Chlamydia pneumoniae: An Etiologic Agent for Late-Onset Dementia

Abstract

The disease known as late-onset Alzheimer’s disease is a neurodegenerative condition recognized as the single most commonform of senile dementia. The condition is sporadic and has been attributed to neuronal damage and loss, both of which have been linked to the accumulation of protein deposits in the brain. Significant progress has been made over the past two decades regarding our overall understanding of the apparently pathogenic entities that arise in the affected brain, both for early-onset disease, which constitutes approximately 5% of all cases, as well as late-onset disease, which constitutes the remainder of cases. Observable neuropathology includes: neurofibrillary tangles, neuropil threads, neuritic senile plaques and often deposits of amyloid around the cerebrovasculature. Although many studies have provided a relatively detailed knowledge of these putatively pathogenic entities, understanding of the events that initiate and support the biological processes generating them and the subsequent observable neuropathology and neurodegeneration remain limited. This is especially true in the case of late-onset disease. Although early-onset Alzheimer’s disease has been shown conclusively to have genetic roots, the detailed etiologic initiation of late-onset disease without such genetic origins has remained elusive. Over the last 15 years, current and ongoing work has implicated infection in the etiology and pathogenesis of late-onset dementia. Infectious agents reported to be associated with disease initiation are various, including several viruses and pathogenic bacterial species. We have reported extensively regarding an association between late-onset disease and infection with the intracellular bacterial pathogen Chlamydia pneumoniae. In this article, we review previously published data and recent results that support involvement of this unusual respiratory pathogen in disease induction and development. We further suggest several areas for future research that should elucidate details relating to those processes, and we argue for a change in the designation of the disease based on increased understanding of its clinical attributes.

Burkholderia pseudomallei invades the olfactory nerve and bulb after epithelial injury in mice and causes the formation of multinucleated giant glial cells in vitro

“…Together, these findings support the "olfactory vector hypothesis"-that external agents entering the nasal cavity and damaging the primary olfactory nervous system and olfactory bulb constitute a basis for neurodegeneration [96,97]. A growing body of work has correlated pathogens with the development of neurodegenerative diseases including AD and PD [98][99][100][101][102][103][104][105][106][107][108]. One known case of post-melioidosis Parkinsonism has been described [109].…”

An agent-based model to investigate microbial initiation of Alzheimer’s via the olfactory system

“…Following the main tenet of the C. pneumoniae hypothesis, it was modeled that infected cells within these regions would cause Aβ plaque and NF tangle formation to form in the specified region. Since it has been found that immune response cells aggregate around areas where amyloid plaque formation by several studies [25,38], areas where microglia swarm an infected cell produces a single patch of plaque in the model. Since there is limited knowledge as to how tangle formation is initiated in a similar way, tangles are formed randomly in the model within the specified region.…”

“…The E4 allele of the APOE gene is currently the strongest risk factor for late-onset AD [46]. This gene, expressed extensively by astrocytes in the brain, encodes a protein component of the low-density lipoprotein (LDL) which transports cholesterol to neurons by binding to several cell surface receptors [25]. Studies have shown that AD patients with the E4 allele, which has also been implicated in the development of atherosclerosis and coronary heart disease, display significantly higher numbers of C. pneumoniae infected cells in affected brain regions compared to congruent samples from AD patients lacking the allele [47].…”

“…Nevertheless, it is extremely difficult to isolate C. pneumoniae from the brain. Numerous papers have expounded on this difficulty, especially in the reproducibility of studies done by researchers [25]. However, there is a definite need for ethical, longitudinal studies to understand the proposed pathway and its mechanistic parameters better.…”

“…Additionally, biopsies of AD patients have revealed microbial concentrations in the entorhinal cortex and hippocampus [11,21,22]. These regions of the brain exhibited both C. pneumoniae immunoreactivity as well as Aβ plaque and NF tangle formation [23,25]. Current understanding of AD suggest that the entorhinal cortex and hippocampus are among earliest regions to be damaged in late-onset AD [26,27].…”