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

Autor: Pallavi Gandhi, Elaine O’Loughlin, Jacob Marcus, Veeravan Mahadomrongkul, Richard C. Stevens, Jason Da Gilliland, Christopher Ware, Bonnie J. Howell, Keith Q. Tanis, Gonzalo Zeballos Zeballos, Joel A. Klappenbach, Michelle Pearson, Sarah M. Rothman, Christian Mirescu, Matthew E. Kennedy, Roger Smith, Vladislav A. Malkov
Rok vydání: 2018
Předmět:
0301 basic medicine
Pathology
Plaque
Amyloid
lcsh:RC346-429
Transcriptome
Amyloid beta-Protein Precursor
Mice
0302 clinical medicine
Neuroinflammation
Correlation of Data
Plaque
Cerebral Cortex
Microglia
General Neuroscience
Microfilament Proteins
Age Factors
medicine.anatomical_structure
Neurology
Cytokines
Alzheimer’s disease
Genetically modified mouse
medicine.medical_specialty
Immunology
Mice
Transgenic
Laser Capture Microdissection
Neuropathology
Biology
03 medical and health sciences
Cellular and Molecular Neuroscience
Immune system
Alzheimer Disease
medicine
Extracellular
Animals
Humans
RNA
Messenger
Transcriptomics
Gene
lcsh:Neurology. Diseases of the nervous system
Amyloid beta-Peptides
Research
Calcium-Binding Proteins
Disease Models
Animal
030104 developmental biology
Gene Expression Regulation
Mutation
030217 neurology & neurosurgery
Zdroj: Journal of Neuroinflammation
Journal of Neuroinflammation, Vol 15, Iss 1, Pp 1-15 (2018)
ISSN: 1742-2094
Popis: 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. Electronic supplementary material The online version of this article (10.1186/s12974-018-1265-7) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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