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Deletion of CD14 attenuates Alzheimer's disease pathology by influencing the brain's inflammatory milieu.

ABSTRACT: Alzheimer's disease (AD) is characterized by the deposition of ?-amyloid (A?)-containing plaques within the brain that is accompanied by a robust microglial-mediated inflammatory response. This inflammatory response is reliant upon engagement of innate immune signaling pathways involving the toll-like receptors (TLRs). Studies assessing the roles of TLRs in AD pathogenesis have yielded conflicting results. We have assessed the roles of the TLRs through genetic inactivation of the TLR2/4 coreceptor, CD14, in a transgenic murine model of AD. Transgenic mice lacking CD14 exhibited reduced insoluble, but not soluble, levels of A? at 7 months of age. This corresponded with decreased plaque burden resulting from a reduction in number and size of both diffuse and thioflavin S-positive plaques and an overall reduction in the number of microglia. These findings are inconsistent with the established actions of these receptors. Moreover, loss of CD14 expression was associated with increased expression of genes encoding the proinflammatory cytokines Tnf? and Ifn?, decreased levels of the microglial/macrophage alternative activation markers Fizz1 and Ym1, and increased expression of the anti-inflammatory gene Il-10. Thus, the loss of CD14 resulted in a significant change in the inflammatory environment of the brain, likely reflecting a more heterogeneous population of microglia within the brains of the animals. The reduction in plaque burden was not a result of changes in the expression of various A? degrading enzymes or proteins associated with A? clearance. These data suggest that CD14 is a critical regulator of the microglial inflammatory response that acts to modulate A? deposition.

SUBMITTER: Reed-Geaghan EG

PROVIDER: S-EPMC2997622 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Deletion of CD14 attenuates Alzheimer's disease pathology by influencing the brain's inflammatory milieu.

Reed-Geaghan Erin G EG Reed Quillan W QW Cramer Paige E PE Landreth Gary E GE

The Journal of neuroscience : the official journal of the Society for Neuroscience 20101101 46

Alzheimer's disease (AD) is characterized by the deposition of β-amyloid (Aβ)-containing plaques within the brain that is accompanied by a robust microglial-mediated inflammatory response. This inflammatory response is reliant upon engagement of innate immune signaling pathways involving the toll-like receptors (TLRs). Studies assessing the roles of TLRs in AD pathogenesis have yielded conflicting results. We have assessed the roles of the TLRs through genetic inactivation of the TLR2/4 corecept ...[more]

PMID: 21084593

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Project description:This study examines the link between peripheral immune changes in perpetuation of the Alzheimer's disease (AD) neuropathology and cognitive deficits. Our research design using human AD patients and rodent model is supported by past evidence from genomic studies. We observed an active immune response against Aβ as indicated by the increased Aβ specific IgG antibody in the serum of AD and patients with mild cognitive impairments as compared to healthy controls. A similar increase in IgG and decrease in IgM antibody against Aβ was also confirmed in the 5xFAD mouse model of AD. More importantly, we observed a negative correlation between reduced IgM levels and cognitive dysfunction that manifested as impaired memory consolidation. Strong peripheral immune activation was supported by increased activation of microglia in the brain and macrophages in the spleen of AD mice compared to wild type control littermates. Furthermore, inflammatory cytokine IL-21 that is involved in antibody class switching was elevated in the plasma of AD patients and correlated positively with the IgG antibody levels. Concurrently, an increase in IL-21 and IL-17 was observed in spleen cells from AD mice. Further investigation revealed that proportions of T follicular helper (Tfh) cells that secrete IL-21 are increased in the spleen of AD mice. In contrast to Tfh, the frequency of B1 cells that produce IgM antibodies was reduced in AD mice. Altogether, these data indicate that in AD the immune tolerance to Aβ is compromised leading to chronic immune/inflammatory responses against Aβ that are detrimental and cause neuropathology. Graphical Abstract Healthy subjects are tolerant to Aβ and usually react weakly to it resulting the in the production of IgM class of antibodies that are efficient at clearing up self-antigens such as Aβ without causing inflammation. In contrast, Alzheimer's disease patients mount a strong immune response against Aβ probably in an effort to clear up excessive Aβ. There is enhanced production of inflammatory cytokines such as IL-21 as well as an increase in Tfh cells that cause antibody class switching form IgM to IgG. The strong immune response is inefficient at clearing up Aβ and instead exacerbates inflammation that causes AD neuropathology and cognitive dysfunction.

Dataset Information

Deletion of CD14 attenuates Alzheimer's disease pathology by influencing the brain's inflammatory milieu.

Publications

Deletion of CD14 attenuates Alzheimer's disease pathology by influencing the brain's inflammatory milieu.

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