Alzheimer Disease: Balin BJ

Balin BJ, Little CS, Hammond CJ, Appelt DM, Whittum-Hudson JA, Gérard HC, Hudson AP. · Department of Pathology, Microbiology, Immunology and Forensic Medicine, Philadelphia PA 19131, USA. · J Alzheimers Dis. · Pubmed #18487846 No free full text.

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.

Itzhaki RF, Wozniak MA, Appelt DM, Balin BJ. · Department of Optometry and Neuroscience, University of Manchester Institute of Science and Technology (UMIST), Manchester M60 1QD, UK. · Neurobiol Aging. · Pubmed #15172740 No free full text.

Abstract: Despite very numerous studies on Alzheimer's disease (AD), especially on amyloid plaques and neurofibrillary tangles, little information has been obtained thus on the causes of the disease. Evidence is described here that implicates firstly herpes simplex virus type 1 (HSV1) as a strong risk factor when it is present in brain of carriers of the type 4 allele of the gene for apolipoprotein E (APOE-4). Indirect support comes from studies indicating the role of APOE in several diverse diseases of known pathogen cause. A second putative risk factor is the bacterium, Chlamydia pneumoniae. This pathogen has been identified and localized in AD brain. Current studies aimed at "proof of principle" address the entry of the organism into the CNS, the neuroinflammatory response to the organism, and the role that the organism plays in triggering AD pathology. An infection-based animal model demonstrates that following intranasal inoculation of BALB/c mice with C. pneumoniae, amyloid plaques/deposits consistent with those observed in the AD brain develop, thus implicating this infection in the etiology of AD.

Balin BJ, Appelt DM. · Department of Pathology/Microbiology, Philadelphia College of Osteopathic Medicine, Pennsylvania 19131, USA. · J Am Osteopath Assoc. · Pubmed #11794745 links to  free full text

Abstract: Alzheimer's disease (AD) is a chronic condition in which inflammation has been shown to contribute to neurodegeneration. Current thinking suggests that deposition of beta-amyloid in the brain promotes inflammation resulting in neuronal damage/death. Alternatively, our data suggest that chronic inflammation observed in late-onset sporadic AD may be stimulated by infection with the obligate, intracellular bacterium, Chlamydia pneumoniae. Our results indicate that C. pneumoniae is found in high frequency in glial cells in areas of neuropathology within the brains of patients with AD. Based on our evidence, nervous system infection with C. pneumoniae should be considered a risk factor for sporadic AD.

Appelt DM, Roupas MR, Way DS, Bell MG, Albert EV, Hammond CJ, Balin BJ. · Department of Neuroscience, Physiology & Pharmacology, Philadelphia College of Osteopathic Medicine, Philadelphia, USA. · BMC Neurosci. · Pubmed #18218130 links to  free full text

Abstract: BACKGROUND: Chlamydophila (Chlamydia) pneumoniae is an intracellular bacterium that has been identified within cells in areas of neuropathology found in Alzheimer disease (AD), including endothelia, glia, and neurons. Depending on the cell type of the host, infection by C. pneumoniae has been shown to influence apoptotic pathways in both pro- and anti-apoptotic fashions. We have hypothesized that persistent chlamydial infection of neurons may be an important mediator of the characteristic neuropathology observed in AD brains. Chronic and/or persistent infection of neuronal cells with C. pneumoniae in the AD brain may affect apoptosis in cells containing chlamydial inclusions. RESULTS: SK-N-MC neuroblastoma cells were infected with the respiratory strain of C. pneumoniae, AR39 at an MOI of 1. Following infection, the cells were either untreated or treated with staurosporine and then examined for apoptosis by labeling for nuclear fragmentation, caspase activity, and membrane inversion as indicated by annexin V staining. C. pneumoniae infection was maintained through 10 days post-infection. At 3 and 10 days post-infection, the infected cell cultures appeared to inhibit or were resistant to the apoptotic process when induced by staurosporine. This inhibition was demonstrated quantitatively by nuclear profile counts and caspase 3/7 activity measurements. CONCLUSION: These data suggest that C. pneumoniae can sustain a chronic infection in neuronal cells by interfering with apoptosis, which may contribute to chronic inflammation in the AD brain.

