Transcriptional, Behavioral and Biochemical Profiling in the 3xTg-AD Mouse Model Reveals a Specific Signature of Amyloid Deposition and Functional Decline in Alzheimer’s Disease

Wencheng Yin,Atahualpa Castillo-Morales,Federico Bermudez-Rattoni,Humberto Gutiérrez,Navei Cerda-Hernández,Perla Moreno-Castilla,Araxi O Urrutia,Mayra L Ruiz-Tejada-Segura,Rodrigo Pérez-Ortega,Jimena Monzón-Sandoval

doi:10.3389/fnins.2020.602642

Abstract

Alzheimer’s disease (AD)-related degenerative decline is associated to the presence of amyloid beta (Aβ) plaque lesions and neuro fibrillary tangles (NFT). However, the precise molecular mechanisms linking Aβ deposition and neurological decline are still unclear. Here we combine genome-wide transcriptional profiling of the insular cortex of 3xTg-AD mice and control littermates from early through to late adulthood (2–14 months of age), with behavioral and biochemical profiling in the same animals to identify transcriptional determinants of functional decline specifically associated to build-up of Aβ deposits. Differential expression analysis revealed differentially expressed genes (DEGs) in the cortex long before observed onset of behavioral symptoms in this model. Using behavioral and biochemical data derived from the same mice and samples, we found that down but not up-regulated DEGs show a stronger average association with learning performance than random background genes in control not seen in AD mice. Conversely, these same genes were found to have a stronger association with Aβ deposition than background genes in AD but not in control mice, thereby identifying these genes as potential intermediaries between abnormal Aβ/NFT deposition and functional decline. Using a complementary approach, gene ontology analysis revealed a highly significant enrichment of learning and memory, associative, memory, and cognitive functions only among down-regulated, but not up-regulated, DEGs. Our results demonstrate wider transcriptional changes triggered by the abnormal deposition of Aβ/NFT occurring well before behavioral decline and identify a distinct set of genes specifically associated to abnormal Aβ protein deposition and cognitive decline.

Highlights

Alzheimer’s disease (AD) is a degenerative disease characterized by progressive memory impairment and loss of other cognitive functions for which there is no current known effective treatment
In order to characterize the transcriptional changes that occur in the insular cortex in response to the build-up of Beta Amyloid protein (Aβ)/NF deposits and cognitive deterioration in the Triple transgenic AD mouse model (3xTg-AD) mouse model, behavioral data and tissue samples were obtained from three transgenic and three wild-type male mice at five time points from two through to 14 months of age (n = 3/time point, Figure 1A)
We conducted the RNA-seq gene expression profiling of the insular cortex of 3xTg-AD mouse model and performed a differential expression analysis to identify the changes in gene expression that occur throughout adulthood (2–14 months), both at symptomatic and pre symptomatic stages, in this animal model

Summary

Introduction

Alzheimer’s disease (AD) is a degenerative disease characterized by progressive memory impairment and loss of other cognitive functions for which there is no current known effective treatment. While AD is more common in people over 65 years of age, with age being the most prominent risk factor, several additional risk factors have been identified including brain injury, smoking, and even low social engagement (Hersi et al, 2017). Abnormal accumulation of Aβ is the result of an imbalance between the levels of Aβ production, aggregation and clearance (Wang et al, 2010). The precise identity of the wider molecular pathways that become compromised during the gradual buildup of abnormal Aβ deposition and NFT remain largely unknown (Selkoe and Hardy, 2016)

Methods

Results

Conclusion