The Emerging Role Of Infection In Alzheimer's Disease 2008

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The Emerging Role Of Infection In Alzheimer's Disease 2008

Post by cave76 » Fri 23 May 2008 17:43

The Emerging Role Of Infection In Alzheimer's Disease

ScienceDaily (May 22, 2008) — A number of chronic diseases are in fact caused by one or more infectious agents. For example, stomach ulcers are caused by Helicobacter pylori, chronic lung disease in newborns and chronic asthma in adults are both caused by Mycoplasmas and Chlamydia pneumonia, while some other pathogens have been associated with atherosclerosis. The realization that pathogens can produce slowly progressive chronic diseases has opened new lines of research into Alzheimer's disease.

In a special issue of the Journal of Alzheimer's Disease published May 2008, guest editors Judith Miklossy, from The University of British Columbia, and Ralph N. Martins, from Edith Cowan University and Hollywood Private Hospital, Perth, Western Australia, and a group of experts explore this exciting topic.

rest of article at

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Re: The Emerging Role Of Infection In Alzheimer's Disease 2008

Post by OneGuest » Fri 23 May 2008 18:19

Nice find!

Here are the journal issue synopses:
(note the use of word "spirochete"!!!!

Volume 13, Number 4, May 2008 - Special Issue "Chronic inflammation and Amyloidogenesis in Alzheimer’s Disease: The Emerging Role of Infection" (Guest Editors: Judith Miklossy and Ralph Martins)

Page 357
Judith Miklossy and Ralph Martins
Preface: Chronic inflammation and amyloidogenesis in Alzheimer’s disease: The emerging role of infection

Pages 359-369
Claudia Schwab and Patrick L. McGeer

Inflammatory Aspects of Alzheimer Disease and Other Neurodegenerative Disorders

Abstract: Alzheimer and a number of other neurodegenerative diseases are characterized by the presence of reactive microglia and reactive astrocytes in association with the lesions. The classic view that microglia exist primarily in either a resting or activated state needs to be broadened in view of recent results. Resting microglia are in constant activity sampling their surround. Activated microglia may be pro-inflammatory, releasing inflammatory cytokines and other inflammatory mediators, or anti-inflammatory, promoting the healing process. There is evidence that microglial phagocytosis is more powerful in the anti-inflammatory state. Activated astrocytes also have pro-inflammatory and anti-inflammatory properties. In the pro-inflammatory state they release inflammatory cytokines. In the anti-inflammatory state they release various growth factors. In AD and other neurodegenerative diseases, both microglia and astrocytes are in a pro-inflammatory state. From a therapeutic point of view it is desirable to find methods of tipping the balance towards an anti-inflammatory state for both types of glia.

Pages 371-380
Brian J. Balin, C. Scott Little, Christine J. Hammond, Denah M. Appelt, Judith A. Whittum-Hudson, Hervé C. Gérard, Alan P. Hudson

Chlamydophila pneumoniae and the etiology of late-onset Alzheimer’s disease

Abstract: Sporadic, late-onset Alzheimer’s disease (LOAD) is a non-familial, progressive neurodegenerative disease that is now the most common and severe form of dementia in the elderly. That dementia is a direct result of neuronal damage and loss associated with accumulations of abnormal protein deposits in the brain. Great strides have been made in the past 20 years with regard to understanding the pathological entities that arise in the AD brain, both for familial AD (~5% of all cases) and LOAD (~95% of all cases). The neuropathology observed includes: neuritic senile plaques (NSPs), neurofibrillary tangles (NFTs), neuropil threads (NPs), and often deposits of cerebrovascular amyloid. Genetic, biochemical, and immunological analyses have provided a relatively detailed knowledge of these entities, but our understanding of the “trigger” events leading to the many cascades resulting in this pathology and neurodegeneration is still quite limited. For this reason, the etiology of AD, in particular LOAD, has remained elusive. However, a number of recent and ongoing studies have implicated infection in the etiology and pathogenesis of LOAD. This review focuses specifically on infection with Chlamydophila (Chlamydia) pneumoniae in LOAD and how this infection may function as a “trigger or initiator” in the pathogenesis of this disease.

