Dataset Information

ABPP using chemical proteomics in Alzheimer's Disease and Resilience

ABSTRACT: pulldown on enzymes targeted by serine hydrolase probes tetrahydrolipstatin-biotin and fluorophosphonate biotin probe in lysates from the frontal cortex of 36 patients (12 conrol, 12 Alzheimer's, 12 Resilient). below is the abstract: Alzheimer’s Disease (AD) is the most common form of dementia. While it has become clear that alterations in lipid metabolism are associated with AD, it is not well understood how they contribute to both cognitive decline and the pathophysiology of AD. To better understand these changes, we performed lipidomics and activity-based proteomic profiling (ABPP) in the frontal cortex of a cohort of control, AD and resilient donors, the latter referring to individuals with AD pathology without declined cognition. We demonstrate that most changes in the lipidome are related to AD pathology. The class of lipids most strongly changed was ω6-derived oxylipins, which reflect a neuroinflammatory response. This lipid class was particularly increased in the AD patients compared to controls, while it showed a similar but non-significant trend in resilient donors. In contrast, both triacylglycerides (TAGs) and lipid droplets were more abundant in the AD donors compared to the resilient donors, but not to the control donors, indicating alterations in neutral lipids in resilient donors. Enzyme activities profiled by ABPP showed a similar direction in the AD and resilient donors, including decreased activity of ABHD6, a lipase involved in mono-acyl glycerol metabolism. Finally, using multi-omics factor analysis, we show that increased oxylipins, loss of inhibitory cells and reduced synaptic plasticity are associated with Aβ plaque load. This response was present in both the AD and resilient donors. Taken together, our multi-omics data show a response associated with Aβ load shared among AD and resilient donors and, for the first time, reduced lipid droplets in resilient donors.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain

DISEASE(S): Alzheimer's Disease 1

SUBMITTER: Daan Van der Vliet

LAB HEAD: Prof. dr. Mario van der Stelt

PROVIDER: PXD057993 | Pride | 2026-02-09

REPOSITORIES: Pride

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Reduced triacylglycerols and lipid droplets are associated with resilience to Alzheimer's disease.

van der Vliet Daan D de Vries Luuk E LE Di Xinyu X Wever Dennis D de Jong Brechtje B van der Meij Marc T C MTC van der Peet Marielle M Harms Amy C AC Hankemeier Thomas T Swaab Dick F DF Huitinga Inge I Verhaagen Joost J van der Stelt Mario M

Alzheimer's & dementia : the journal of the Alzheimer's Association 20260201 2

<h4>Introduction</h4>Although it has become clear that alterations in lipid metabolism are associated with Alzheimer's disease (AD), it is unclear how they contribute to both cognitive decline and the pathophysiology of AD.<h4>Methods</h4>Lipidomics and activity-based protein profiling (ABPP) were performed in the frontal cortex of control, AD and resilient donors, that is, individuals with AD pathology without cognitive decline.<h4>Results</h4>The most pronounced alterations in lipids were in ω ...[more]

PMID: 41630598

Similar Datasets

Project description:Some individuals show a discrepancy between cognition and the amount of neuropathological changes characteristic for Alzheimer’s disease (AD). This phenomenon has been referred to as ‘resilience’. The molecular and cellular underpinnings of resilience remain poorly understood. To obtain an unbiased understanding of the molecular changes underlying resilience, we investigated global changes in gene expression in the superior frontal gyrus of a cohort of cognitively and pathologically well-defined AD patients, resilient individuals and age-matched controls (n=11-12 per group). 897 genes were significantly altered between AD and control, 1121 between resilient and control and 6 between resilient and AD. Gene set enrichment analysis (GSEA) revealed that the expression of metallothionein (MT) and of genes related to mitochondrial processes was higher in the resilient donors. Weighted gene co-expression network analysis (WGCNA) identified gene modules related to the unfolded protein response, mitochondrial processes and synaptic signaling to be differentially associated with resilience or dementia. As changes in MT, mitochondria, heat shock proteins and the unfolded protein response (UPR) were the most pronounced changes in the GSEA and/or WGCNA, immunohistochemistry was used to further validate these processes. MT was significantly increased in astrocytes in resilient individuals. A higher proportion of the mitochondrial gene MT-CO1 was detected outside the cell body versus inside the cell body in the resilient compared to the control group and there were higher levels of heat shock protein 70 (HSP70) and X-box-binding protein 1 spliced (XBP1s), two proteins related to heat shock proteins and the UPR, in the AD donors. Finally, we show evidence for putative sex-specific alterations in resilience, including gene expression differences related to autophagy in females compared to males. Taken together, these results show possible mechanisms involving MTs, mitochondrial processes and the UPR by which individuals might maintain cognition despite the presence of AD pathology.

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	20200814_uniprot_human_reviewed.fasta	Fasta
	MM05_01.raw	Raw
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