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

Abstract

BackgroundAlzheimer’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.MethodsIn 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.ResultsWe 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.ConclusionThis 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.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1265-7) contains supplementary material, which is available to authorized users.

Transcriptional signatures of progressive neuropathology in transgenic tau and amyloid mouse models

“…brain regions (hippocampus: factorial ANOVA, F(3,62) = 12.60, P = 1.56E-06; cortex: factorial ANOVA, F(3,62) = 18.13, P = 1.47E-08; thalamus: factorial ANOVA, F(3,62) = 18.85, P = 8.37E-09) (SupplementaryFigure 9). Together our results reflect the dramatic upregulation of microglial genes observed in studies of other AD rodent models[13][14][15]43,46,47 , and support a roleeither causal or consequentialfor dysregulation of the central nervous system (CNS) immune system in the development of AD pathology. Of note, the list of transcripts progressively altered in rTg4510 mice includes genes robustly associated with familial AD from genetic studies of human patients, including App(Supplementary Figure.10a, LRT statistic = 13.88, FDR = 0.037) a key driver of amyloid pathology.…”

“…LRT statistic = 86.85, FDR = 6.54E-15), and Clec7a (Figure 3e; LRT statistic = 83.20, FDR = 2.97E-14). These genes have all been previously reported to be upregulated in hippocampal tissue from 6-month old rTg4510 female mice 17 , in isolated microglia from rTg4510 mice 25 , in the cortex of amyloid mice at late stages of pathology 15 , and in the neocortex, hippocampus and microglia of mice with amyloid and tau pathology 13,43 . Furthermore, recent transcriptional studies in human brain have shown that microglial gene networks are upregulated in response to AD neuropathology 44 .…”

“…A number of recent studies have described further evidence for differential gene expression in transgenic models of familial AD gene mutations [12][13][14][15]17,25,43 . We therefore explored hippocampal RNA-seq data from two other transgenic models (TAU (CaMKII-MAPTP301L) and TAS10 (SwAPP, K670N/M671L)) downloaded from the Mouseac database 14,51 (www.mouseac.org) to identify consistencies in the transcriptional signatures between different models of tau and amyloid pathology.…”

“…Mouse models of tau and amyloid have played a major role in defining critical pathology-related processes, including facilitating our understanding of the brain's transcriptional response to the production and gradual deposition of tau and amyloid into tangles and plaques 11 . Recent studies have identified widespread gene expression differences in transgenic mice harbouring a diverse range of AD-associated mutations [12][13][14][15][16][17] . However, most analyses to date have been undertaken on relatively small numbers of animals and have not attempted to directly relate transcriptional alterations to the progressive burden of pathology in the same mice.…”

BHBA treatment improves cognitive function by targeting pleiotropic mechanisms in transgenic mouse model of Alzheimer's disease

“…61 Region-specific enrichment of populations of mRNAs in the mouse hippocampus and prefrontal cortex (PFC) as well as characteristic lncRNA expression signatures in subregions of the brain and specific neuronal populations have been reported. Most agents that exclusively target amyloid-related alterations in AD have been unsuccessful so far.…”