Premium
P1‐157: Increased TLR8 and 9 Expression Correlates with Preserved Hyppocampal Volumes and Lack of Progression to Alzheimer's Disease in Individuals with A Diagnosis of Mild Cognitive Impairment
Author(s) -
La Rosa Francesca,
Saresella Marina,
Piancone Federica,
Marventano Ivana,
Calabrese Elena,
Nemni Raffaello,
Clerici Mario
Publication year - 2016
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2016.06.905
Subject(s) - innate immune system , tlr2 , neuroinflammation , immunology , cd14 , tlr9 , cytokine , neurodegeneration , cd16 , dementia , immune system , pathogenesis , disease , inflammasome , medicine , biology , inflammation , cd8 , gene expression , biochemistry , dna methylation , cd3 , gene
Background: The pathogenesis of Alzheimer’s disease (AD), characterized by accumulation of extracellular amyloid beta (Abeta) plaques within the brain, is associated with profound microglia activation around the plaques. Furthermore, aging of the brain has been associated with enhanced sensitivity of microglia to proinflammatory stimuli, so-called microglia priming. In this study, we investigated to which extent microglia priming is associated with Abeta plaque pathology. Methods:We measured the expression of markers for microglia priming in three established mouse models for AD, i.e. APP23, APPPS1 and 5XFAD mice, as well as in human AD brain. Results:Expression of specific protein markers for microglia priming, Mac-2 and MHC II, was observed in Abeta plaque-associated microglia in 16and 20-month-old APP23 mice, 18-month-old APPPS1 mice and 12-month-old 5XFAD mice, but not in microglia outside the plaque areas nor in microglia of age-matched wild-type (WT) mice. After i.p. injection of LPS, the expression of Mac2 and MHC II was enhanced in APP23 mice and the expression of the pro-inflammatory cytokine interleukin-1beta (IL-1beta) was enhanced specifically in plaque-associated microglia in 20-month-old APP23 mice and 12-month-old 5XFAD mice. In contrast, microglia outside the plaque areas showed only moderate expression of IL-1beta in response to LPS, comparable to what was observed in wild-type mice. In the cortex of old (24 months) wild-type mice, specific markers for microglia priming were detected sporadically. Gene expression profile of Abeta plaque-associated microglia (MHC II microglia) in 9-monthold 5XFAD mice also revealed the primed phenotype. In early-onset familial AD (EOFAD), expression of priming markers, HLA-DR (MHC II), Apoe and Axl, was specifically higher in mature plaque regions, compared to non-plaque regions. Conclusions: In transgenic AD mouse models, APP23 mice, APPPS1 mice and 5XFAD mice, microglia priming is confined to the Abeta plaque areas at early age, and later on occurs in tandem with aging-associated priming. In EOFAD patients but not in late-onset AD (LOAD), microglia priming occurred in the vicinity of Abeta plaques.