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.
Highlights
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
Our findings show that the human AD neuroimmune signature develops progressively in the TgCRND8 mouse cortex, coincident with known trajectories of Aβ deposition, but not in the Tg2576 mouse, raising intriguing questions about how the brain responds to different composition states of Aβ
The current study highlights the importance of careful consideration and selection of appropriate Amyloid precursor protein (APP) mouse models for exploring neuroimmune modulation, in particular Immunoreceptor tyrosine-based inhibition motif (ITIM)/Immunoreceptor tyrosinebased activation motif (ITAM)-associated mechanisms, such as TREM2 and CD33
Summary
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. While histological studies have characterized the morphology and process complexity of glial cells in a wide-range of neurodegenerative diseases, specific genomic and proteomic data regarding how microglia and astrocytes are modulated by disease, and vice versa, remain unknown. The lack of data regarding microglial reactivity in neurodegeneration is somewhat due to controversy regarding the utility of specific AD mouse models as windows into or prototype for human disease, and a paucity of studies using panoramic unbiased molecular profiling approaches to better describe local pathological changes occurring within the Aβ niche. One goal of the current study was to complete longitudinal evaluation of two different APP mouse models using RNAseq in brain regions demonstrating heavy plaque burden to evaluate their overlap with gene expression signatures previously identified in human AD brain samples
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