Parallel molecular alteration between Alzheimer’s disease and major depressive disorder in the human brain dorsolateral prefrontal cortex: an insight from gene expression and methylation profile analyses

Abstract

Alzheimer's disease (AD) and major depressive disorder (MDD) are comorbid neuropsychiatric disorders that are among the leading causes of long-term disability worldwide. Recent research has indicated the existence of parallel molecular mechanisms between AD and MDD in the dorsolateral prefrontal cortex (DLPFC). However, the premorbid history and molecular mechanisms have not yet been well characterized. In this study, differentially expressed gene (DEG), differentially co-expressed gene and protein-protein interaction (PPI) network propagation analyses were applied to gene expression data of postmortem DLPFC samples from human individuals diagnosed with and without AD or MDD (AD: cases = 310, control = 157; MDD: cases = 75, control = 161) to identify the main genes in the two disorders' specific and shared biological pathways. Subsequently, the results were evaluated using another four assessment datasets (n1 = 230, n2 = 65, n3 = 58, n4 = 48). Moreover, the postmortem DLPFC methylation status of human subjects with AD or MDD was compared using 68 and 608 samples for AD and MDD, respectively. Eight genes (XIST, RPS4Y1, DDX3Y, USP9Y, DDX3X, TMSB4Y, ZFY and E1FAY) were common DEGs in DLPFC of subjects with AD or MDD. These genes play important roles in the nervous system and the innate immune system. Furthermore, we found HSPG2, DAB2IP, ARHGAP22, TXNRD1, MYO10, SDK1 and KRT82 as common differentially methylated genes in the DLPFC of cases with AD or MDD. Finally, as evidence of shared molecular mechanisms behind this comorbidity, we propose some genes as candidate biomarkers for both AD and MDD. However, more research is required to clarify the molecular mechanisms underlying the co-existence of these two important neuropsychiatric disorders.

Early depressive manifestations in patients with dementia caused by Alzheimer's disease

“…In AD, amyloid-β plaques and neurofibrillary tangles are extensively reported substrates that can induce disruption of neural function, culminating in neuronal cell death. A relative increase in non-neuronal cell numbers, both in the cerebral cortex and subcortical white matter, can contribute to the reactive glial cell response to neuronal death ( 21 , 22 ). A number of previous studies have suggested that neurodegenerative diseases are caused by cortical network dysfunction instead of dysregulation in any isolated brain region.…”

“…A number of previous studies have suggested that neurodegenerative diseases are caused by cortical network dysfunction instead of dysregulation in any isolated brain region. However, the isolated brain regions that are selectively damaged are likely to act as ‘nodes’ in the pathological brain network ( 21-24 ). This was proposed as the ‘network degradation hypotheses.…”

“…According to this hypothesis, the functional circuits may disconnect or weaken due to misfolded protein aggregates, resulting in small and selectively vulnerable neuron populations. Consequently, their aberrant excitability disrupts neuronal homeostasis and function, triggering a progressive degeneration of the entire functional network ( 21-24 ).…”

Redefining Autoimmune Disorders’ Pathoetiology: Implications for Mood and Psychotic Disorders’ Association with Neurodegenerative and Classical Autoimmune Disorders

“…MDD modulates the initiation and/or episodic symptom exacerbations of most 'autoimmune'/'immune-mediated' disorders, including multiple sclerosis [184], rheumatoid arthritis [183], Alzheimer's disease [185], Parkinson's disease [186] and SLE [187], indicating the role that MDD pathophysiology has in their course. MDD pathophysiology includes gut dysbiosis/permeability, pro-inflammatory cytokines, IDO induction and the conversion of tryptophan to kynurenine, leading to enhanced AhR activation, thereby dysregulating the tryptophan-melatonin pathway [188], and allowing the MDD pathophysiology to be intimately linked to the pathophysiological processes underpinning 'autoimmune' disorders.…”