Astrocytes infected with Chlamydia pneumoniae demonstrate altered expression and activity of secretases involved in the generation of β-amyloid found in Alzheimer disease

Abstract

Background Epidemiologic studies strongly suggest that the pathophysiology of late-onset Alzheimer disease (AD) versus early-onset AD has environmental rather than genetic causes, thus revealing potentially novel therapeutic targets to limit disease progression. Several studies supporting the “pathogen hypothesis” of AD demonstrate a strong association between pathogens and the production of β-amyloid, the pathologic hallmark of AD. Although the mechanism of pathogen-induced neurodegeneration of AD remains unclear, astrocytes, a key player of the CNS innate immune response and producer/metabolizer of β-amyloid, have been implicated. We hypothesized that Chlamydia pneumoniae infection of human astrocytes alters the expression of the amyloid precursor protein (APP)-processing secretases, ADAM10, BACE1, and PSEN1, to promote β-amyloid formation. Utilizing immunofluorescent microscopy, molecular, and biochemical approaches, these studies explore the role of an intracellular respiratory pathogen, Chlamydia pneumoniae , as an environmental trigger for AD pathology. Human astrocytoma cells in vitro were infected with Chlamydia pneumoniae over the course of 6–72 h. The gene and protein expression, as well as the enzymatic activity of non-amyloidogenic (ADAM10), and pro-amyloidogenic (BACE1 and PSEN1) secretases were qualitatively and quantitatively assessed. In addition, the formation of toxic amyloid products as an outcome of pro-amyloidogenic APP processing was evaluated through various modalities. Results Chlamydia pneumoniae infection of human astrocytoma cells promoted the transcriptional upregulation of numerous genes implicated in host neuroinflammation, lipid homeostasis, microtubule function, and APP processing. Relative to that of uninfected astrocytes, BACE1 and PSEN1 protein levels were enhanced by nearly twofold at 48–72 h post- Chlamydia pneumoniae infection. The processing of APP in Chlamydia pneumoniae- infected astrocytes favors the pro-amyloidogenic pathway, as demonstrated by an increase in enzymatic activity of BACE1, while that of ADAM10 was decreased. Fluorescence intensity of β-amyloid and ELISA-quantified levels of soluble-APP by products revealed temporally similar increases, confirming a BACE1/PSEN1-mediated processing of APP. Conclusions Our findings suggest that Chlamydia pneumoniae infection of human astrocytes promotes the pro-amyloidogenic pathway of APP processing through the upregulation of expression and activity of β-secretase, upregulated expression of γ-secretase, and decreased activity of α-secretase. These effects of astrocyte infection provide evidence for a direct link between Chlamydia pneumoniae and AD pathology. Electronic supplementary material The online version of this ar...

The progress of gut microbiome research related to brain disorders

“…Intestinal germ-free APP transgenic mice were found to have a reduction of cerebral amyloid pathology compared to controls [198]. More recently, Chlamydia pneumoniae infection in astrocytes has been demonstrated to be involved in the generation of β-amyloid, which promotes AD [199]. Ingestion of probiotics has been reported to be beneficial in AD.…”

Pharmacological Inhibition of Amyloidogenic APP Processing and Knock-Down of APP in Primary Human Macrophages Impairs the Secretion of Cytokines

“…Kumar and his colleagues demonstrated that APP knockout mice had a reduced survival, while mice transgenic for APP had an improved survival in a model of infectious meningitis (30). Fitting into this hypothesis, an increased expression of APP, an accumulation of Aβ peptides in the brain and reduced concentrations of Aβ peptides in the CSF were not only observed in patients with Alzheimer's disease but also with meningitis and other inflammatory diseases (14,15,(45)(46)(47).…”

“…One reason for this finding might be that Aβ peptides bind and agglutinate microorganisms and are therefore no longer measurable in the CSF. Astrocytes express higher amounts of the APP processing enzymes BACE-1 and presenilin 1 upon infection with C. pneumonia e ( 16 ). Therefore, an immunological function of APP and Aβ peptides can be assumed.…”

“…Also, a knock-out of APP or the β-site amyloid cleaving enzyme (BACE-1) in mice was associated with a reduced activity of microglia and a reduced secretion of pro-inflammatory cytokines (9)(10)(11)(12)(13). Likewise, reduced concentrations of Aβ peptides in cerebrospinal fluid (CSF) were also found during brain infections (14,15). One reason for this finding might be that Aβ peptides bind and agglutinate microorganisms and are therefore no longer measurable in the CSF.…”

Pharmacological inhibition of APP processing and knock-down of APP in primary human macrophages impairs the secretion of cytokines

“…Vice versa, reduced concentrations of Aβ peptides in cerebrospinal fluid (CSF) were also found during brain infections (14,15). Astrocytes express higher amounts of the APP processing enzymes BACE-1 and presenilin 1 upon infection with C. pneumonia (16). Therefore, an immunological function of APP and Aβ peptides can be assumed.…”