Pages 381-391
Judith Miklossy

Chronic inflammation and amyloidogenesis in Alzheimer's disease – role of spirochetes

Abstract: Alzheimer's disease (AD) is associated with dementia, brain atrophy and the aggregation and accumulation of a cortical amyloid-β peptide (Aβ). Chronic bacterial infections are frequently associated with amyloid deposition. Bacteria or their toxic components are powerful inflammatory stimulators and are amyloidogenic. It had been known from a century that the spirochete Treponema pallidum can cause dementia in the atrophic form of general paresis where. It is noteworthy that the pathological hallmarks of this atrophic form are similar to those of AD. Recent observations showed that bacteria, including spirochetes contain amyloidogenic proteins and also that Aβ deposition and tau phosphorylation can be induced in vitro or in vivo following exposure to bacteria or LPS. Bacteria or their poorly degradable debris are powerful inflammatory cytokine inducers, activate complement, affect vascular permeability, generate nitric oxide and free radicals, induce apoptosis and are amyloidogenic. All these processes are involved in the pathogenesis of AD. Old and new observations, reviewed here, indicate that to consider the possibility that bacteria, including several types of spirochetes highly prevalent in the population at large or their persisting debris may initiate cascade of events leading to chronic inflammation and amyloid deposition in AD is important, as appropriate antibacterial and antiinflammatory therapy would be available to prevent dementia.

Pages 393-405

Ruth F. Itzhaki and Matthew A. Wozniak

Herpes Simplex Virus Type 1 in Alzheimer’s disease: The Enemy Within

Abstract: Alzheimer's disease is a modern scourge and is likely to become increasingly so in the future, with increasing longevity. The disease has been investigated for over one hundred years yet the causes of the disease and of the neuropathological characteristics seen in AD brain are still completely unknown. Evidence for a major causative role of a common virus, herpes simplex virus type 1 (HSV1), acting in combination with a genetic factor – the type 4 allele of the apolipoprotein gene, a known susceptibility factor – is presented here. The characteristics of the virus, some of which make it an especially likely candidate for this role, are described, as are the many precedents for the action of a genetic factor modulating outcome of infection. Various possible ways in which HSV1 might lead to development of AD, such as its up-regulation of various enzymes and in particular certain kinases, its effect on the cell cycle, on autophagy, and its inflammatory and oxidative effects are discussed also. It is concluded that there is strong evidence that the virus is indeed a major factor in AD and therefore there is a strong case for appropriate treatment, and possibly for prevention in the future.

Pages 407-419

Neal D. Hammer, Xuan Wang, Bryan A. McGuffie, Matthew R. Chapman

Amyloids: Friend or Foe?

Abstract: Amyloidogenesis is the aggregation of soluble proteins into structurally conserved fibers. Amyloid fibers are distinguished by their resistance to proteinase K, tinctorial properties and β-sheet-rich secondary structure. Amyloid formation is a hallmark of many human diseases including Alzheimer’s, Huntington’s and the prion diseases. Therefore, understanding amyloidogenesis will provide insights into the development of therapeutics that target these debilitating diseases. A new class of ‘functional’ amyloids promises a unique glimpse at how nature has harnessed the amyloid fiber to accomplish important physiological tasks. Functional amyloids are produced by organisms spanning all aspects of cellular life. Herein we review amyloidogenesis, with special attention focused on the similarities and differences between the best characterized disease-associated amyloidogenic protein amyloid-β and the formation of several functional amyloids. The implications of studying functional amyloidogenesis and the strategies organisms employ to limit exposure to toxic intermediates will also be discussed.

