Herpes simplex virus type 1 DNA is located within Alzheimer's disease amyloid plaques

Herpes simplex virus type 1 DNA is located within Alzheimer's disease amyloid plaques

MA Wozniak 1, AP Mee 2 a, RF Itzhaki 1 *

1Faculty of Life Sciences, University of Manchester, UK 2Department of Medicine, Manchester Royal Infirmary, UK

email: RF Itzhaki (ruth.itzhaki@manchester. ac.uk)

^*Correspondence to RF Itzhaki, Faculty of Life Sciences (North Campus), Moffat Building, University of Manchester, PO Box 88, Manchester M60 1QD, UK.

^aCurrent address: Directorate of Laboratory Medicine, CMMC, Oxford Road, Manchester M13 9PL, UK

No conflicts of interest were declared.

Keywords

brain • Alzheimer's disease • herpes simplex encephalitis • herpes simplex virus type 1 • amyloid plaques • apolipoprotein E • in situ polymerase chain reaction • thioflavin S staining • immunohistochemistry

Abstract

The brains of Alzheimer's disease sufferers are characterized by amyloid plaques and neurofibrillary tangles. However, the cause(s) of these features and those of the disease are unknown, in sporadic cases. We previously showed that herpes simplex virus type 1 is a strong risk factor for Alzheimer's disease when in the brains of possessors of the type 4 allele of the apolipoprotein E gene (APOE-4), and that -amyloid, the main component of plaques, accumulates in herpes simplex virus type 1-infected cell cultures and mouse brain. The present study aimed to elucidate the relationship of the virus to plaques by determining their proximity in human brain sections. We used in situ polymerase chain reaction to detect herpes simplex virus type 1 DNA, and immunohistochemistry or thioflavin S staining to detect amyloid plaques. We discovered a striking localization of herpes simplex virus type 1 DNA within plaques: in Alzheimer's disease brains, 90% of the plaques contained the viral DNA and 72% of the DNA was associated with plaques; in aged normal brains, which contain amyloid plaques at a lower frequency, 80% of plaques contained herpes simplex virus type 1 DNA but only 24% of the viral DNA was plaque-associated (p < src="http://www3.interscience.wiley.com/giflibrary/12/beta.gif" align="absbottom" border="0">-amyloid (A), so that less of the viral DNA is seen to be associated with A in the brain. Our present data, together with our finding of A accumulation in herpes simplex virus type 1-infected cells and mouse brain, suggest that this virus is a major cause of amyloid plaques and hence probably a significant aetiological factor in Alzheimer's disease. They point to the usage of antiviral agents to treat the disease and possibly of vaccination to prevent it. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Received: 24 June 2008; Revised: 6 August 2008; Accepted: 5 September 2008

Digital Object Identifier (DOI)

10.1002/path.2449 About DOI

Source

Article on this discovery from The Washington Post:

Cold Sore Virus Linked to Alzheimer's

People who develop cold sores may be at increased risk for Alzheimer's disease, according to British researchers who said the herpes virus that causes cold sores is a major cause of the brain protein plaques associated with Alzheimer's.

The University of Manchester team found DNA evidence of the herpes simplex virus (HSV) type 1 in 90 percent of plaques in Alzheimer's patients'brains, BBC News reported. The findings were published in the Journal of Pathology.

"We suggest that HSV1 enters the brain in the elderly as their immune systems decline and then establishes a dormant infection from which it is repeatedly activated by events such as stress, immunosuppression, and various infections," said Professor Ruth Itzhaki. This causes damage to brain cells, which die and disintegrate, releasing the proteins that form the plaques that cause Alzheimer's, the study suggested.

The potential good news in this study is that antiviral drugs used to treat cold sores may also prevent dementia. Itzhaki and colleagues plan to test that theory, BBC News reported.

Nanoparticle method may be able to inject drugs deep into the brain

Last Updated:10:01pm BST 22/09/2008

A new way to fight Alzheimer's and other neurological diseases aims to deliver a drug deep into the brain using nanoparticles

