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6.17. JAD SPECIALN ISSUE: "INVOLVEMENT OF CHRONIC INFLAMMATION AND INFECTION IN ALZHEIMER'S DISEASE"

For the first time, in a special issue of the Journal of Alzheimer's Disease (JAD), historic and new observations were reviewed with respect to the involvement of  infectious agents in Alzheimer's disease.

Press release

Editorial comment

Guest Editors: Judith Miklossy and Ralph Martins

Chronic inflammation and Amyloidogenesis in Alzheimer’s Disease: The Emerging Role of Infection.

Journal of Alzheimer’s Disease 13 (2008) 357

The realization that pathogens can produce slowly rogressive chronic diseases has resulted in new concepts f infectious diseases. A number of chronic diseases ae caused by one or more infectious agents: e.g, stomach ulcer is caused by Helicobacter pylorii; chronic lung disease in newborns and chronic asthma in adults are both caused by Mycoplasmas; and, Chlamydia pneumoniae and some other pathogens have been associated with atherosclerosis

 It has been known from a century that dementia and amyloidosis can be caused by chronic bacterial infection, namely by Treponema pallidum in the atrophic form of general paresis in syphilis.

Alzheimer’s disease (AD) the most frequent cause of dementia, is a  form of amyloidosis. The pathological mechanisms driving the accumulation of amyloid remain unclear.  Pathogens  (e.g., bacteria, viruses) are powerful stimulators of inflammation and were suggested to be one of  the contributors in generating and sustaining chronic inflammation and amyloid deposition in AD.
The concept is not new as it was discussed by Alzheimer and his colleagues a century ago. The fact that pathogens may  sppress, subvert or evade host defenses and establish chronic or latent infection has received little attention in the past. During infection, active oxygen and nitrogen
species generated by inflammatory cells may cause D NA damage, induce apoptosis, and modulate enzyme activities and gene expression. Depending upon the biology of the pathogen and the host defense mechanisms the organism can persist in the infected tissues, resulting in chronic inflammation. Pathogens may also  elicit an autoimmune response without persistence of the initiating agent. The outcome of infection is as much determined by the genetic predisposition of the patient as by the virulence and biology of the infecting agent. Environmental factors and nutrition are critical determinants of disease expression as well. The goal of this special issue is to bring together a few of those scientists who have contributed significantly to this emerging field of research in order to guide new researchers toward highly productive investigations.

Highest priority should be given for such research in the future. It may have major implications
for public health, treatment, and prevention as adequate anti-bacterial and anti-viral drugs are available. Treatment of a bacterial infection and associated viral infection may result in regression and, if started early, prevention of disease. The impact on reducing health-care costs would be substantial.


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Reviews of the special issue of JAD


Schwab C, McGeer PL. Inflammatory Aspects of Alzheimer Disease and Other Neurodegenerative Disorders.  J Alzheimers Dis. 2008 May;13(4):359-69.

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.


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Balin BJ, Little CS, Hammond CJ, Appelt DM, Whittum-Hudson JA, Gérard HC, Hudson AP.
Chlamydophila pneumoniae and the etiology of late-onset Alzheimer’s disease.  J Alzheimers Dis. 2008 May;13(4):371-80.

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 ( approximately 5% of all cases) and LOAD ( approximately 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.


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Judith Miklossy  Chronic inflammation and amyloidogenesis in Alzheimer's disease – role of spirochetes. J Alzheimers Dis. 2008 May;13(4):381-91.

Alzheimer's disease (AD) is associated with dementia, brain atrophy and the aggregation and accumulation of a cortical amyloid-beta peptide (Abeta). Chronic bacterial infections are frequently associated with amyloid deposition. It had been known from a century that the spirochete Treponema pallidum can cause dementia in the atrophic form of general paresis. 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 Abeta deposition and tau phosphorylation can be induced in 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.


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Itzhaki RF, Wozniak MA.  Herpes Simplex Virus Type 1 in Alzheimer’s disease: The Enemy Within.  J Alzheimers Dis. 2008 May;13(4):393-405.

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 its causes and that 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 also discussed. 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.


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Hammer ND, Wang X, McGuffie BA, Chapman MR. Amyloids: Friend or Foe? J Alzheimers Dis. 2008 May;13(4):407-19.

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 beta-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-beta 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.


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Urosevic N, Martins RN.  Infection and Alzheimer’s disease: The ApoE e4 connection and lipid metabolism. J Alzheimers Dis. 2008 May;13(4):421-35.

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 epsilon4, 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).


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Kamer AR, Dasanayake AP, Craig RG, Glodzik-Sobanska L, Bry M, de Leon   Alzheimer's disease and peripheral infections: the possible contribution from periodontal infections, model and hypothesis. J Alzheimers Dis. 2008 May;13(4):437-49.

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.


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Weinberg ED, Miklossy J. Iron withholding: a defense against disease. J Alzheimers Dis. 2008 May;13(4):451-63.

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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