Pages 421-435

Nadezda Urosevic and Ralph N. Martins

Infection and Alzheimer’s disease: The ApoE e4 connection and lipid metabolism

Abstract: Microorganisms, bacteria and viruses, may infect and cause a range of acute and chronic diseases in humans dependent on the genetic background, age, sex, immune and health status of the host, as well as on the nature, virulence and dose of infectious agent. Late onset Alzheimer’s disease (AD) is a progressive neurodegenerative illness of broad aetiology with a strong genetic component and a significant contribution of age, sex and life style factors. Both infectious diseases and AD are characterised by an increased production of an array of immune mediators, cytokines, chemokines and complement proteins by the host cells as well as by changes in the host lipid metabolism. In this review, we re-examine a dangerous liaison between several viral and bacterial infections and the most significant genetic factor for AD, APOE ε4, and the possible impact of this alliance on AD development. This connection was discussed in the broader context of lipid metabolism and in the light of different capacity of various infectious agents, their toxic lipophilic products and host lipoprotein particles for binding to cell receptor(s).

Pages 437-449

Angela R. Kamer, Ananda Dasanayeke, Ronald G. Craig, Lidia Glodzik-Sobanska, Miroslow Bry, Mony J. de Leon

Alzheimer’s disease and peripheral infections: The possible contribution from periodontal infections, model and hypothesis

Abstract: Alzheimer’s disease (AD) affects approximately 4.5 million people in the U.S. and this number will increase as the population ages and the life-span increases. Therefore, of paramount importance is identifying mechanisms and factors that affect the risk of developing AD. The etiology and pathogenic mechanisms for AD have not been defined, although inflammation within the brain is thought to play a role. Consistent with this hypothesis, studies suggest that peripheral infections contribute to the inflammatory state of the central nervous system. Periodontitis is a prevalent, persistent peripheral infection associated with gram negative, anaerobic bacteria that are capable of exhibiting localized and systemic infections in the host. This review offers a hypothetical link between periodontitis and AD and will present possible mechanistic links between periodontitis related inflammation and AD. It will review the pathogenesis of periodontitis and the mechanisms by which periodontal infections may affect the onset and progression of AD. Since periodontitis is a treatable condition, it may be a readily modifiable risk factor for AD.

Pages 451-463
Eugene D. Weinberg, Judith Miklossy

Iron withholding: a defense against disease

Abstract: Excessive and misplaced iron promotes an array of neurodegenerative and endocrine diseases as well as cardiomyopathy, arthropathy, neoplasia and infection. Vertebrates maintain an iron withholding defense system designed to prevent accumulation of redox-active (free) iron in sensitive sites and to sequester the metal in innocuous packages. Numerous genetic, behavioral and environmental factors counteract the defense system. Our increasing awareness of the pathologic roles of iron, as well as of the methods for prevention of iron loading coupled with intensified research and development of tissue specific iron chelator drugs, can be expected to yield marked improvements in human health.

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Re: The Emerging Role Of Infection In Alzheimer's Disease 2008

Post by minitails2 » Sun 25 May 2008 6:18

Thanks, guys. :)

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Re: The Emerging Role Of Infection In Alzheimer's Disease 2008

Post by Joe Ham » Sun 25 May 2008 19:13

Miklossy now has a web site devoted to exploring the links between chronic infectious diseases and Alzheimer's.
Index page

However it is not very professionally done. The text of white on a blue background is not the easiest to read and the cutesy little floating squares add nothing but distraction. Maybe it will improve in time. In the meantime it can be made more readable by copying the text to a text editor program so that you can set it to black on white text.

Nevertheless, the site is well worth the trouble because Miklossy is on top of her game and a leader of exploring the infectious causes of Alzheimer's including, and maybe especially from our point of view, the Lyme disease connection.

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Re: The Emerging Role Of Infection In Alzheimer's Disease 2008

Post by cave76 » Sun 25 May 2008 19:25

****devoted to exploring the links between chronic infectious diseases and Alzheimer's.****

Alzheimer's = almost always in the later years of life

Chronic infectious diseases = If a disease is 'chronic' it often hasn't killed the patient in the 'acute' years.
So this infectious disease has had a long time to work on the brain and CNS of that patient.

Ergo-----untreated or chronic disease=Alzheimer's. In some people. Not in all. Which is another puzzle. :(

Good site. Lose the white on blue!