Alzheimer's is linked with the build up of damaging protein deposits in the brain and now a novel way to hinder this process is under development by a team at University College Dublin. The team has a fundamental discovery in predicting how particles of the order of a billionth of a metre - nanoparticles - move around the body. They report in the Proceedings of the National Academy of Sciences today that the size and the electrical charge of the nanoparticle matters, not just what it is made of. The team found that a coating of proteins, called a corona, built up around the particles and this response mainly depends on the size and the charge of the nanoparticle. This discovery, which shows that different sizes of the same materials pick up different proteins from the body, has a number of fundamental implications. "The find knocked my socks off," said Prof Kenneth Dawson, who led the work. This find can be exploited to guide nanoparticles around the body. The Dublin team is investigating how to exploit this to design nanoparticles to take an Alzheimer's drug to the brain. Work by Prof Günter Oberdörster at the University of Rochester and Wolfgang Kreyling in Germany shows that nanoparticles can move into the brains of animals. "It could change the face of health care if we learn how to exploit this potential to guide particles to important destinations in the body, such as the brain" said Prof Dawson. "We have also now just found that certain nanoparticles are able to reverse the growth of Alzheimer plaques (the deposits of protein linked with the disease)," he said, explaining how they particles disrupt the smaller protein deposits that are thought to be the most toxic. These experiments are only at the test tube stage, "but if we can combine the capacity of nanoparticles to get into the brain with this effect of reversing the growth of plaques that would point a way forward in these diseases." By the same token of course, there should be caution and, as with any new technology, it must be "tested very carefully first," said Prof Dawson. Thus, when people are exposed to nanoparticles they may penetrate into different parts of the body, with unknown health effects. So it is important to study the problems carefully, and not jump to conclusions, one way or the other, too quickly, he said. Nanoparticles are as much as a million times smaller than the head of a pin, and have unusual properties compared with larger objects made from the same material. The potential interactions of nanomaterials with the body and the environment have attracted increasing attention from the public as well as manufacturers of nanomaterial based products, academic researchers, and policy makers. Nanoparticles can in principle make faster computers, and smaller mobile phones, as well as address some of the most intractable diseases. Nanotechnology is expected to become a $1 trillion industry within the next decade. However, it is important that the be introduced safely and a new international research alliance to establish protocols for reproducible toxicological testing of nanomaterials in both cultured cells and animals was unveiled a few days ago at Nanotox 2008, a major research meeting. This Alliance will be able to check each others work around the world, and build confidence in science, and further afield. "When this team of scientists from Europe, the US and Japan are able to get the same results for interactions of nanomaterials with biological organisms, then science and society can have higher confidence in the safety of these materials," said Prof Dawson. "This will open the doors to many potential benefits for society at large." Source Also see The Scientist: A new twist on nanoparticle behavior Posted by Bob Grant [Entry posted at 23rd September 2008 04:02 PM GMT] View comments(2) | Comment on this blog Researchers hoping to develop nanoparticles as medicines or carriers of therapeutic molecules have much more to worry about than the type of material they plan on miniaturizing, according to a study in this week's issue of the Proceedings of the National Academy of Science. Researchers in Ireland found that the corona, or cloud of proteins and other biomolecules that adheres to a nanoparticle immersed in biological media (in this study human blood plasma), changes depending on the size of the nanoparticle and the charge on its surface. That, in turn, can affect the particles' therapeutic action in the body. Nanotechnology is "an enormously powerful tool, but we need to know how to control it," Kenneth Dawson, a University College Dublin physical chemist and the study's senior author, told The Scientist. "We have to look at what's happening at the surface of these materials rather than just the materials themselves. It's a new science really." According to Dawson, the study represents a "paradigm shift" in how chemists typically think about the interaction of nanoparticles in biological settings. Traditionally the composition of the nanoparticle itself was thought to be the most important safety and functionality consideration. With Dawson's paper, the importance of the corona, and the physical factors which shape it, comes to the fore. "The biological identity of a particle depends not only on its own material, but also what it picks up in the surroundings," Dawson said. Dawson and his group last year coined the term "corona" for the conglomeration of proteins adhering to nanoparticles in biological media. Since then, the group has been exploring the properties of coronas. In the present study, the researchers found that nanoparticles introduced, in vitro, to human plasma accumulated markedly different coronas depending on their size and charge. For example, his team found that uncharged particles attracted more immunoglobulins while charged particles pulled in more fat-shuttling proteins. "They pulled on quite different proteins," Dawson explained. This, Dawson said, could have major implications for nanoparticles used as human therapeutics. For example, a particle of one size and surface charge might be trafficked to the brain of a patient, while another particle of a different size and charge, even though it's made of the same material, might be shuttled to the liver. "[A nanoparticle] can go places you didn't want it to go, and when it gets there it might pick up different signals that can be confusing," he said. Drug makers and regulators should consider the effects of nanoparticle size and surface when developing and monitoring therapies that use nanotechnology, he added. University of Rochester professor of environmental medicine and toxicology Gunter Oberdorster, who was not involved in the study, noted that drug makers may be able to make use of the differing physiological effects different coronas have on a nanoparticle's fate in the body. "Nanomedicine may take advantage of this and target a specific organ." While he called Dawson's study "an important step," he cautioned that in vivo studies must confirm the effects of nanoparticle size and surface character in living organisms. According to Dawson, other researchers are conducting preliminary in vivo studies in mice to explore how nanoparticle sizes and surface properties affect the physiological activity of the tiny particles in living systems. Although no treatments or therapeutics that use nanoparticles are currently on the market, experimental cancer treatments and other nanotechnology-based therapies are nearing FDA approval, according to Rice University chemist and Director of the International Council on Nanotechnology, Kristen Kulinowski. "This [study] bolsters the argument about the vital need for good, quality characterization [of nanomedicines], the actual species the body will experience," she told The Scientist.