Abstract
BackgroundMajor depression (MD) is the most prevalent psychiatric disease in the population and is considered a prodromal stage of the Alzheimer’s disease (AD). Despite both diseases having a robust genetic component, the common transcriptomic signature remains unknown.MethodsWe investigated the cognitive and emotional behavioural responses in 3- and 6-month-old APP/PSEN1-Tg mice, before β-amyloid plaques were detected. We studied the genetic and pathway deregulation in the prefrontal cortex, striatum, hippocampus and amygdala of mice at both ages, using transcriptomic and functional data analysis.ResultsWe found that depressive-like and anxiety-like behaviours, as well as memory impairments, are already present at 3-month-old APP/PSEN1-Tg mutant mice together with the deregulation of several genes, such as Ciart, Grin3b, Nr1d1 and Mc4r, and other genes including components of the circadian rhythms, electron transport chain and neurotransmission in all brain areas. Extending these results to human data performing GSEA analysis using DisGeNET database, it provides translational support for common deregulated gene sets related to MD and AD.ConclusionsThe present study sheds light on the shared genetic bases between MD and AD, based on a comprehensive characterization from the behavioural to transcriptomic level. These findings suggest that late MD could be an early manifestation of AD.
Highlights
Major depression (MD) is the most prevalent psychiatric disease in the population and is considered a prodromal stage of the Alzheimer’s disease (AD)
It has recently been described the implication of triggering receptor expressed on myeloid cells (TREM)APOE pathway related with microglial β-amyloid plaque clearance [17] and neuroinflammatory responses in neurodegenerative diseases, such as AD [12], with a dysregulation of Clec7 and Itgax transcripts related to inflammation and apoptotic processes, crucial components in the early-onset AD [18]
The transgenic mice expressing human Beta-amyloid precursor protein (APP)/PSEN1Tg carrying familial AD mutations used in these studies (B6C3-Tg) have an onset of plaque pathology at around 6 months [47], which is followed by cognitive impairments with both increasing by 12–18 months of age [48]
Summary
Major depression (MD) is the most prevalent psychiatric disease in the population and is considered a prodromal stage of the Alzheimer’s disease (AD). There is a close association between mutations and the number of APOE alleles, App and presenilin (Psen) genes with early-onset AD [14, 15], as observed in subjects with Down syndrome who carry three copies of APP and develop early-onset AD pathology, due to the trisomy of chromosome 21 [16] It has recently been described the implication of triggering receptor expressed on myeloid cells (TREM)APOE pathway related with microglial β-amyloid plaque clearance [17] and neuroinflammatory responses in neurodegenerative diseases, such as AD [12], with a dysregulation of Clec and Itgax transcripts related to inflammation and apoptotic processes, crucial components in the early-onset AD [18]. Cognitive and functional impairments are the predominant symptoms of AD, other behavioural and psychological symptoms of dementia (BPSD) that include depression, sleep and activity disturbances are common manifestations of the disease [19, 20] These observations have led to the suggestion that MD may in some cases be a prodromal phase of AD. Recent studies have sought to uncover a common molecular signature between both AD and MD including from genome-wide association studies (GWAS) that have identified shared vulnerability genes for both disorders [27, 28]
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