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Re: The Emerging Role Of Infection In Alzheimer's Disease 2008

Post by minitails2 » Mon 26 May 2008 7:43

I'll have to check that out, even with the floaty things getting in the way! :mrgreen: Thanks again.

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Re: The Emerging Role Of Infection In Alzheimer's Disease 2008

Post by LymeEnigma » Mon 26 May 2008 19:44

cave76 wrote:****devoted to exploring the links between chronic infectious diseases and Alzheimer's.****

Alzheimer's = almost always in the later years of life

Chronic infectious diseases = If a disease is 'chronic' it often hasn't killed the patient in the 'acute' years.
So this infectious disease has had a long time to work on the brain and CNS of that patient.

Ergo-----untreated or chronic disease=Alzheimer's. In some people. Not in all. Which is another puzzle. :(

Good site. Lose the white on blue!
Also consider what happens to one's immune system as one ages. It is only reasonable to consider what may have been kept under "better" control by a healthy immune system may very well go completely rampant once there isn't much of an immune system to keep things in check.

My adoptive grandfather died at a young age from an "Alzheimer's-like" mystery illness. Instead of affecting mostly the frontal lobe, however, it started in the occipital and spread from there, first making him go crazy, while losing all short-term memory, and then literally turning him into a vegetable for many years before he finally passed on (could not talk, move his body, or respond whatsoever to outside stimuli ... for years). No one was ever able to say what, specifically, was wrong with him, although I know the running theory was that the degeneration may have begun after a good, unchecked, knock on the head. He loved the outdoors, though, always had his knees in the soil before he got sick. I think he loved gardening almost as much as he loved his family. Hmm....

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Re: The Emerging Role Of Infection In Alzheimer's Disease 2008

Post by Joe Ham » Wed 3 Sep 2008 20:27

The Journal of Immunology, 2008, 180: 8241-8249.
Copyright © 2008 by The American Association of Immunologists, Inc. ... 80/12/8241
Neurogenic Exacerbation of Microglial and Astrocyte Responses to Neisseria meningitidis and Borrelia burgdorferi[1]

Vinita S. Chauhan, David G. Sterka, Jr., David L. Gray, Kenneth L. Bost and Ian Marriott[2]
Department of Biology, University of North Carolina, Charlotte, NC 28223

Although glial cells are recognized for their roles in maintaining neuronal function, there is growing appreciation of the ability of resident CNS cells to initiate and/or augment inflammation following trauma or infection.

The tachykinin, substance P (SP), is well known to augment inflammatory responses at peripheral sites and its presence throughout the CNS raises the possibility that this neuropeptide might serve a similar function within the brain.
In support of this hypothesis, we have recently demonstrated the expression of high affinity receptors for SP (Neurokinin-1 (NK-1) receptors) on microglia and shown that this tachykinin can significantly elevate bacterially induced inflammatory prostanoid production by isolated cultures of these cells.
In the present study, we demonstrate that endogenous SP/NK-1R interactions are an essential component in the initiation and/or progression of CNS inflammation in vivo following exposure to two clinically relevant bacterial CNS pathogens, Neisseria meningitidis and Borrelia burgdorferi.
We show that in vivo elevations in inflammatory cytokine production and decreases in the production of an immunosuppressive cytokine are markedly attenuated in mice genetically deficient in the expression of the NK-1R or in mice treated with a specific NK-1R antagonist.
Furthermore, we have used isolated cultures of microglia and astrocytes to demonstrate that SP can augment inflammatory cytokine production by these resident CNS cell types following exposure to either of these bacterial pathogens.
Taken together, these studies indicate a potentially important role for neurogenic exacerbation of resident glial immune responses in CNS inflammatory diseases, such as bacterial meningitis.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This work was supported by Grants NS050325 and NS057434 to I.M. from the National Institutes of Health.

