Skip to main content

01.12.2018 | Research | Ausgabe 1/2018 Open Access

Journal of Neuroinflammation 1/2018

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

Journal of Neuroinflammation > Ausgabe 1/2018
Sarah M. Rothman, Keith Q. Tanis, Pallavi Gandhi, Vladislav Malkov, Jacob Marcus, Michelle Pearson, Richard Stevens, Jason Gilliland, Christopher Ware, Veeravan Mahadomrongkul, Elaine O’Loughlin, Gonzalo Zeballos, Roger Smith, Bonnie J. Howell, Joel Klappenbach, Matthew Kennedy, Christian Mirescu
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1186/​s12974-018-1265-7) contains supplementary material, which is available to authorized users.



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.


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.


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.


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.
Additional file 1: Figure S1. Nanostring confirmation of plaque associate selected gene in TgCRND8. Selected plaque associated genes that were upregulated in LCM tissue in TgCRND8 mice by RNAseq were confirmed using a Nanostring customized chip (n=4 per group). Bar graphs show nCounts (mean ± s.e.m) to highlight changes for a subset of specific transcripts included for direct comparison. *p < 0.05, **p < 0.01, by student t-test, 2-tailed. (JPG 51 kb)
Additional file 2: Figure S2. Nanostring confirmation of plaque associate selected gene in TgCRND8. Selected plaque associated genes that were upregulated in LCM tissue in TgCRND8 mice by RNA seq confirmed using Nanostring customized chip (n=4 per group). Dot plots show mRNAs transcripts (mean ± s.e.m). *p < 0.05, **p < 0.01, ***p < 0.001, by student t-test, 2-tailed. (JPG 175 kb)
Additional file 5: Figure S3. Tg2576 brain sections illustrating amyloid-beta pathology. Representative images of plaque pathology in 15-month old transgenic mice via anti-amyloid-β, 1-12 (26D6). (JPG 183 kb)
Additional file 7: Table S4. Laser captured plaque transcriptomic signature. RNAseq data of laser-capture microscopy of TgCRND8 plaques versus non-plaque tissue as outlined in schematic in Fig. 2. Data shows statistical analysis of TgCRND8 plaques versus non-plaque tissue at 6 months of age (p-value) and log10 analysis of the ratio of TgCRND8 plaques versus non-plaque tissue. Differentially expressed genes were identified by Pearson correlation or T-test using Matlab R2010b (Mathworks). A p-value cutoff of < 0.001 was used to identify differentially expressed genes. The FDR corresponding to this p-value is given in each of the comparisons to convey relative signature confidence. Set annotation analysis was performed by comparing input sets to GeneGo (www.​genego.​com), Ingenuity (www.​ingenuity.​com) and KEGG (www.​genome.​jp/​kegg/​) pathway sets. Bonferroni corrected hypergeometric p-values (expectation (e)-values) of less than 0.1 were considered significant overlap between sets. (XLS 1410 kb)
Additional file 8: Figure S4. Expression of microglial versus peripheral macrophage markers. Data were analyzed for fold changes in genes associated with either resident microglia (A) or peripheral macrophages (B) as outlined by Hickman et al., 2013. Results demonstrate significant (*p < 0.001) expression of 7 out of the top 25 most abundant genes in microglia in plaque samples compared to non-plaque controls whereas only 1 gene, C4b, of genes associated with peripheral macrophages displayed significant expression in plaque compared to non-plaque samples. For whole cortex samples, half of the top 25 microglial genes were significantly increased in plaque samples compared to non-plaque. (JPG 43 kb)
Über diesen Artikel

Weitere Artikel der Ausgabe 1/2018

Journal of Neuroinflammation 1/2018 Zur Ausgabe

Neu in den Fachgebieten Neurologie und Psychiatrie

Meistgelesene Bücher in der Neurologie & Psychiatrie

  • 2016 | Buch


    Das Lehrbuch vermittelt Ihnen das gesamte Neurologie-Prüfungswissen für Ihr Medizinstudium und bereitet auch junge Assistenzärzte durch detailliertes Fachwissen optimal auf die Praxis vor. Die komplett überarbeitete Auflage enthält sechs neue, interdisziplinäre Kapitel.

    Werner Hacke
  • 2016 | Buch

    Komplikationen in der Neurologie

    Das Buch schildert Ereignisse im Rahmen der Neuromedizin, die während der Diagnostik und Therapie neurologischer Erkrankungen und Symptome auftreten können. Die Fallbeispiele sensibilisieren Sie für mögliche Risikofaktoren, um das Auftreten solcher Komplikationen zu vermeiden.

    Frank Block
  • 2017 | Buch

    Facharztwissen Psychiatrie, Psychosomatik und Psychotherapie

    Leitsymptome, Untersuchungsmethoden, Krankheitsbilder, Notfälle & Co. – mit der Neuauflage des "Facharztwissens" sind Sie auf die Facharztprüfung in Psychiatrie und Psychotherapie optimal vorbereitet. In dieser 2. Auflage sind die Kapitel zu psychosomatischen Störungen deutlich ausgebaut.

    Prof. Dr. Dr. Frank Schneider
  • 2019 | Buch

    Kompendium der Psychotherapie

    Für Ärzte und Psychologen

    Dieses Werk wendet sich an Ärzte und Psychologen, die an psychiatrischen und psychosomatischen Kliniken oder an Psychotherapeutischen Ausbildungsinstituten arbeiten und in den vorhandenen Lehrbüchern der Psychotherapie den Brückenschlag zur …

    Tilo Kircher