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Two nearly ubiquitous herpes viruses are abundant in the brains of people with Alzheimer’s disease and appear to integrate themselves into the patient’s own genome, where the viruses play havoc with genes involved in Alzheimer’s pathogenesis, among other things, a new study reports.
The genomic analysis of hundreds of Alzheimer’s disease (AD) brain samples found human herpesvirus 6a and 7 (HHV-6a, HHV-7) in the entorhinal cortex and the hippocampus, the initial sites of beta-amyloid overexpression in the disease, first authors Benjamin Readhead, MBBS, Jean-Vianney Haure-Mirande, PhD, and colleagues reported June 21 in Neuron.
The viruses appear to interact with genes implicated in the risk for AD and for regulation and processing of the amyloid precursor protein, including presenilin-1 (PSEN1), BACE1, BIN1, PICALM, and several others. Their presence was directly related to the donors’ Clinical Dementia Rating score, and a mouse model suggests a potential pathway linking HHV infection and brain amyloidosis through a microRNA that’s been previously linked to AD.
It’s impossible to say whether HHV-6a and HHV-7 infections, which occur in nearly 100% of small children, trigger late-life amyloid pathology or whether the viruses reactivate and cross into the brain after amyloid-related damage has already begun, said Keith Fargo, PhD, director of scientific programs and outreach at the Alzheimer’s Association. But the data in this paper are strong enough to give real credence, for the first time, to the idea that Alzheimer’s disease may have an infective component.
“This paper, which is quite dense, presents an idea we have seen before, but which has been mostly dismissed,” Dr. Fargo said in an interview. “For the first time, a world-class group of researchers have completed a landmark paper packed with evidence. It’s not definitive evidence yet, but it will certainly bring that hypothesis into the mainstream in a way it has not been before. The Alzheimer’s research world will sit up and take notice.”
The viruses were present in about 20% of AD brain samples taken from four separate brain banks, but not in control samples or in samples from patients with other neurodegenerative diseases. The commonality suggests that the association is real, and something unique to Alzheimer’s, said Sam Gandy, MD, PhD, one of the paper’s senior authors, and a professor of neurology at Mount Sinai Medical Center, New York.
Joel T. Dudley, PhD, director of the Mount Sinai Institute for Next Generation Healthcare, was the other senior author.
“It seems obvious to us that the AD brains around this country are accumulating the genomes of this particular pair of viruses,” Dr. Gandy said in an interview. “For whatever reason, these people were accumulating the genomes of an infectious agent which crossed the blood-brain barrier, went into the brain, and was present there when they were dying of AD. It was not a remote relationship, such as we would see with serology. This was there when they were dying, and it’s hard to imagine it was doing anything good.”
HHV6 causes a primary illness – roseola – when it first enters the body, usually in early childhood. It then enters a life-long latency, but can reactivate in adulthood, according to the HHV-6 Foundation.
“Reactivation can occur in the brain, lungs, heart, kidney, and gastrointestinal tract, especially in patients with immune deficiencies and transplant patients. In some cases, HHV-6 reactivation in the brain tissue can cause cognitive dysfunction, permanent disability, and death.”
The Neuron paper describes several separate investigations that led the team to conclude that HHV-6a and HHV-7 may be implicated in AD pathogenesis.
Dr. Gandy, Dr. Dudley, and their team were not looking for potentially infective agents when they started down this road 5 years ago. Instead, they wanted to see how genes and gene networks change as patients progress from preclinical Alzheimer’s to Alzheimer’s dementia, in the hope of finding novel drug targets.
“This was a surprise result. We were looking for genes differentially expressed as AD progressed. Instead, we found gene expression changes associated with viral infections.”
A transcriptome analysis pointed to microRNA-155, a molecule that helps control viral infections. This lead the team to look for viral RNA in 643 brain samples from the Mount Sinai Brain Bank. “What we found was that HHV-6a and HHV-7 appeared to be driving these changes,” Dr. Gandy said.
HHV-6a interacted with some of the most well-known AD risk genes, Dr. Gandy said.
