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

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.

A History of Repeated Alcohol Intoxication Promotes Cognitive Impairment and Gene Expression Signatures of Disease Progression in the 3xTg Mouse Model of Alzheimer’s Disease

“…The transcriptional profiling of the 3xTg-AD mouse model from 2 to 14 months of age was previously reported by Yin et al (2020) . Differentially expressed genes between 3xTg-AD and WT mouse insular cortex samples for the earliest and latest time points separately were obtained from Yin et al (2020 , refer to their Supplementary Table S1).…”

“…The transcriptional profiling of the 3xTg-AD mouse model from 2 to 14 months of age was previously reported by Yin et al (2020) . Differentially expressed genes between 3xTg-AD and WT mouse insular cortex samples for the earliest and latest time points separately were obtained from Yin et al (2020 , refer to their Supplementary Table S1). GSEA was performed using the corto version 1.1.11 package ( Mercatelli et al, 2020 ) considering the upregulated genes (log2 fold change > 0) at 2 and 14 months as gene sets to determine their enrichment in our pseudo-bulk signatures of 3xTg-AD mice with histories of repeated alcohol intoxication versus WT controls and of 3xTg-AD mice without alcohol exposure versus WT mice without alcohol exposure.…”

“…To test the hypothesis that a history of repeated alcohol intoxication promotes disease progression in 3xTg-AD mice, we compared transcriptional responses of our dataset with those generated with age-dependent AD progression data by Yin et al (2020) . We searched for similarities in genes upregulated in a dataset of the insular cortex of 3xTg-AD mice at 14 months of age and 2 months of age in the study by Yin et al (2020) by overlaying them onto the pseudo-bulk signature in our experiment, defined by the comparison of the PFC of 3xTg-AD mice exposed to alcohol to WT mice without alcohol exposure using the GSEA algorithm ( Subramanian et al, 2005 ; Fig. 5 A ).…”

Neurodegenerative Disease Associated Pathways in the Brains of Triple Transgenic Alzheimer’s Model Mice Are Reversed Following Two Weeks of Peripheral Administration of Fasudil

“…The model exhibits both amyloid plaques and tau tangles [ 17 , 21 ] as well as gliosis [ 31 ] and presents relatively early cognitive deficits [ 32 ]. The 3xTg-AD mice have been extensively investigated at the transcriptional level and shown to recapitulate neuronal inflammation [ 33 , 34 ], the dysregulation of genes involved in learning and memory [ 35 ], and psychiatric disorders [ 36 ]. With a view to testing the robustness of the model’s relationship to AD at the global transcriptional level, we performed a meta-analysis of publicly available data on the gene expression changes in 3xTg mouse brains relative to wild-type animals across multiple time points; see Methods section.…”

“…The expression changes in the triple transgenic mouse model of AD were derived from three RNAseq series (GSE168428 (3 3xTG v 3 WT at 2 months, 6 3xTG v 6 WT at 7/8 months, and 6 3xTG v 6 WT at 11/14 months) [ 33 ], GSE161904 (4 3xTG v 4 WT at 3 months, 8 months, and 15 months) [ 35 ], and GSE189693 (4 3xTG v 4 WT at 10 months) [ 72 ]) and five microarray series (GSE35210 (3 3xTG v 3 WT at 12 months) [ 73 ], GSE36981 (3 3xTG v 3 WT at 14 months) [ 36 ], GSE60460 (4 3xTG v 4 WT at 7 months), GSE60911 (5 3xTG v 5 WT at 20 months) [ 74 ], and GSE92926 (3 3xTG v 3 WT at 12 months) [ 34 ]) resulting in 12 transcriptional profiles that were combined into a single composite Z score profile; see Table S2 .…”