Gérard HC, Dreses-Werringloer U, Wildt KS, Deka S, Oszust C, Balin BJ, Frey WH, Bordayo EZ, Whittum-Hudson JA, Hudson AP. · Department of Immunology and Microbiology, Wayne State University School of Medicine, Detroit, MI 48201, USA. · FEMS Immunol Med Microbiol. · Pubmed #17052268 No free full text.

Abstract: We assessed the presence and characteristics of the intracellular pathogen Chlamydophila (Chlamydia) pneumoniae in brain-tissue samples from 25 patients with late-onset Alzheimer's disease (AD) and 27 non-AD control individuals. 20/27 AD patients, but only 3/27 controls, were PCR-positive in multiple assays targetting the Cpn1046 and Cpn0695 genes. Culture of the organism from brain-tissue homogenate from one AD patient, and assessment of various chlamydial transcripts in RNA preparations from several patients, demonstrated that the organisms were viable and metabolically active in those samples. Immunohistochemical analyses showed that astrocytes, microglia, and neurons all served as host cells for C. pneumoniae in the AD brain, and that infected cells were found in close proximity to both neuritic senile plaques and neurofibrillary tangles in the AD brain. These observations confirm and significantly extend our earlier study suggesting that this unusual pathogen may play a role in the neuropathogenesis characteristic of AD.

Little CS, Hammond CJ, MacIntyre A, Balin BJ, Appelt DM. · Department of Pathology, Microbiology, and Immunology, Philadelphia College of Osteopathic Medicine, 4170 City Avenue, Philadelphia, PA 19131, USA. · Neurobiol Aging. · Pubmed #15013562 No free full text.

Abstract: Amyloid deposits resembling plaques found in Alzheimer's disease (AD) brains were formed in the brains of non-transgenic BALB/c mice following intranasal infection with Chlamydia pneumoniae. The mice were infected at 3 months of age with C. pneumoniae isolated from an AD brain. Infection was confirmed by light and electron microscopy in olfactory tissues of the mice. C. pneumoniae was still evident in these tissues 3 months after the initial infection indicating that a persistent infection had been established. Amyloid beta (Abeta) 1-42 immunoreactive deposits were identified in the brains of infected BALB/c mice up to 3 months post-infection with the density, size, and number of deposits increasing as the infection progressed. A subset of deposits exhibited thioflavin-s labeling. Intracellular Abeta1-42 labeling was observed in neuronal cells. Experimental induction of amyloid deposition in brains of non-transgenic BALB/c mice following infection with C. pneumoniae may be a useful model for furthering our understanding of mechanisms, linked to infection, involved in the initiation of the pathogenesis of sporadic AD.

MacIntyre A, Abramov R, Hammond CJ, Hudson AP, Arking EJ, Little CS, Appelt DM, Balin BJ. · Department of Biomedical Sciences, Philadelphia College of Osteopathic Medicine, Philadelphia, Pennsylvania, USA. · J Neurosci Res. · Pubmed #12584732 No free full text.

Abstract: We have investigated the effects of Chlamydia pneumoniae on human brain endothelial cells (HBMECs) and human monocytes as a mechanism for breaching the blood-brain barrier (BBB) in Alzheimer's disease (AD). HBMECs and peripheral blood monocytes may be key components in controlling the entry of C. pneumoniae into the human brain. Our results indicate that C. pneumoniae infects blood vessels and monocytes in AD brain tissues compared with normal brain tissue. C. pneumoniae infection stimulates transendothelial entry of monocytes through HBMECs. This entry is facilitated by the up-regulation of VCAM-1 and ICAM-1 on HBMECs and a corresponding increase of LFA-1, VLA-4, and MAC-1 on monocytes. C. pneumoniae infection in HBMECs and THP-1 monocytes up-regulates monocyte transmigration threefold in an in vitro brain endothelial monolayer. In this way, C. pneumoniae infection in these cell types may contribute to increased monocyte migration and promote inflammation within the CNS resulting from infection at the level of the vasculature. Thus, infection at the level of the vasculature may be a key initiating factor in the pathogenesis of neurodegenerative diseases such as sporadic AD.

Balin BJ, Loewy AG, Appelt DM. · Department of Pathology, Microbiology, and Immunology, Philadelphia College of Osteopathic Medicine, Pennsylvania 19131, USA. · Methods Enzymol. · Pubmed #10507024 No free full text.

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