2 Address correspondence and reprint requests to Dr. Ian Marriott, Department of Biology, 9201 University City Boulevard, University of North Carolina, Charlotte, NC 28223. E-mail address:

3 Abbreviations used in this paper: SP, substance P; NK-1, neurokinin-1; i.c., intracerebral; GFAP, glial fibrillary acidic protein.

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Re: The Emerging Role Of Infection In Alzheimer's Disease 2008

Post by Joe Ham » Sun 1 Feb 2009 0:48

The title is a bit of a misnomer. There are two separate diseases discussed in this article and no connection is made between Malaria and Alzheimer's.
Malaria and Alzheimer's disease
A jab of hope

Dec 11th 2008
From The Economist print edition
Vaccines may help defeat both a scourge of the poor and a rich-world affliction

FOR much of the 19th century, Bagamoyo was a dreadful place, at the heart of the east African slave trade. The very name of the Tanzanian port means “lay down your heart” in Swahili. But that tragic association may be supplanted by a happier one, thanks to an important new study done in the city that shows how to tackle a killer that has long outlasted Bagamoyo’s trade in human beings.

Most malaria experts have pinned their hopes of tackling that disease with new drugs, such as artemisinin-combination therapies, and the use of bed-nets impregnated with long-lasting insecticides. However, the Bagamoyo study suggests that vaccination deserves a serious look. By coincidence, an unrelated report suggests that vaccines may also have an important part to play in tackling Alzheimer’s disease, which tends to afflict longer-lived people in richer countries.

Joe Cohen of GlaxoSmithKline, a British drugs giant, and his colleagues present their case for the speedy development of a malaria vaccine in this week’s New England Journal of Medicine. In earlier studies, researchers have shown that RTS,S (as the vaccine is known) showed promise, although doubts remained. Christian Loucq of the PATH Malaria Vaccine Initiative, a charity that co-sponsored the study, says some naysayers have pointed to historical difficulties in getting African governments to accept and distribute new vaccines as grounds for scepticism.

Which is why the work in Bagamoyo tested whether the malaria vaccine could be integrated into African countries’ existing system for inoculating infants with a group of established vaccines. It showed that giving all the jabs simultaneously did not affect the safety or efficacy of any of the vaccines and that the malaria vaccine reduced the risk of infection by over 60%.

Dr Cohen points to novel adjuvants (ingredients that increase the body’s response to vaccines) as one of the reasons why the vaccine works when many earlier versions failed. A second study in the same journal was conducted in both Tanzania and Kenya, and it shows the vaccine is indeed improved by using a better adjuvant. The researchers are keen to push ahead with this improved version of RTS,S early next year, but Dr Loucq worries about funding a big final-stage clinical trial that may cost $500m or more.

Funding also worries Ruth Itzhaki of the University of Manchester. She is the lead author of a striking paper in the latest issue of the Journal of Pathology.
It suggests that the herpes simplex virus, which leads to cold sores, may be important in the development of Alzheimer’s. One of the telltale signs of this disease is the deposit of beta-amyloid plaques in the brain. Using sophisticated scanning techniques, her team has located DNA of this herpes virus specifically within the amyloid plaques in the brain.

Could this be mere coincidence rather than causation? No, insists Dr Itzhaki. Earlier work done by her team has shown that, in mice at least, the herpes infection of nerve cells induces accumulation of beta amyloid, the main component of amyloid plaques. Alzheimer’s has many causes, but Dr Itzhaki estimates that genetics and this virus taken together may account for up to 60% of the explanation.
[And the other >40% ? Cpn? H pylori? Borrelia?
See also the referenced article:
Herpes simplex virus type 1 DNA is located within Alzheimer's disease amyloid plaques. 2009 Jan]
If she is right, this costly and devastating disease could be tackled at last. Until a proper vaccine is developed, patients could use inexpensive antiviral drugs to contain the problem. More work would verify her thesis, but the team has been unable to get the funding for the necessary further research that will be needed to underpin future clinical trials. Why not? “There is very strong polarisation among scientists over our findings,” says Dr Itzhaki. Perhaps it is worth spending some money to settle this disagreement.
Welcome to the club, Dr Itzhaki.

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