“The story is full of tantalizing, yet not quite definitive pieces. Presenilin 1 is the most common cause of genetic forms of AD. There are about two dozen genes associated with late-onset sporadic AD. As we scrutinized the computational analysis of the data, whom should we find lurking there among the genes regulated by HHV-6a and HHV-7 but several of our old gene friends from conventional AD genetics and genome-wide association studies: PSEN1, BIN1, PICALM, among others, all of which are linked to causing AD.”
They validated the results from the Mount Sinai Brain Bank in three other data sets: the Religious Orders Study (300 samples from AD patients and healthy controls) the Rush Memory and Aging Project (298 samples from AD patients and healthy controls), and a collection of temporal cortex studies from the Mayo Clinic (278 samples from patients with AD, pathological aging, or progressive supranuclear palsy, and healthy controls).
Again, they saw HHV-6a and HHV-7 in the AD samples, but not in the normal controls or those with pathological aging. Compared with the AD samples, HHV-7 was present in the progressive supranuclear palsy samples, but HHV-6a was reduced.
Whole-exome sequencing found HHV-6a DNA integrated into host DNA. “This may indicate that the HHV-6a DNA that we find as more abundant in AD reflects HHV-6A that has undergone reactivation from a chromosomally integrated form, although we have not evaluated this directly,” Dr. Readhead and his co-investigators wrote in the paper.
Dr. Gandy said that the presence of the two viruses correlated directly with the patients’ Clinical Dementia Rating scale score, neuritic plaque density across multiple regions, and Braak stage, a measure of neurofibrillary tangles.
Another investigation looked at the fractions of the four major brain cells (neurons, astrocytes, microglia, and endothelial cells) and their relationship to viral RNA. HHV-6a was associated with decreases in the neuronal content of fractions from multiple brain regions, and in all four datasets.
Dr. Haure-Mirande and the team also studied a mouse model lacking the virus-suppressing microRNA-155 molecule and crossed this with one of the most commonly used AD research strains that overexpresses human amyloid precursor protein and develops brain amyloidosis. At 4 months, these mice had larger, more frequent amyloid plaques than the standard amyloidosis mice. Cortical RNA sequencing revealed overlap between upregulated genes in the microRNA-155 knockout mice and the HHV-6a–upregulated genes in human brains.
“These findings support the view of microRNA-155 as a regulator of complex anti- and pro-viral actions, offer a mechanism linking viral activity with AD pathology, and support the hypothesis that viral activity contributes to AD,” the investigators wrote.
As Dr. Gandy said, while not definitive, the studies are tantalizing and lay a solid framework for further investigation. He is confident enough about the association to view HHV as a potential therapeutic target for AD.
“The first step is to find a way to detect the viruses in people. We do have our first antibody to recognize one of the viral proteins, so we’re about to test that on blood serum, blood cells, and spinal fluid, and we will also look for viral DNA in the blood cells. Potentially – way down the road – we might be able to conduct a trial using antivirals,” to see if treatment could slow, or prevent, Alzheimer’s progression.
“These are nice, discrete, testable hypotheses, which makes them attractive,” Dr. Gandy said, “but the truth could be different and is almost certainly a lot messier.”
Dr. Gandy has received research funding from Baxter and Amicus Therapeutics, and personal remuneration from Pfizer and DiaGenic.
SOURCE: Readhead B et al. Neuron. 2018 June 21. doi: 10.1016/j.neuron.2018.05.023.
The study by Readhead and colleagues is a scientific tour de force and is likely to elevate the infective hypothesis to a greater height than ever before and deservedly so. Still, the findings are puzzling, at least to this relative virologic novice.
The relationship of infective agents with seemingly degenerative brain diseases has been a complex puzzle that has led to at least two major discoveries. First was the description of a lifeform simpler than viruses, the prion and identification of the human PrP gene that when mutated is the cause of familial Creutzfeldt-Jakob disease (CJD), which can also be transmitted from human to human (or human to monkey) via tissue transplants.
The data provided by Readhead and colleagues are compelling, however, and unquestionably deserve further attention. Where this will lead is still too early to tell, but given the failure of existing paradigms to translate into meaningful disease-modifying therapies, we have new reason to hope that such a therapy may yet be possible in our lifetime.
Richard J. Caselli, MD, is a professor of neurology at the Mayo Clinic Arizona in Scottsdale and is also associate director and clinical core director of the Arizona Alzheimer’s Disease Center.
