Cross-disease analysis of Alzheimer’s disease and type-2 Diabetes highlights the role of autophagy in the pathophysiology of two highly comorbid diseases

Abstract

Evidence is accumulating that the main chronic diseases of aging Alzheimer’s disease (AD) and type-2 diabetes mellitus (T2DM) share common pathophysiological mechanisms. This study aimed at applying systems biology approaches to increase the knowledge of the shared molecular pathways underpinnings of AD and T2DM. We analysed transcriptomic data of post-mortem AD and T2DM human brains to obtain disease signatures of AD and T2DM and combined them with protein-protein interaction information to construct two disease-specific networks. The overlapping AD/T2DM network proteins were then used to extract the most representative Gene Ontology biological process terms. The expression of genes identified as relevant was studied in two AD models, 3xTg-AD and ApoE3/ApoE4 targeted replacement mice. The present transcriptomic data analysis revealed a principal role for autophagy in the molecular basis of both AD and T2DM. Our experimental validation in mouse AD models confirmed the role of autophagy-related genes. Among modulated genes, Cyclin-Dependent Kinase Inhibitor 1B, Autophagy Related 16-Like 2, and insulin were highlighted. In conclusion, the present investigation revealed autophagy as the central dys-regulated pathway in highly co-morbid diseases such as AD and T2DM allowing the identification of specific genes potentially involved in disease pathophysiology which could become novel targets for therapeutic intervention.

Autophagy: Supporting cellular and organismal homeostasis by self-eating

“…A recent study analyzed transcriptomics data of post-mortem brains of Alzheimer's and type 2 diabetes patients. Data analysis indicated a principal role for autophagy dysfunction in both diseases (Caberlotto et al, 2019). The role of autophagy-related genes was confirmed using an Alzheimer mouse model.…”

Cognitive dysfunction: A growing link between diabetes and Alzheimer's disease

“…Moreover, in an insulin‐deficient mice model, phosphorylation of GSK‐3α and GSK‐3β levels showed a significant fall in 9 weeks old diabetic brain (Jolivalt et al, ). Other than the insulin signaling pathway, there is a recent report which shows deregulation of autophagy and its related genes to be involved in the pathophysiology of two diseases (Caberlotto et al, ).…”

The Bewildering Effect of AMPK Activators in Alzheimer’s Disease: Review of the Current Evidence

“…Alzheimer's disease (AD) is a progressive neurodegenerative disease clinically characterized by cognitive, functional, and behavioral alterations. It is also characterized by histopathological, molecular, and biochemical abnormalities such as cell loss, intracellular accumulation of neurofibrillary tangles, dystrophic neurites, amyloid-β deposits, deranged energy metabolism, mitochondrial dysfunction, chronic oxidative stress, and DNA damage [1]. Of these pathologic changes, intracellular accumulation of neurofibrillary tangles is both spatially and temporally closely associated with neuronal degeneration and cognitive symptoms [2].…”

“…Insulin is found to inhibit amyloid-β generation and to prevent hyperphosphorylation of tau protein (the main pathologic hallmark of AD) [16,17]. In contrast, insulin resistance and insulin deficiency are associated with the increased extracellular amyloid-β accumulation and intracellular hyperphosphorylated tau [1,[18][19][20]. Postmortem studies showed decreased synaptic plasticity in T2DM patients [21], and other studies showed insulin administration to improve synaptic formation [22,23] and cognitive performance [24][25][26].…”

“…Recent studies show that one of the common pathways for AD and T2DM involves AMP-activated protein kinase (AMPK) [29,30]. In an attempt to investigate the molecular basis of the comorbidity in AD and T2DM, Caberlotto et al applied systems biology approach and showed that autophagy is at the center of the comorbidity [1]. A wealth of recent studies also showed that AMPK is the principal player in both energy metabolism and autophagy [31][32][33].…”