Dataset Information

Alzheimer's disease proteomics

ABSTRACT: This project aims to determine how the brain proteome is remodeled in Alzheimer's disease (AD). AD is pathologically characterized by an accumulation of insoluble aggregates composed of Abeta peptides in the brain and is clinically characterized by progressive memory impairment. While the precise pathogenic mechanism(s) that drive AD remain unclear, synapse loss is a pathological hallmark and correlates with cognitive decline. Abeta peptides accumulate due in large part to perturbed protein degradation pathways, and increasing evidence shows that Abeta peptides impair multiple cellular pathways. To advance our understanding of these complex processes we have completed a comprehensive proteomic characterization of the three different AD mouse models before and after the onset of pathology.

INSTRUMENT(S): LTQ Orbitrap Velos, Orbitrap Fusion, LTQ Orbitrap Elite

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Jeffrey N. Savas, PhD

PROVIDER: MSV000080431 | MassIVE | Mon Dec 19 14:22:00 GMT 2016

SECONDARY ACCESSION(S): PXD005595

REPOSITORIES: MassIVE

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Publications

Amyloid Accumulation Drives Proteome-wide Alterations in Mouse Models of Alzheimer's Disease-like Pathology.

Savas Jeffrey N JN Wang Yi-Zhi YZ DeNardo Laura A LA Martinez-Bartolome Salvador S McClatchy Daniel B DB Hark Timothy J TJ Shanks Natalie F NF Cozzolino Kira A KA Lavallée-Adam Mathieu M Smukowski Samuel N SN Park Sung Kyu SK Kelly Jeffery W JW Koo Edward H EH Nakagawa Terunaga T Masliah Eliezer E Ghosh Anirvan A Yates John R JR

Cell reports 20171101 9

Amyloid beta (Aβ) peptides impair multiple cellular pathways and play a causative role in Alzheimer's disease (AD) pathology, but how the brain proteome is remodeled by this process is unknown. To identify protein networks associated with AD-like pathology, we performed global quantitative proteomic analysis in three mouse models at young and old ages. Our analysis revealed a robust increase in Apolipoprotein E (ApoE) levels in nearly all brain regions with increased Aβ levels. Taken together wi ...[more]

PMID: 29186695

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Project description:Extracellular senile plaques of amyloid beta (Abeta) are a pathological hallmark in brain of patients with Alzheimer`s Disease (AD). Abeta is generated by the amyloidogenic processing of the amyloid precursor protein (APP). Concomitant to Abeta load, AD brain is characterized by an increase in protein level and activity of the angiotensin-converting enzyme (ACE). ACE inhibitors are a widely used class of drugs with established benefits for patients with cardiovascular disease. However, the role of ACE and ACE inhibition in the development of Abeta plaques and the process of AD-related neurodegeneration is not clear since ACE was reported to degrade Abeta. To investigate the effect of ACE inhibition on AD-related pathomechanisms, we used Tg2576 mice with neuron-specific expression of APPSwe as AD model. From 12 months of age, substantial Abeta plaque load accumulates in the hippocampus of Tg2576 mice as a brain region, which is highly vulnerable to AD-related neurodegeneration. The effect of central ACE inhibition was studied by treatment of 12 month-old Tg2576 mice for six months with the brain penetrating ACE inhibitor captopril. At an age of 18 months, hippocampal gene expression profiling was performed of captopril-treated Tg2576 mice relative to untreated 18 month-old Tg2576 controls with high Abeta plaque load. As an additional control, we used 12 month-old Tg2576 mice with low Abeta plaque load. Whole genome microarray gene expression profiling revealed gene expression changes induced by the brain-penetrating ACE inhibitor captopril, which could reflect the neuro-regenerative potential of central ACE inhibition. Microarray gene expression profiling was performed of hippocampi isolated from aged, 18 month-old Tg2576 (APPSwe-transgenic) AD mice with high Abeta plaque load relative to age-matched Tg2576 mice, which were treated for 6 months with the centrally active ACE inhibitor captopril. Another study group consisted of 12 month-old Tg2576 mice with low Abeta plaque load. In total, three study groups were analyzed, i.e. (i) 18 month-old untreated Tg2576 mice with high Abeta plaque load, (ii) age-matched Tg2576 mice treated for 6 months with the brain-penetrating ACE inhibitor captopril (20 mg/kg body weight/day in drinking water), and (iii) untreated 12 month-old Tg2576 mice with low Abeta plaque load reflecting the time point when captopril treatment was initiated. Two biological replicates were made of each group, and total hippocampal RNA of four mice was pooled for one gene chip.