The study by Readhead and colleagues is a scientific tour de force and is likely to elevate the infective hypothesis to a greater height than ever before and deservedly so. Still, the findings are puzzling, at least to this relative virologic novice.
The relationship of infective agents with seemingly degenerative brain diseases has been a complex puzzle that has led to at least two major discoveries. First was the description of a lifeform simpler than viruses, the prion and identification of the human PrP gene that when mutated is the cause of familial Creutzfeldt-Jakob disease (CJD), which can also be transmitted from human to human (or human to monkey) via tissue transplants.
The data provided by Readhead and colleagues are compelling, however, and unquestionably deserve further attention. Where this will lead is still too early to tell, but given the failure of existing paradigms to translate into meaningful disease-modifying therapies, we have new reason to hope that such a therapy may yet be possible in our lifetime.
Richard J. Caselli, MD, is a professor of neurology at the Mayo Clinic Arizona in Scottsdale and is also associate director and clinical core director of the Arizona Alzheimer’s Disease Center.
The study by Readhead and colleagues is a scientific tour de force and is likely to elevate the infective hypothesis to a greater height than ever before and deservedly so. Still, the findings are puzzling, at least to this relative virologic novice.
The relationship of infective agents with seemingly degenerative brain diseases has been a complex puzzle that has led to at least two major discoveries. First was the description of a lifeform simpler than viruses, the prion and identification of the human PrP gene that when mutated is the cause of familial Creutzfeldt-Jakob disease (CJD), which can also be transmitted from human to human (or human to monkey) via tissue transplants.
The data provided by Readhead and colleagues are compelling, however, and unquestionably deserve further attention. Where this will lead is still too early to tell, but given the failure of existing paradigms to translate into meaningful disease-modifying therapies, we have new reason to hope that such a therapy may yet be possible in our lifetime.
Richard J. Caselli, MD, is a professor of neurology at the Mayo Clinic Arizona in Scottsdale and is also associate director and clinical core director of the Arizona Alzheimer’s Disease Center.
Two nearly ubiquitous herpes viruses are abundant in the brains of people with Alzheimer’s disease and appear to integrate themselves into the patient’s own genome, where the viruses play havoc with genes involved in Alzheimer’s pathogenesis, among other things, a new study reports.
The genomic analysis of hundreds of Alzheimer’s disease (AD) brain samples found human herpesvirus 6a and 7 (HHV-6a, HHV-7) in the entorhinal cortex and the hippocampus, the initial sites of beta-amyloid overexpression in the disease, first authors Benjamin Readhead, MBBS, Jean-Vianney Haure-Mirande, PhD, and colleagues reported June 21 in Neuron.
The viruses appear to interact with genes implicated in the risk for AD and for regulation and processing of the amyloid precursor protein, including presenilin-1 (PSEN1), BACE1, BIN1, PICALM, and several others. Their presence was directly related to the donors’ Clinical Dementia Rating score, and a mouse model suggests a potential pathway linking HHV infection and brain amyloidosis through a microRNA that’s been previously linked to AD.
It’s impossible to say whether HHV-6a and HHV-7 infections, which occur in nearly 100% of small children, trigger late-life amyloid pathology or whether the viruses reactivate and cross into the brain after amyloid-related damage has already begun, said Keith Fargo, PhD, director of scientific programs and outreach at the Alzheimer’s Association. But the data in this paper are strong enough to give real credence, for the first time, to the idea that Alzheimer’s disease may have an infective component.
“This paper, which is quite dense, presents an idea we have seen before, but which has been mostly dismissed,” Dr. Fargo said in an interview. “For the first time, a world-class group of researchers have completed a landmark paper packed with evidence. It’s not definitive evidence yet, but it will certainly bring that hypothesis into the mainstream in a way it has not been before. The Alzheimer’s research world will sit up and take notice.”
The viruses were present in about 20% of AD brain samples taken from four separate brain banks, but not in control samples or in samples from patients with other neurodegenerative diseases. The commonality suggests that the association is real, and something unique to Alzheimer’s, said Sam Gandy, MD, PhD, one of the paper’s senior authors, and a professor of neurology at Mount Sinai Medical Center, New York.
Joel T. Dudley, PhD, director of the Mount Sinai Institute for Next Generation Healthcare, was the other senior author.
