Journal of Alzheimer's Disease - Volume 13, issue 4

Authors: Miklossy, Judith | Martins, Ralph N.

Article Type: Editorial

DOI: 10.3233/JAD-2008-13401

Citation: Journal of Alzheimer's Disease, vol. 13, no. 4, pp. 357-357, 2008

Authors: Schwab, Claudia | McGeer, Patrick L.

Article Type: Research Article

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. Show more

Keywords: Amyloid-β protein, amyotrophic lateral sclerosis, astrocytes, microglia, neurotoxicity, Parkinson disease, synuclein

DOI: 10.3233/JAD-2008-13402

Citation: Journal of Alzheimer's Disease, vol. 13, no. 4, pp. 359-369, 2008

Authors: Balin, Brian J. | Little, C. Scott | Hammond, Christine J. | Appelt, Denah M. | Whittum-Hudson, Judith A. | Gérard, Hervé C. | Hudson, Alan P.

Article Type: Research Article

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. Show more

Keywords: Alzheimer's disease, amyloid, animal models antibiotic, APOE, Chlamydia pneumoniae, etiology, infection, LOAD, neuroinflammation

DOI: 10.3233/JAD-2008-13403

Citation: Journal of Alzheimer's Disease, vol. 13, no. 4, pp. 371-380, 2008

Authors: Miklossy, Judith

Article Type: Research Article

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. 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 Aβ 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. Show more

Keywords: Alzheimer's disease, amyloid-β, bacteria, borrelia burgdorferi, chronic inflammation, dementia, general paresis, intestinal spirochetes, LPS, lyme neuroborreliosis, neurospirochetosis, oral spirochetes, spirochetes, syphilis, treponema pallidum

DOI: 10.3233/JAD-2008-13404

Citation: Journal of Alzheimer's Disease, vol. 13, no. 4, pp. 381-391, 2008

Authors: Itzhaki, Ruth F. | Wozniak, Matthew A.

Article Type: Research Article

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. Show more

Keywords: Abnormal tau phosphorylation, Alzheimer's disease, amyloid-β, apolipoprotein E, autophagy, cell cycle, cholesterol, herpes simplex virus type 1, inflammation, oxidation

DOI: 10.3233/JAD-2008-13405

Citation: Journal of Alzheimer's Disease, vol. 13, no. 4, pp. 393-405, 2008

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

Article Type: Research Article

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. Show more

DOI: 10.3233/JAD-2008-13406

Citation: Journal of Alzheimer's Disease, vol. 13, no. 4, pp. 407-419, 2008

Authors: Urosevic, Nadezda | Martins, Ralph N.

Article Type: Review Article

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). Show more

Keywords: Apolipoprotein E4, Chlamydia, Hepatitis C virus, Herpes Simplex virus 1, Human Immunodeficiency virus, LDL receptors, lipopolysaccharide, spirochetes

DOI: 10.3233/JAD-2008-13407

Citation: Journal of Alzheimer's Disease, vol. 13, no. 4, pp. 421-435, 2008

Authors: Kamer, Angela R. | Dasanayake, Ananda P. | Craig, Ronald G. | Glodzik-Sobanska, Lidia | Bry, Miroslow | de Leon, Mony J.

Article Type: Review Article

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. Show more

Keywords: Alzheimer's disease, cytokines, periodontal bacteria, periodontitis, peripheral infection

DOI: 10.3233/JAD-2008-13408

Citation: Journal of Alzheimer's Disease, vol. 13, no. 4, pp. 437-449, 2008

Authors: Weinberg, Eugene D. | Miklossy, Judith

Article Type: Review Article

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.

Keywords: Alzheimer's disease, bacteria, cardiovascular disease, cerebrovascular disease, dementia, infectious disease, iron, iron withholding defense, neoplastic disease, neurodegenerative disorders

DOI: 10.3233/JAD-2008-13409

Citation: Journal of Alzheimer's Disease, vol. 13, no. 4, pp. 451-463, 2008

Article Type: Announcement

DOI: 10.3233/JAD-2008-13410

Citation: Journal of Alzheimer's Disease, vol. 13, no. 4, pp. 465-466, 2008