Proteomics Analysis of CA1 Region of the Hippocampus in Pre-, Progression and Pathological Stages in a Mouse Model of the Alzheimer’s Disease

Abstract

Background: CA1 subregion of the hippocampal formation is one of the primarily affected structures in AD, yet not much is known about proteome alterations in the extracellular milieu of this region. Objective: In this study, we aimed to identify the protein expression alterations throughout the pre-pathological, progression and pathological stages of AD mouse model. Method: The CA1 region perfusates were collected by in-vivo intracerebral push-pull perfusion from transgenic 5XFAD mice and their non-transgenic littermates at 3, 6 and 12 wereβmonths of age. Morris water maze test and immunohistochemistry staining of A performed to determine the stages of the disease in this mouse model. The protein expression differences were analyzed by label-free shotgun proteomics analysis. Results: A total of 251, 213 and 238 proteins were identified in samples obtained from CA1 regions of mice at 3, 6 and 12 months of age, respectively. Of these, 68, 41 and 33 proteins showed statistical significance. Pathway analysis based on the unique and common proteins within the groups revealed that several pathways are dysregulated during different stages of AD. The alterations in glucose and lipid metabolisms respectively in pre-pathologic and progression stages of the disease, lead to imbalances in ROS production via diminished SOD level and impairment of neuronal integrity. Conclusion: We conclude that CA1 region-specific proteomic analysis of hippocampal degeneration may be useful in identifying the earliest as well as progressional changes that are associated with Alzheimer’s disease.

Temporal and Sex-Linked Protein Expression Dynamics in a Familial Model of Alzheimer’s Disease

“…3 ). As glucose and lipid metabolism dysregulation have been proposed to occur in the 5XFAD model prior to AD pathogenesis ( 9 ), and as the DNA damage signature, which is enhanced in females, is seen to be triggered early in our data, investigation of ROS versus neuroinflammation targets appears to be a promising point for further investigation in this model.…”

“…Mouse models are highly suited to examining changes in temporal features of AD progression. For example, a longitudinal study that probed hippocampus perfusates of a gold standard amyloid-driven AD model (5XFAD mice) showed glucose and lipid metabolism dysregulation prior to AD pathogenesis, providing a proof of concept for distinguishing early from late events in the molecular pathology of progression ( 9 ). The present research also utilizes 5XFAD mice to better understand the temporal variation in protein expression in mouse brain for WT compared to the AD-like mouse model at various time points relevant to disease progression hallmarks in humans.…”

Proteins associated with neutrophil degranulation are upregulated in nasopharyngeal swabs from SARS-CoV-2 patients

“…The digest was acidified with 1 ul formic acid and transferred to an LC vial for injection. The samples were analyzed by the protocols in our previous studies [1]. Briefly, tryptic peptides were trapped on a Symmetry C18 (5μm,180μm i.d.…”

The amyloid peptide β disrupts intercellular junctions and increases endothelial permeability in a NADPH oxidase 1-dependent manner

“…The use of an alternative mouse model (i.e. 5XFAD) [ 54 ], also led to the discovery of the alteration of redox homeostasis pathways in the hippocampus in association with disease development (in particular, superoxide dismutases, which also appear amongst the changes on protein level associated to AD in our study) [ 55 ].…”