“It seems obvious to us that the AD brains around this country are accumulating the genomes of this particular pair of viruses,” Dr. Gandy said in an interview. “For whatever reason, these people were accumulating the genomes of an infectious agent which crossed the blood-brain barrier, went into the brain, and was present there when they were dying of AD. It was not a remote relationship, such as we would see with serology. This was there when they were dying, and it’s hard to imagine it was doing anything good.”
HHV6 causes a primary illness – roseola – when it first enters the body, usually in early childhood. It then enters a life-long latency, but can reactivate in adulthood, according to the HHV-6 Foundation.
“Reactivation can occur in the brain, lungs, heart, kidney, and gastrointestinal tract, especially in patients with immune deficiencies and transplant patients. In some cases, HHV-6 reactivation in the brain tissue can cause cognitive dysfunction, permanent disability, and death.”
The Neuron paper describes several separate investigations that led the team to conclude that HHV-6a and HHV-7 may be implicated in AD pathogenesis.
Dr. Gandy, Dr. Dudley, and their team were not looking for potentially infective agents when they started down this road 5 years ago. Instead, they wanted to see how genes and gene networks change as patients progress from preclinical Alzheimer’s to Alzheimer’s dementia, in the hope of finding novel drug targets.
“This was a surprise result. We were looking for genes differentially expressed as AD progressed. Instead, we found gene expression changes associated with viral infections.”
A transcriptome analysis pointed to microRNA-155, a molecule that helps control viral infections. This lead the team to look for viral RNA in 643 brain samples from the Mount Sinai Brain Bank. “What we found was that HHV-6a and HHV-7 appeared to be driving these changes,” Dr. Gandy said.
HHV-6a interacted with some of the most well-known AD risk genes, Dr. Gandy said.
“The story is full of tantalizing, yet not quite definitive pieces. Presenilin 1 is the most common cause of genetic forms of AD. There are about two dozen genes associated with late-onset sporadic AD. As we scrutinized the computational analysis of the data, whom should we find lurking there among the genes regulated by HHV-6a and HHV-7 but several of our old gene friends from conventional AD genetics and genome-wide association studies: PSEN1, BIN1, PICALM, among others, all of which are linked to causing AD.”
They validated the results from the Mount Sinai Brain Bank in three other data sets: the Religious Orders Study (300 samples from AD patients and healthy controls) the Rush Memory and Aging Project (298 samples from AD patients and healthy controls), and a collection of temporal cortex studies from the Mayo Clinic (278 samples from patients with AD, pathological aging, or progressive supranuclear palsy, and healthy controls).
Again, they saw HHV-6a and HHV-7 in the AD samples, but not in the normal controls or those with pathological aging. Compared with the AD samples, HHV-7 was present in the progressive supranuclear palsy samples, but HHV-6a was reduced.
Whole-exome sequencing found HHV-6a DNA integrated into host DNA. “This may indicate that the HHV-6a DNA that we find as more abundant in AD reflects HHV-6A that has undergone reactivation from a chromosomally integrated form, although we have not evaluated this directly,” Dr. Readhead and his co-investigators wrote in the paper.
Dr. Gandy said that the presence of the two viruses correlated directly with the patients’ Clinical Dementia Rating scale score, neuritic plaque density across multiple regions, and Braak stage, a measure of neurofibrillary tangles.
Another investigation looked at the fractions of the four major brain cells (neurons, astrocytes, microglia, and endothelial cells) and their relationship to viral RNA. HHV-6a was associated with decreases in the neuronal content of fractions from multiple brain regions, and in all four datasets.
Dr. Haure-Mirande and the team also studied a mouse model lacking the virus-suppressing microRNA-155 molecule and crossed this with one of the most commonly used AD research strains that overexpresses human amyloid precursor protein and develops brain amyloidosis. At 4 months, these mice had larger, more frequent amyloid plaques than the standard amyloidosis mice. Cortical RNA sequencing revealed overlap between upregulated genes in the microRNA-155 knockout mice and the HHV-6a–upregulated genes in human brains.
“These findings support the view of microRNA-155 as a regulator of complex anti- and pro-viral actions, offer a mechanism linking viral activity with AD pathology, and support the hypothesis that viral activity contributes to AD,” the investigators wrote.
