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Compound AD16 Reduces Amyloid Plaque Deposition and Modifies Microglia in a Transgenic Mouse Model of Alzheimer's Disease.

ABSTRACT: Microglial dysfunction is involved in the pathological cascade of Alzheimer's disease (AD). The regulation of microglial function may be a novel strategy for AD therapy. We previously reported the discovery of AD16, an antineuroinflammatory molecule that could improve learning and memory in the AD model. Here, we studied its properties of microglial modification in the AD mice model. In this study, AD16 reduced interleukin-1β (IL-1β) expression in the lipopolysaccharide-induced IL-1β-Luc transgenic mice model. Compared with mice receiving placebo, the group treated with AD16 manifested a significant reduction of microglial activation, plaque deposition, and peri-plaques microgliosis, but without alteration of the number of microglia surrounding the plaque. We also found that AD16 decreased senescent microglial cells marked with SA-β-gal staining. Furthermore, altered lysosomal positioning, enhanced Lysosomal Associated Membrane Protein 1 (LAMP1) expression, and elevated adenosine triphosphate (ATP) concentration were found with AD16 treatment in lipopolysaccharide-stimulated BV2 microglial cells. The underlying mechanisms of AD16 might include regulating the microglial activation/senescence and recovery of its physiological function via the improvement of lysosomal function. Our findings provide new insights into the AD therapeutic approach through the regulation of microglial function and a promising lead compound for further study.

SUBMITTER: Sun P

PROVIDER: S-EPMC7737203 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:PurposePathological studies suggest that neuroinflammation is exacerbated by increased beta-amyloid (A?) levels in the brain early in Alzheimer's disease (AD). The time course and relationships between astrocytosis and A? deposition were examined using multitracer in vivo positron emission tomography (PET) imaging in an AD transgenic mouse model, followed by postmortem autoradiography and immunohistochemistry analysis.MethodsPET imaging with the amyloid plaque tracer (11)C-AZD2184 and the astroglial tracer (11)C-deuterium-L-deprenyl ((11)C-DED) was carried out in APPswe mice aged 6, 8-15 and 18-24 months (4-6 animals/group) and in wild-type (wt) mice aged 8-15 and 18-24 months (3-6 animals/group). Tracer uptake was quantified by region of interest analysis using PMOD software and a 3-D digital mouse brain atlas. Postmortem brain tissues from the same APPswe and wt mice in all age groups were analysed for A? deposition and astrocytosis by in vitro autoradiography using (3)H-AZD2184, (3)H-Pittsburgh compound B (PIB) and (3)H-L-deprenyl and immunostaining performed with antibodies for A?42 and glial fibrillary acidic protein (GFAP) in sagittal brain sections.Results(11)C-AZD2184 PET retention in the cerebral cortices of APPswe mice was significantly higher at 18-24 months than in age-matched wt mice. Cortical and hippocampal (11)C-DED PET binding was significantly higher at 6 months than at 8-15 months or 18-24 months in APPswe mice, and it was also higher than at 8-15 months in wt mice. In vitro autoradiography (3)H-AZD2184 and (3)H-PIB binding confirmed the in vivo findings with (11)C-AZD2184 and demonstrated age-dependent increases in A? deposition in APPswe cortex and hippocampus. There were no significant differences between APPswe and wt mice in (3)H-L-deprenyl autoradiography binding across age groups. Immunohistochemical quantification demonstrated more A?42 deposits in the cortex and hippocampus and more GFAP(+) reactive astrocytes in the hippocampus at 18-24 months than at 6 months in APPswe mice.ConclusionThe findings provide further in vivo evidence that astrocytosis occurs early in AD, preceding A? plaque deposition.

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Compound AD16 Reduces Amyloid Plaque Deposition and Modifies Microglia in a Transgenic Mouse Model of Alzheimer's Disease.

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