Common genetic signatures of Alzheimer's disease in Down Syndrome

Abstract

Background: People with Down Syndrome (DS) are born with an extra copy of Chromosome (Chr) 21 and many of these individuals develop Alzheimer's Disease (AD) when they age. This is due at least in part to the extra copy of the APP gene located on Chr 21. By 40 years, most people with DS have amyloid plaques which disrupt brain cell function and increase their risk for AD. About half of the people with DS develop AD and the associated dementia around 50 to 60 years of age, which is about the age at which the hereditary form of AD, early onset AD, manifests. In the absence of Chr 21 trisomy, duplication of APP alone is a cause of early onset Alzheimer's disease, making it likely that having three copies of APP is important in the development of AD and in DS. Methods: We investigate the relationship between AD and DS through integrative analysis of genesets derived from a MeSH query of AD and DS associated beta amyloid peptides, Chr 21, GWAS identified AD risk factor genes, and differentially expressed genes in individuals with DS. Results: Unique and shared aspects of each geneset were evaluated based on functional enrichment analysis, transcription factor profile and network interactions. Genes that may be important to both disorders in the context of direct association with APP processing, Tau post translational modification and network connectivity are ACSM1, APBA2, APLP1, BACE2, BCL2L, COL18A1, DYRK1A, IK, KLK6, METTL2B, MTOR, NFE2L2, NFKB1, PRSS1, QTRT1, RCAN1, RUNX1, SAP18 SOD1, SYNJ1, S100B. Conclusions: Our findings confirm that oxidative stress, apoptosis, inflammation and immune system processes likely contribute to the pathogenesis of AD and DS which is consistent with other published reports.

Keywords: Alzheimer’s Disease; Behavior; Down Syndrome; Learning; Memory.

Figure 1.. GeneSet overlap.

UpSet plot showing geneset overlap highlighting gene content similarity between the AD-DS, Chr21, AD risk factors DEX DFC, and DEX CBC genes.

Figure 2.. Keyword enrichment.

Identification of genes associated with terms relating to AD and DS based on gene ontology term classification. AD-DS genes: blue, Chr 21 genes: orange, DEX DFC genes: green, DEX CBC genes: gray, X-axis, keyword categories; Y-axis, frequency of occurrence in the geneset.

Figure 3.. Evaluation of GO classification terms based on behavioral, memory, and learning categories.

Comparison of frequencies of behavior related genes in the AD-DS, Chr 21, DEX DFC, and DEX CBC genesets. X-axis, geneset; Y-axis, frequency of occurrence (percentage of total genes) in the geneset.

Figure 4.. APP protein-protein interaction network.

( A) Geneset overlap between 1 ^st and 2 ^nd shell interactions and the AD-DS, Chr 21, DEX DFC, and DEX CBC genesets. AD-DS genes unique: red; Chr 21 genes unique: gray; DEX DFC genes unique: purple; CBC genes unique: orange; AD risk factors (RF) and AD-DS genes shared: green; DEX DFC genes shared with RF & AD-DS genes: green oval; CBC and DFC shared genes: dark blue V; CBC genes shared with RF: green triangle; APP: yellow rectangle. ( B) Interaction network gene clusters. Cluster 1: red – COP subunits, signalosome complex, development; Ubiquitin, Cluster 2: yellow – Tubulin, microtubules, motors, intracellular transport; Cluster 3: green – apoptosis, insulin signaling, ubiquitin, VEGFR growth factor signaling; Cluster 4: blue – Ubiquitin, autophagy; and Cluster 5: black – APP processing (PSEN, gamma secretase complex). ( C) Distribution frequency for interaction score.