P1–010: Apolipoprotein E isoform–specific modulation of innate immune response neurotoxicity in a targeted replacement APOE mouse model
Year: 2006
Type: article
Abstract: Glial innate immune response has been associated with several degenerative diseases of brain including Alzheimer's disease (AD), while numerous genetic studies have associated inheritance of apolipoprotein E (APOE) 4 with increased risk, earlier onset, or poorer clinical outcome for these same diseases. Since APOE has been shown to have an immune modulatory function, there may be a mechanistic connection between these two observations. We tested the hypothesis that inheritance of different APOE alleles may modulate the neurotoxicity arising from CD14/Toll–like receptor 4–activated glial innate immune response to lipopolysaccharide (LPS). We used homozygous APOE2, APOE3 and APOE4 targeted replacement (TR) mice ‘humanized’ at APOE to perform the following experiments. (1) Primary dissociated cultures of wt neurons and TR APOE microglia were exposed to LPS and the number of NeuN immunoreactive cells quantified as an index of neurotoxicity. (2) Cytokine secretion by TR APOE microglia following LPS exposure was measured using the LiquiChip Mouse 10–Cytokine assay and a Luminex 100 X–Map reader. (3) Relative p38 microtubule–associated protein (MAP) K activity in TR APOE microglia following LPS exposure was determined by comparing secreted interleukin–6 and transforming growth factor alpha concentrations with and without a specific inhibitor of p38MAPK activity, SB203580 (SB). (4) TR APOE hippocampal slice cultures were exposed to LPS and several endpoints measured. Cytokines were measured as described in (3). Activated (P–) p38MAPK was localized by immunohistochemistry. Neurotoxicity was assessed by determining relative levels of the synaptic membrane proteins PSD95, drebrin, and synaptophysin on Western blots, as well as by MAP–2 immunohistochemistry. LPS treatment of slice cultures was repeated with and without SB to determine p38MAPK dependence of the response. (1) Neurotoxicity from glial innate immune response was greatest with TR APOE4 microglia in primary dissociated cultures. (2) Cytokine secretion by TR APOE microglia was TR APOE–dependent. (3) TR APOE4 microglia were significantly more sensitive to a p38MAPK inhibitor than TR APOE2 microglia. (4) Innate immunity–mediated neural damage in hippocampal slice cultures occurred with TR APOE4 and TR APOE3, but not TR APOE2, and was p38MAPK–dependent.
Source: Alzheimer s & Dementia
Language: English
Subfield: Neurology
Field: Neuroscience
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W3022102489