Human Alzheimer’s disease gene expression signatures and immune profile in APP mouse models: a discrete transcriptomic view of Aβ plaque pathology

Abstract Background Alzheimer’s disease (AD) is a chronic neurodegenerative disease with pathological hallmarks including the formation of extracellular aggregates of amyloid-beta (Aβ) known as plaques and intracellular tau tangles. Coincident with the formation of Aβ plaques is recruitment and activation of glial cells to the plaque forming a plaque niche. In addition to histological data showing the formation of the niche, AD genetic studies have added to the growing appreciation of how dysfunctional glia pathways drive neuropathology, with emphasis on microglia pathways. Genomic approaches enable comparisons of human disease profiles between different mouse models informing on their utility to evaluate secondary changes to triggers such as Aβ deposition. Methods In this study, we utilized two animal models of AD to examine and characterize the AD-associated pathology: the Tg2576 Swedish APP (KM670/671NL) and TgCRND8 Swedish plus Indiana APP (KM670/671NL + V717F) lines. We used laser capture microscopy (LCM) to isolate samples surrounding Thio-S positive plaques from distal non-plaque tissue. These samples were then analyzed using RNA sequencing. Results We determined age-associated transcriptomic differences between two similar yet distinct APP transgenic mouse models, known to differ in proportional amyloidogenic species and plaque deposition rates. In Tg2576, human AD gene signatures were not observed despite profiling mice out to 15 months of age. TgCRND8 mice however showed progressive and robust induction of lysomal, neuroimmune, and ITIM/ITAM-associated gene signatures overlapping with prior human AD brain transcriptomic studies. Notably, RNAseq analyses highlighted the vast majority of transcriptional changes observed in aging TgCRND8 cortical brain homogenates were in fact specifically enriched within the plaque niche samples. Data uncovered plaque-associated enrichment of microglia-related genes such as ITIM/ITAM-associated genes and pathway markers of phagocytosis. Conclusion This work may help guide improved translational value of APP mouse models of AD, particularly for strategies aimed at targeting neuroimmune and neurodegenerative pathways, by demonstrating that TgCRND8 more closely recapitulates specific human AD-associated transcriptional responses

Magnetization and spin gap in two-dimensional organic ferrimagnet BIPNNBNO

A magnetization process in the two-dimensional ferrimagnet BIPNNBNO is analyzed. The compound consists of ferrimagnetic (1,1/2) chains coupled by two sorts of antiferromagnetic interaction. Whereas the behavior of the magnetization curve in higher magnetic fields can be understood within a process for the separate ferrimagnetic chain, the appearance of the singlet plateau at lower fields is an example of non-Lieb-Mattis type ferrimagnetism. By using the exact diagonalization technique for finite clusters of size 4×6, 4×8 and 4×10 we show that the interchain frustration coupling plays an essential role in stabilization of the singlet phase. These results are complemented by an analysis of four cylindrically coupled ferrimagnetic (1,1/2) chains via an Abelian bosonization technique and an effective theory based on the XXZ spin-1/2 Heisenberg model when the interchain interactions are sufficiently weak/strong, respectively. © 2012 IOP Publishing Ltd