Differences in the proteomic profile of the brain in Alzheimer’s disease in Down syndrome and early‐onset Alzheimer’s disease

Abstract

AbstractBackgroundDown syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21) and is a leading genetic cause of Alzheimer’s disease (AD‐DS). People with DS have a third copy of amyloid precursor protein (APP) which causes the increased risk to develop AD neuropathology and dementia, decades earlier than in the general population. However, other genes on Hsa21 have been shown to modify AD‐DS development compared to the development of AD in the general population. Here, we aim to understand how AD‐DS differs to EOAD at end‐stage disease.MethodLabel‐free mass spectrometry was performed using a SYNAPT G2‐Si High‐Definition machine with 2D fractionation on prefrontal cortex tissue (BA10) from individuals with AD‐DS, early‐onset AD (EOAD) (both Braak‐stage VI), and healthy age‐matched controls. Proteins identified were ranked by significance (p < 0.05) and a fold‐change of difference between groups was calculated. qPCR was used to measure transcript levels of altered proteins in the same samples and to assess if transcript levels of raised proteins were altered in the Dp1Tyb (MGI:5703798) mouse model of DS which has three‐copies of ∼148 Hsa21 orthologous genes.ResultRaised abundance of Hsa21 encoded proteins, including PDXK, APP and S100B, were identified in individuals with AD‐DS compared to EOAD. Importantly, non‐chromosome 21 encoded proteins were also shown to be raised in individuals with AD‐DS compared to EOAD, including APOE, NLRP8 and PTN. Raised APOE protein in AD‐DS compared to EOAD brain tissue is Apolipoprotein E genotype independent. Apoe is not raised in the Dp1Tyb hippocampus or cortex at 6‐months of age.ConclusionPeople with AD‐DS exhibit an altered proteomic profile compared to people with EOAD, likely driven by having three‐copies of Hsa21 genes. Raised APOE may be driven by an interaction of trisomy 21 and AD pathogenesis, as this phenotype is not seen in the Dp1Tyb mouse model. Understanding the differences in AD pathogenesis is key for including people with DS in future AD clinical trials. Future work will validate protein expression of candidates of interest in an independent cohort of human post‐mortem brain samples, as well as determine the cell types in which proteins of interest are expressed.