Molecular and functional signatures in a novel Alzheimer’s disease mouse model assessed by quantitative proteomics

Abstract

BackgroundAlzheimer’s disease (AD), the most common neurodegenerative disorder, is characterized by the deposition of extracellular amyloid plaques and intracellular neurofibrillary tangles. To understand the pathological mechanisms underlying AD, developing animal models that completely encompass the main features of AD pathologies is indispensable. Although mouse models that display pathological hallmarks of AD (amyloid plaques, neurofibrillary tangles, or both) have been developed and investigated, a systematic approach for understanding the molecular characteristics of AD mouse models is lacking.MethodsTo elucidate the mechanisms underlying the contribution of amyloid beta (Aβ) and tau in AD pathogenesis, we herein generated a novel animal model of AD, namely the AD-like pathology with amyloid and neurofibrillary tangles (ADLPAPT) mice. The ADLPAPT mice carry three human transgenes, including amyloid precursor protein, presenilin-1, and tau, with six mutations. To characterize the molecular and functional signatures of AD in ADLPAPT mice, we analyzed the hippocampal proteome and performed comparisons with individual-pathology transgenic mice (i.e., amyloid or neurofibrillary tangles) and wild-type mice using quantitative proteomics with 10-plex tandem mass tag.ResultsThe ADLPAPT mice exhibited accelerated neurofibrillary tangle formation in addition to amyloid plaques, neuronal loss in the CA1 area, and memory deficit at an early age. In addition, our proteomic analysis identified nearly 10,000 protein groups, which enabled the identification of hundreds of differentially expressed proteins (DEPs) in ADLPAPT mice. Bioinformatics analysis of DEPs revealed that ADLPAPT mice experienced age-dependent active immune responses and synaptic dysfunctions.ConclusionsOur study is the first to compare and describe the proteomic characteristics in amyloid and neurofibrillary tangle pathologies using isobaric label-based quantitative proteomics. Furthermore, we analyzed the hippocampal proteome of the newly developed ADLPAPT model mice to investigate how both Aβ and tau pathologies regulate the hippocampal proteome. Because the ADLPAPT mouse model recapitulates the main features of AD pathogenesis, the proteomic data derived from its hippocampus has significant utility as a novel resource for the research on the Aβ-tau axis and pathophysiological changes in vivo.Electronic supplementary materialThe online version of this article (10.1186/s13024-017-0234-4) contains supplementary material, which is available to authorized users.

Acetylation changes tau interactome to degrade tau in Alzheimer’s disease animal and organoid models

“…As an in vivo preclinical study, we tested the therapeutic efficacy of CKD‐504 in ADLP APT mice. To determine the efficacy of CKD‐504 before and after memory impairment, which appears at about 6 months of age in ADLP APT mice (Kim et al, ), we assigned two cohorts of mice to preventive or therapeutic models. In the preventive model, dose‐dependent efficacy was tested by injecting two different doses of CKD‐504 (1 and 2.5 mg/kg) for 4 months beginning at 4.5 months of age.…”

“…We investigated whether CKD‐504 exerts therapeutic efficacy after the appearance of memory impairment. Because ADLP APT mice show cognitive impairment from 6‐month‐old (Kim et al, ), we employed a therapeutic paradigm with 6.5‐month‐old ADLP APT mice. Those mice were injected with CKD‐504 for 2 months.…”

“…Here, we investigated the therapeutic effects of CKD‐504, which is a novel, selective, and highly blood–brain barrier (BBB)‐penetrating HDAC6 inhibitor. CKD‐504 effectively modified acetylation both in brain organoids formed from AD patient‐derived induced pluripotent stem cells (iPSCs) and ADLP APT (Alzheimer's disease‐like pathology APP & Tau ) mice exhibiting both Aβ and tau pathologies (Kim et al, ). We found that CKD‐504 reduced tau in AD patient‐iPSC‐derived brain organoids.…”

HIV-1 and Amyloid Beta Remodel Proteome of Brain Endothelial Extracellular Vesicles

“…Another brain proteomic study using a different AD mouse model with amyloid and neurofibrillary tangle pathologies indicated age-dependent immune responses and synaptic dysfunctions. It was proposed that these changes were evoked by the advancing Aβ pathology in the brain [25], further demonstrating the importance of proteomic analyses in studies on the mechanisms of amyloid pathology.…”

Hematopoietic cell-specific lyn substrate (HCLS1 or HS1): A versatile actin-binding protein in leukocytes

“…HS1 was overexpressed in hippocampus lysates of 4‐mo‐old ADLP APT mice, a mouse model for AD that exhibits the pathologic diagnosis hallmarks, early neuronal loss, and memory impairment. Interestingly, this overexpression was much less pronounced in 10‐mo‐old ADLP APT mice . Bioinformatics analyses showed that HS1 was part of a protein network bridging tau and the amyloid precursor protein.…”