alzheimer’s disease – a spirochetosis?” Neuroreport, 4:841-48, 1993.
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7. B.J. Balin et al., “Identification and localiz…
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