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Cited by 37Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

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

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Al-Atrache, Zein, Lopez, Danielle B., Hingley, Susan T., Appelt, Denah M.·2019·BMC Neuroscience
DOI 10.1186/s12868-019-0489-5PMC PMC6383264
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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.

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  • Following infection, activated microglia and astrocytes secrete pro-inflammatory cytokines, including IL-1β, TNFα and IL-6, which are neurotoxic and may directly increase Aβ production via activation of β-secretase (BACE).

    “It has been shown that following infection, activated microglia and astrocytes secrete pro-inflammatory cytokines, including IL-1β, TNFα and IL-6 which are neurotoxic and may directly increase Aβ production via activation of β-secretase (BACE)66,74.”

    From Chlamydia pneumoniae can infect the central nervous system via the olfactory and trigeminal nerves and contributes to Alzheimer’s disease risk (2022) · cites this paper as [66]

    The Background (page unavailable) links infectious stimuli to inflammatory cytokine release and altered BACE1 activity, and the Results report increased BACE1 activity after infection of astrocytoma cells. The paper does not show that infected microglia and astrocytes secrete the specified IL-1β, TNFα, and IL-6, or that those cytokines directly cause the increase in Aβ through BACE1. Its Discussion reports increased transcription of IL-1α, not IL-1β, in infected astrocytes. (LLM, conf=0.88)

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Cited by

Sorted by citations

Authors
Al-Atrache, Z., Lopez, D. B., Hingley, S. T., & Appelt, D. M.
Affiliations
Philadelphia College of Osteopathic Medicine (US)
Corresponding author
Appelt, Denah M.
ORCID
Venue
BMC Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2019-02-20
Volume
20
Issue
1
Pages
6-6
ISSN
1471-2202 (ISSN-L)
DOI
10.1186/s12868-019-0489-5
PMC
PMC6383264
OpenAlex
W2940493085
Cited by
37
References
10
Citations by year
2026: 6 · 2025: 8 · 2024: 2 · 2023: 4 · 2022: 8 · 2021: 3 · 2020: 6
FWCI
2.85
Type
journal article
Language
en
Open access
Licence
Locations
  • BMC Neuroscience (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Digital Commons - PCOM (Philadelphia College of Osteopathic Medicine) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Center for chronic disorders of aging (Internal institutional funding at PCOM)
  • The Adolph and Rose Levis Foundation for Alzheimer Disease Research (Private foundation)
  • Giunta Family Research Scholarship (Private Foundation)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Alzheimer's disease, astrocytes, amyloid-beta, APP processing, BACE1, ADAM10, presenilin 1, secretases, neuroinflammation, respiratory pathogens, soluble APP, amyloidogenic pathway, astrocytoma cells, environmental risk factors, innate immunity, lipid homeostasis, microtubule function
MeSH terms
ADAM10 Protein, Alzheimer Disease, Astrocytes, Humans, Inflammation, Membrane Proteins, Gene Expression, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Chlamydophila pneumoniae, Chlamydophila Infections, Cell Line, Tumor, Presenilin-1, Amyloid Precursor Protein Secretases

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