C. Scott Little

Chlamydia pneumoniae induces Alzheimer-like amyloid plaques in brains of BALB/c mice

Amyloid deposits resembling plaques found in Alzheimers 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.

Immunohistological detection of Chlamydia pneumoniae in the Alzheimer's disease brain

BackgroundSporadic late-onset Alzheimers disease (AD) appears to evolve from an interplay between genetic and environmental factors. One environmental factor that continues to be of great interest is that of Chlamydia pneumoniae infection and its association with late-onset disease. Detection of this organism in clinical and autopsy samples has proved challenging using a variety of molecular and histological techniques. Our current investigation utilized immunohistochemistry with a battery of commercially available anti-C. pneumoniae antibodies to determine whether C. pneumoniae was present in areas typically associated with AD neuropathology from 5 AD and 5 non-AD control brains.ResultsImmunoreactivity for C. pneumoniae antigens was observed both intracellularly in neurons, neuroglia, endothelial cells, and peri-endothelial cells, and extracellularly in the frontal and temporal cortices of the AD brain with multiple C. pneumoniae-specific antibodies. This immunoreactivity was seen in regions of amyloid deposition as revealed by immunolabeling with two different anti-beta amyloid antibodies. Thioflavin S staining, overlaid with C. pneumoniae immunolabeling, demonstrated no direct co-localization of the organism and amyloid plaques. Further, the specificity of C. pneumoniae labeling of AD brain sections was demonstrated using C. pneumoniae antibodies pre-absorbed against amyloid β 1-40 and 1-42 peptides.ConclusionsAnti-C. pneumoniae antibodies, obtained commercially, identified both typical intracellular and atypical extracellular C. pneumoniae antigens in frontal and temporal cortices of the AD brain. C. pneumoniae, amyloid deposits, and neurofibrillary tangles were present in the same regions of the brain in apposition to one another. Although additional studies are required to conclusively characterize the nature of Chlamydial immunoreactivity in the AD brain, these results further implicate C. pneumoniae infection with the pathogenesis of Alzheimers disease.

Rational design of cytotoxic T-cell inhibitors.

This study describes the use of the CD8/major histocompatibility complex (MHC) class I crystal structure as a template for the de novo design of low-molecular-weight surface mimetics. The analogs were designed from a local surface region on the CD8 α-chain directly adjacent to the bound MHC class I, to block the protein associations in the T-cell activation cluster that occur upon stimulation of the cytotoxic T lymphocytes (CTLs). One small conformationally restrained peptide showed dose-dependent inhibition of a primary allogeneic CTL assay while having no effect on the CD4-dependent mixed lymphocyte reaction (MLR). The analogs activity could be modulated through subtle changes in its side chain composition. Administration of the analog prevented CD8-dependent clearance of a murine retrovirus in BALB/c mice. In C57BL/6 mice challenged with the same retrovirus, the analog selectively inhibited the antiviral CTL responses without affecting the ability of the CTLs to generate robust allogeneic responses.

Effect of Age and Vaccination on Extent and Spread of Chlamydia pneumoniae Infection in C57BL/6 Mice

BackgroundChlamydia pneumoniae is an obligate intracellular respiratory pathogen for humans. Infection by C. pneumoniae may be linked etiologically to extra-respiratory diseases of aging, especially atherosclerosis. We have previously shown that age promotes C. pneumoniae respiratory infection and extra-respiratory spread in BALB/c mice.FindingsAged C57BL/6 mice had a greater propensity to develop chronic and/or progressive respiratory infections following experimental intranasal infection by Chlamydia pneumoniae when compared to young counterparts. A heptavalent CTL epitope minigene (CpnCTL7) vaccine conferred equal protection in the lungs of both aged and young mice. This vaccine was partially effective in protecting against C. pneumoniae spread to the cardiovascular system of young mice, but failed to provide cardiovascular protection in aged animals.ConclusionsOur findings suggest that vaccine strategies that target the generation of a C. pneumoniae-specific CTL response can protect the respiratory system of both young and aged animals, but may not be adequate to prevent dissemination of C. pneumoniae to the cardiovascular system or control replication in those tissues in aged animals.

Evidence for an Infectious Etiology in Alzheimer's Disease

The possibility of an infectious etiology of several chronic diseases, including Alzheimer′s Disease, has long been debated. More than a century ago Alois Alzheimer studied neurological infection with Treponema pallidum, the causative agent of syphilis, a spirochete later associated with dementia (Noguchi and Moore, 1913). There are many chronic diseases for which there is strong evidence of an infectious etiology (see table 1), and numerous chronic diseases for which there is suspicion of infection as the etiologic agent for that disease (see table 2) (Tables 1 and 2 are adapted from a colloquium sponsored by the American Academy of Microbiology from June 2004). Koch’s postulates, that can, in some cases, provide absolute proof that a particular microorganism causes a particular disease, have been invaluable in the prevention and treatment of many diseases as well as in advancing microbiology. However, the postulates do not hold for most chronic diseases of microbial etiology, particularly those occurring late in life. Furthermore, they do not hold true for those of possible viral etiology, or for those that are multi-factorial in origin. In diseases of relatively old age, microbes acting earlier in life might operate by a “hit-andhide” mechanism, or could over time be present at an extremely low level, so that searches for the organism might not reveal the culprit until long after damage has been initiated. In viral diseases and for those involving unique organisms such as obligate intracellular bacteria (eg, Chlamydia), the postulates requiring isolation and growth in pure culture cannot be met completely as these organisms reproduce only within living cells. In multifactorial diseases, a causative organism might not be readily apparent, as other factors may be more prominent. However, absence of evidence is not proof of absence; in several cases when overwhelming experimental evidence was obtained, the pathogen concept had to be accepted even though it had met with great opposition initially. Two examples, among many, are the involvement of viruses in certain types of cancer such as human papillomavirus in cervical cancer, and of the bacterium Helicobacter pylori in stomach ulcers. Alzheimer′s Disease(AD) is a neurodegenerative disease that is considered to be the single most significant cause of dementia in the elderly (Keefover, 1996). There are two major categories of AD, familial and sporadic late-onset. The familial form of AD accounts for approximately 5% of total cases and usually presents in individuals in their 40’s and 50’s. This form of disease is caused by rare mutations in genes associated with β-amyloid

P2-003: Effects of antibiotic treatment on cellular inflammatory processes in the brain during persistent Chlamydia pneumoniae infection of BALB/c mice

upon symptoms in the Mood cluster at both weeks 12 (P .034) and 24 (P .033), with 65.5% of patients in the memantine group showing a positive response at week 24. Memantine also had a significant effect over placebo (OC) upon symptoms of Psychosis at both weeks 12 (P .006) and 24 (P .001), with 80.7% of patients in the memantine group showing a positive response in this domain at week 24. The response difference (OC) between memantine and placebo patients at week 24 was 12.2% and 18.9% for Mood and Psychosis clusters, respectively. LOCF analysis yielded comparable results. Effects of memantine on Frontal symptoms were not significant, while the effects on Other symptoms were significant at week 24 using LOCF analysis (P .037), but not OC analysis (P .058). Conclusions: Taken together, these results suggest that memantine provides specific behavioral benefits for mood and psychosis-related symptoms associated with AD.