Steun ons werk
Decorative header background

Gene-expression profiling of individuals resilient to Alzheimer’s disease reveals higher expression of genes related to metallothionein and mitochondrial processes and no changes in the unfolded protein response

Onderzoeksgroep Verhaagen
Publicatiejaar 2024
Gepubliceerd in Acta neuropathologica communications
Auteur(s) Luuk E de Vries, Aldo Jongejan, Jennifer Monteiro Fortes, Rawien Balesar, Annemieke J M Rozemuller, Perry D Moerland, Inge Huitinga, Dick F Swaab, Joost Verhaagen

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.

Steun ons werk

De Stichting Vrienden van het Herseninstituut ondersteunt baanbrekend hersenonderzoek. U kunt ons daarbij helpen.

Steun ons werk

Wij, hersenonderzoekers, willen het brein nog beter begrijpen en zo doorbraken realiseren in de behandeling van ziektes als MS, Parkinson, Alzheimer en depressie. Om onze missie te volbrengen, willen wij ons volledig concentreren op ons onderzoek. Wil je ons daarbij helpen?

Doe een donatie of  schrijf je in voor onze nieuwsbrief!

Hartelijk dank!