Characteristics of peripheral immune system in a novel AppNL‐G‐F knock‐in mouse model of Alzheimer’s disease

Abstract

AbstractBackgroundIncreasing epidemiological, clinical, and experimental evidence suggests that Alzheimer’s disease (AD) pathogenesis is closely associated with systemic abnormalities, including dynamic processes in the peripheral immune compartment and inflammation1,2,3. Recent reports in transgenic AD animal models propose a role of dysregulated peripheral immune system in memory impairment4,5. In this regard, the contribution of peripheral immune response in driving different pathological stages in AD is less understood. Therefore, utilizing a novel App knock‐in mouse model (AppNL‐G‐F) exhibiting robust Aβ pathology, neuroinflammation and memory impairment, we have explored the relation of Aβ pathology development in the brain with alterations in the peripheral immune compartment.MethodUsing flowcytometry, we characterized the AppNL‐G‐F mice at different stages of Aβ pathology (early‐plaque: 3‐month‐old; plaque + early memory impairment: 7‐month‐old; late stages: 12‐month‐old) and investigated the distribution and activation status of various peripheral immune cells in splenic primary cells.ResultAmong various immune cells from innate immunity including macrophages, natural killer and dendritic cells, there was a significant increase in macrophage number in AppNL‐G‐F mice. While percent distribution of B cells from adaptive immunity was reduced (as observed in AD patients2), no significant changes in total T cell distribution following 3, 7 and 12‐months of age compared to wild‐type controls was observed. B cells showed reduced activation examined by CD69 and PD‐L1 expression in 7 and 12‐months old AppNL‐G‐F mice. Among T cell subsets, CD4, CD8 and regulatory T (Treg) cell distribution in AppNL‐G‐F mice was comparable to control mice in all age groups. However, there was rise in follicular T helper (Tfh) cells at 3‐month of age, with altered activation molecule ICOS expression in AppNL‐G‐Fmice.ConclusionThese findings in AD mice model show a reduction in B cell and their activation status during aggressive Aβ plaque deposition in brain, reflecting their possible contribution in Aβ pathology reinforcing the importance of further investigation. Our data suggest a possible role of Tfh cell in early stage of Aβ pathology. An altered Tfh cell activation may answer the impaired protective antibody production from B cells reported in AD6,7. The observed increase in macrophages in the peripheral system during Aβ pathology development demands further investigation.