Re: [neuroimmune-xmrv-alliance] Article: Virus that causes cold sores linked to Alzheimers

April 6, 2011

here's what I posted to my list-serves- including the scientific studies that

support the link. (Sorry, thought I had posted them here).

Researchers link herpes to Alzheimers disease

'Cold sores' connected to cognitive decline

ALBUQUERQUE, NM - Laboratories at the University of New Mexico (UNM), Brown

University, and House Ear Institute (HEI) have developed a new technique to

observe herpes simplex virus type 1 (HSV1) infections growing inside cells.

HSV1, the cause of the common cold sore, persists in a latent form inside nerve

cells. Re-activation and growth of HSV1 infections contribute to cognitive

decline associated with Alzheimer's disease. Details are published in the March

31 issue of PLoS ONE magazine from the Public Library of Science.

" Herpes infects mucous membranes, such as the lip or eye, and generates viral

particles, " submits study Principal Investigator Elaine Bearer, M.D., Ph.D.,

Harvey Family Professor and Vice Chair for Research, Department of Pathology,

UNM School of Medicine. " These viral particles burst out of the cells of the

mucous membrane and enter sensory nerve cells where they travel inside the nerve

toward the brain. We now can see this cellular transportation system and watch

how the newly formed virus engages cellular APP on its journey out of the cell. "

Tagging herpes virus inside cells with green fluorescent protein, scientists

used live confocal imaging to watch HSV1 particles emerge from infected cells.

Newly produced viral particles exit the cell nucleus and then bud into cellular

membranes containing amyloid precursor protein (APP). Electron microscopy at HEI

detailed the ultrastructural relationship between HSV1 particles and APP.

This dance between viral particles and cellular APP results in changes in

cellular architecture and the distribution of APP, the major component of senile

plaques found in the brains of Alzheimer's disease patients. Results from this

study indicate that most intracellular HSV1 particles undergo frequent, dynamic

interplay with APP, which facilitates viral transport while interfering with

normal APP transport and distribution. This dynamic interaction reveals a

mechanism by which HSV1 infection leads to Alzheimer's disease.

In developed countries such as the U.S., approximately 20 percent of children

are infected with HSV1 prior to the age of five. By the second and third decades

of life, as much as 60 percent of the population is infected, and late-in-life

infection rate reaches 85 percent.

Symptoms of primary HSV1 infection include painful blisters of the mouth, lips

or eyes. After infection, HSV1 persists in nerve cells by becoming latent. Upon

re-awakening, new viral particles are made in the neuron and then travel back

out its pathways to re-infect the mucous membrane. Many infected people

experience sporadic episodes of viral outbreaks as the well-known recurrent cold

sore.

" Clinicians have seen a link between HSV1 infection and Alzheimer's disease in

patients, so we wanted to investigate what might be going on in the body that

would account for this, " adds Dr. Shi-Bin Cheng, post-doctoral associate,

Department of Pathology and Laboratory Medicine, Alpert Medical School, Brown

University. " What we were able to see in the lab strongly suggests a causal link

between HSV1 and Alzheimer's Disease. "

" It's no longer a matter of determining whether HSV1 is involved in cognitive

decline, but rather how significant this involvement is, " Bearer asserts. " We'll

need to investigate anti-viral drugs used for acute herpes treatment to

determine their ability to slow or prevent cognitive decline. "

Researchers recommend people treat a cold sore as quickly as possible to

minimize the amount of time the virus is actively traveling through a person's

nervous system. The faster a cold sore is treated, the faster the HSV1 returns

to a dormant stage.

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Herpes Simplex Virus Dances with Amyloid Precursor Protein while Exiting the

Cell

Herpes simplex type 1 (HSV1) replicates in epithelial cells and secondarily

enters local sensory neuronal processes, traveling retrograde to the neuronal

nucleus to enter latency. Upon reawakening newly synthesized viral particles

travel anterograde back to the epithelial cells of the lip, causing the

recurrent cold sore. HSV1 co-purifies with amyloid precursor protein (APP), a

cellular transmembrane glycoprotein and receptor for anterograde transport

machinery that when proteolyzed produces A-beta, the major component of senile

plaques. Here we focus on transport inside epithelial cells of newly synthesized

virus during its transit to the cell surface. We hypothesize that HSV1 recruits

cellular APP during transport. We explore this with quantitative

immuno-fluorescence, immuno-gold electron-microscopy and live cell confocal

imaging. After synchronous infection most nascent VP26-GFP-labeled viral

particles in the cytoplasm co-localize with APP (72.8+/?6.7%) and travel

together with APP inside living cells (81.1+/?28.9%). This interaction has

functional consequences: HSV1 infection decreases the average velocity of APP

particles (from 1.1+/?0.2 to 0.3+/?0.1 µm/s) and results in APP mal-distribution

in infected cells, while interplay with APP-particles increases the frequency

(from 10% to 81% motile) and velocity (from 0.3+/?0.1 to 0.4+/?0.1 µm/s) of

VP26-GFP transport. In cells infected with HSV1 lacking the viral Fc receptor,

gE, an envelope glycoprotein also involved in viral axonal transport, APP-capsid

interactions are preserved while the distribution and dynamics of dual-label

particles differ from wild-type by both immuno-fluorescence and live imaging.

Knock-down of APP with siRNA eliminates APP staining, confirming specificity.

Our results indicate that most intracellular HSV1 particles undergo frequent

dynamic interplay with APP in a manner that facilitates viral transport and

interferes with normal APP transport and distribution. Such dynamic interactions

between APP and HSV1 suggest a mechanistic basis for the observed clinical

relationship between HSV1 seropositivity and risk of Alzheimer's disease.

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a.. Abstract

b.. Introduction

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h.. Author Contributions

i.. References

Shi-Bin Cheng1, ette Ferland1, Webster2, Elaine L. Bearer1,3*

1 Department of Pathology and Laboratory Medicine, Alpert Medical School of

Brown University, Providence, Rhode Island, United States of America, 2 House

Ear Institute, Los Angeles, California, United States of America, 3 Departments

of Pathology and of Neurosurgery, University of New Mexico School of Medicine,

Albuquerque, New Mexico, United States of America

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