Proteomic Profiles of the Early Mitochondrial Changes in APP/PS1 and ApoE4 Transgenic Mice Models of Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is one of the most common progressive neurodegenerative diseases. Apolipoprotein E4 (ApoE4) carriers account for 40% of all AD cases, emphasizing the importance of ApoE4 in the pathogenesis of AD. In the present study, we explored the changes of hippocampal proteins expression profile at the early stage (3 month-old) of APP/PS1 and ApoE4 knockin mice with the aim to find potential key pathways involved in AD progression. Proteomic analysis showed a lot of differentially expressed proteins (DEPs), 247 (137 increased and 110 decreased) and 1125 (642 increased and 484 decreased) in the hippocampus of APP/PS1 and ApoE4 mice, respectively, compared with the wild-type (WT) mice, using a cutoff of 1.2-fold change. Functional classification of DEPs revealed that these proteins mainly comprise proteins involved in acetylation, methylation, endocytosis/exocytosis, chaperone, oxidoreductase, mitochondrial, cytoskeletal, and synaptic proteins in APP/PS1 mice compared with the WT mice. Likewise in ApoE4 mice compared with the WT mice, the DEPs are mostly involved in the functions of synapses, ribosomes, mitochondria, spliceosomes, endocytosis/exocytosis, oxidative phosphorylation, and proteasomes. STRING analysis suggested that some DEPs were involved in insulin signaling and mitochondrial electron transport chain in the two mouse models. The abnormal changes of insulin signaling and mitochondrial electron transport chain were further verified by Western blot. Taken together, our study exposed the changes of hippocampal protein expression profiles at the early stage of APP/PS1 and ApoE4 knockin mice, and the change of insulin signaling and mitochondrial electron transport chain may be the key molecular processes involved in AD progression.

Meta-Analysis of Gene Expression Changes in the Blood of Patients with Mild Cognitive Impairment and Alzheimer’s Disease Dementia

“…This result is in accordance with a proteomic study in which a downregulation of hnRNP-related proteins was observed after Aβ peptide incubation on neuroblastoma cells [93]. More recently, a pathway enrichment analysis of the hippocampal proteome from ApoE4 mice compared to that of wild type highlighted the importance of the spliceosome in ADD [69].…”

“…The oxidative phosphorylation pathway was the second most highly ranked dysregulated pathway in both MCI and ADD. Recently, this pathway was enriched in ApoE4 hippocampal proteomic analysis [69]. Mitochondrial dysfunction and oxidative damage have been shown to have a crucial role in the pathogenesis of ADD [70].…”

“…Another pathway that is shared between MCI and ADD is the non-alcoholic fatty liver disease pathway (NAFLD). Interestingly, NAFLD was also enriched in a proteomic study from hippocampal extracts from APP/PS1 mice [69]. It has been shown that the liver contributes to the clearance of circulating Aβ in the periphery [73].…”

Acer Truncatum Seed Oil Alleviates Learning and Memory Impairments of Aging Mice

“…Peptide analysis was conducted according to previous research methods (He et al, 2019). The analytical capillary column (Upchurch, Oak Harbor, WA, United States) packed with C18 silica resin (Varian, Lexington, MA, United States) was used to separate peptides.…”

Utility of Animal Models to Understand Human Alzheimer’s Disease, Using the Mastermind Research Approach to Avoid Unnecessary Further Sacrifices of Animals

“…In AD animal models, proteomic biomarker profiles from the brain hippocampus homogenate of ADLPAPT mice [187], APP/PS1 mice, and ApoE4 knock-in mice models [188] have been identified with age-dependent alterations; many of the differentially expressed proteins were identical at presymptomatic stage of the mice, earlier than the formation of Aβ plaque. However, body-fluid-based proteomic biomarkers in AD animal models are still missing.…”