As Dr. Gandy said, while not definitive, the studies are tantalizing and lay a solid framework for further investigation. He is confident enough about the association to view HHV as a potential therapeutic target for AD.
“The first step is to find a way to detect the viruses in people. We do have our first antibody to recognize one of the viral proteins, so we’re about to test that on blood serum, blood cells, and spinal fluid, and we will also look for viral DNA in the blood cells. Potentially – way down the road – we might be able to conduct a trial using antivirals,” to see if treatment could slow, or prevent, Alzheimer’s progression.
“These are nice, discrete, testable hypotheses, which makes them attractive,” Dr. Gandy said, “but the truth could be different and is almost certainly a lot messier.”
Dr. Gandy has received research funding from Baxter and Amicus Therapeutics, and personal remuneration from Pfizer and DiaGenic.
SOURCE: Readhead B et al. Neuron. 2018 June 21. doi: 10.1016/j.neuron.2018.05.023.
Two nearly ubiquitous herpes viruses are abundant in the brains of people with Alzheimer’s disease and appear to integrate themselves into the patient’s own genome, where the viruses play havoc with genes involved in Alzheimer’s pathogenesis, among other things, a new study reports.
The genomic analysis of hundreds of Alzheimer’s disease (AD) brain samples found human herpesvirus 6a and 7 (HHV-6a, HHV-7) in the entorhinal cortex and the hippocampus, the initial sites of beta-amyloid overexpression in the disease, first authors Benjamin Readhead, MBBS, Jean-Vianney Haure-Mirande, PhD, and colleagues reported June 21 in Neuron.
The viruses appear to interact with genes implicated in the risk for AD and for regulation and processing of the amyloid precursor protein, including presenilin-1 (PSEN1), BACE1, BIN1, PICALM, and several others. Their presence was directly related to the donors’ Clinical Dementia Rating score, and a mouse model suggests a potential pathway linking HHV infection and brain amyloidosis through a microRNA that’s been previously linked to AD.
It’s impossible to say whether HHV-6a and HHV-7 infections, which occur in nearly 100% of small children, trigger late-life amyloid pathology or whether the viruses reactivate and cross into the brain after amyloid-related damage has already begun, said Keith Fargo, PhD, director of scientific programs and outreach at the Alzheimer’s Association. But the data in this paper are strong enough to give real credence, for the first time, to the idea that Alzheimer’s disease may have an infective component.
“This paper, which is quite dense, presents an idea we have seen before, but which has been mostly dismissed,” Dr. Fargo said in an interview. “For the first time, a world-class group of researchers have completed a landmark paper packed with evidence. It’s not definitive evidence yet, but it will certainly bring that hypothesis into the mainstream in a way it has not been before. The Alzheimer’s research world will sit up and take notice.”
The viruses were present in about 20% of AD brain samples taken from four separate brain banks, but not in control samples or in samples from patients with other neurodegenerative diseases. The commonality suggests that the association is real, and something unique to Alzheimer’s, said Sam Gandy, MD, PhD, one of the paper’s senior authors, and a professor of neurology at Mount Sinai Medical Center, New York.
Joel T. Dudley, PhD, director of the Mount Sinai Institute for Next Generation Healthcare, was the other senior author.
“It seems obvious to us that the AD brains around this country are accumulating the genomes of this particular pair of viruses,” Dr. Gandy said in an interview. “For whatever reason, these people were accumulating the genomes of an infectious agent which crossed the blood-brain barrier, went into the brain, and was present there when they were dying of AD. It was not a remote relationship, such as we would see with serology. This was there when they were dying, and it’s hard to imagine it was doing anything good.”
HHV6 causes a primary illness – roseola – when it first enters the body, usually in early childhood. It then enters a life-long latency, but can reactivate in adulthood, according to the HHV-6 Foundation.
“Reactivation can occur in the brain, lungs, heart, kidney, and gastrointestinal tract, especially in patients with immune deficiencies and transplant patients. In some cases, HHV-6 reactivation in the brain tissue can cause cognitive dysfunction, permanent disability, and death.”
The Neuron paper describes several separate investigations that led the team to conclude that HHV-6a and HHV-7 may be implicated in AD pathogenesis.
