Dataset Information

Quantitative proteomic characterization of senile plaques from Alzheimer's disease and non-demented brain

ABSTRACT: The deposition of amyloid senile plaques (SPs) play a central role in Alzheimer’s disease (AD), but the mechanisms by which SPs induce neural toxicity are disputed. Genetically engineered mouse models emphasising SPs have had limited success in reproducing the neuropathology of AD, and have also failed to be good indicators of successful amyloid-targeting therapies. Moreover, elderly people with a heavy plaque burden can show normal cognition. Therefore, it is fundamentally important to fully characterize and distinguish the pathological changes elicited by SPs in human and mouse brains. Using laser capture microdissection (LCM) combined with high-throughput mass spectrometry, we quantified ~5000 proteins with high confidence in SPs and non-plaque regions from AD and non-AD human postmortem brain. We found proteomic alteration in SPs is more evident than in non-plaque regions, and identified more than 30 human that are significantly enriched in SPs. We found that AD SPs elicited much more extensive proteomic alterations compared to non-AD SPs. Together, our findings represent the most systematic analysis of sub-proteome of senile plaques and provide a framework for future studies on plaque pathology and AD progression.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain

DISEASE(S): Alzheimer's Disease

SUBMITTER: Wei Ge

LAB HEAD: Wei Ge

PROVIDER: PXD005824 | Pride | 2019-02-18

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	AD_Plaque_Human_Lumos.msf	Msf
	AD_Plaque_Human_Lumos.pdResult	Other
	AD_Plaque_Human_Lumos.pep.xml	Pepxml
	AD_Plaque_Human_Lumos.prot.xml	Xml
	Human20160802.fasta	Fasta

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Publications

Quantitative proteomics reveals distinct composition of amyloid plaques in Alzheimer's disease.

Xiong Feng F Ge Wei W Ma Chao C

Alzheimer's & dementia : the journal of the Alzheimer's Association 20190102 3

<h4>Introduction</h4>We investigated the proteomic profiles of amyloid plaques (APs) from Alzheimer's disease (AD) and age-matched non-AD brains and APP/PS1 transgenic model mice.<h4>Methods</h4>APs and adjacent control regions were collected from fresh-frozen brain sections using laser capture dissection. Proteins were quantitated using tag-labeling coupled high-throughput mass spectra.<h4>Results</h4>Over 4000 proteins were accurately quantified, and more than 40 were identified as highly enri ...[more]

PMID: 30502339

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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.