Dr. Gandy, Dr. Dudley, and their team were not looking for potentially infective agents when they started down this road 5 years ago. Instead, they wanted to see how genes and gene networks change as patients progress from preclinical Alzheimer’s to Alzheimer’s dementia, in the hope of finding novel drug targets.
“This was a surprise result. We were looking for genes differentially expressed as AD progressed. Instead, we found gene expression changes associated with viral infections.”
A transcriptome analysis pointed to microRNA-155, a molecule that helps control viral infections. This lead the team to look for viral RNA in 643 brain samples from the Mount Sinai Brain Bank. “What we found was that HHV-6a and HHV-7 appeared to be driving these changes,” Dr. Gandy said.
HHV-6a interacted with some of the most well-known AD risk genes, Dr. Gandy said.
“The story is full of tantalizing, yet not quite definitive pieces. Presenilin 1 is the most common cause of genetic forms of AD. There are about two dozen genes associated with late-onset sporadic AD. As we scrutinized the computational analysis of the data, whom should we find lurking there among the genes regulated by HHV-6a and HHV-7 but several of our old gene friends from conventional AD genetics and genome-wide association studies: PSEN1, BIN1, PICALM, among others, all of which are linked to causing AD.”
They validated the results from the Mount Sinai Brain Bank in three other data sets: the Religious Orders Study (300 samples from AD patients and healthy controls) the Rush Memory and Aging Project (298 samples from AD patients and healthy controls), and a collection of temporal cortex studies from the Mayo Clinic (278 samples from patients with AD, pathological aging, or progressive supranuclear palsy, and healthy controls).
Again, they saw HHV-6a and HHV-7 in the AD samples, but not in the normal controls or those with pathological aging. Compared with the AD samples, HHV-7 was present in the progressive supranuclear palsy samples, but HHV-6a was reduced.
Whole-exome sequencing found HHV-6a DNA integrated into host DNA. “This may indicate that the HHV-6a DNA that we find as more abundant in AD reflects HHV-6A that has undergone reactivation from a chromosomally integrated form, although we have not evaluated this directly,” Dr. Readhead and his co-investigators wrote in the paper.
Dr. Gandy said that the presence of the two viruses correlated directly with the patients’ Clinical Dementia Rating scale score, neuritic plaque density across multiple regions, and Braak stage, a measure of neurofibrillary tangles.
Another investigation looked at the fractions of the four major brain cells (neurons, astrocytes, microglia, and endothelial cells) and their relationship to viral RNA. HHV-6a was associated with decreases in the neuronal content of fractions from multiple brain regions, and in all four datasets.
Dr. Haure-Mirande and the team also studied a mouse model lacking the virus-suppressing microRNA-155 molecule and crossed this with one of the most commonly used AD research strains that overexpresses human amyloid precursor protein and develops brain amyloidosis. At 4 months, these mice had larger, more frequent amyloid plaques than the standard amyloidosis mice. Cortical RNA sequencing revealed overlap between upregulated genes in the microRNA-155 knockout mice and the HHV-6a–upregulated genes in human brains.
“These findings support the view of microRNA-155 as a regulator of complex anti- and pro-viral actions, offer a mechanism linking viral activity with AD pathology, and support the hypothesis that viral activity contributes to AD,” the investigators wrote.
As Dr. Gandy said, while not definitive, the studies are tantalizing and lay a solid framework for further investigation. He is confident enough about the association to view HHV as a potential therapeutic target for AD.
“The first step is to find a way to detect the viruses in people. We do have our first antibody to recognize one of the viral proteins, so we’re about to test that on blood serum, blood cells, and spinal fluid, and we will also look for viral DNA in the blood cells. Potentially – way down the road – we might be able to conduct a trial using antivirals,” to see if treatment could slow, or prevent, Alzheimer’s progression.
“These are nice, discrete, testable hypotheses, which makes them attractive,” Dr. Gandy said, “but the truth could be different and is almost certainly a lot messier.”
Dr. Gandy has received research funding from Baxter and Amicus Therapeutics, and personal remuneration from Pfizer and DiaGenic.
SOURCE: Readhead B et al. Neuron. 2018 June 21. doi: 10.1016/j.neuron.2018.05.023.
FROM NEURON