Pharmaceutical, Biomedical and Veterinary Sciences

PhD Defences 2024

A deep dive into Alzheimer risk gene ABCA7: elucidating the underlying pathomechanisms of ABCA7 mutation carriers - Lena Duchateau (08/02/2024)

Lena Duchateau

  • 8 February 2024, 4pm - 6pm
  • Promotiezaal, Q.002 (CDE)
  • Promoter: Kristel Sleegers


Alzheimer’s disease (AD) is the leading cause of dementia and a growing problem worldwide. ABCA7 was identified as a risk gene for AD in genome-wide association studies (GWAS). ABCA7 is suggested to play a role in lipid metabolism, phagocytosis and amyloid pathology. Since its discovery as a risk gene for AD, several risk-increasing variants have been identified. These variants include premature termination codon (PTC) mutations, variable number of tandem repeats (VNTR) polymorphism expansion mutations and predicted pathogenic missense mutations. The aim of this thesis was to get a better insight into the underlying pathomechanisms of these ABCA7 variants.

Firstly, we leveraged different transcriptomic approaches to study these mechanisms, including long-read nanopore sequencing (on brain and lymphoblastoid cell lines), single-nuclei sequencing (SNS) and spatial sequencing on brain of AD patients and controls with ABCA7 PTC, missense and/or VNTR mutations. Our data suggest a high amount of splicing complexity in ABCA7 in general, with increased levels in carriers of PTC mutations. NMD escape and rescue splice events, able to rescue the effect of the mutation, were identified but did not alter phenotype or age at onset, though rescue splicing did impact gene expression. Both single-nuclei and spatial sequencing methods suggested neurons to be the main expressor of ABCA7 but using SNS we found average ABCA7 expression was not highest in the excitatory neurons, but in microglia. Remarkably, mutation carriers who were theoretically expected to have lower ABCA7 expression levels, had highest expression in microglia, suggesting a specific upregulation in this cell type. Of interest, we identified several differentially expressed genes between carrier and non-carrier AD patients in microglia, and pathway analysis in microglia suggested downregulation of translation and inflammatory reaction terms compared to non-carriers. Spatial analysis of the brain additionally put the choroid plexus forward as a region of interest due to its high ABCA7 expression.

Finally, we performed cerebrospinal fluid (CSF) biomarker analysis on PTC and VNTR carriers suggesting altered APP processing in VNTR, and to lesser extent, PTC carriers. Moreover, decreased YKL-40 levels in expansion carriers suggested that these patients potentially have a reduced inflammatory response to AD damage.

In conclusion, this thesis provided further insight into possible pathomechanisms in the different mutation groups and suggested these might not be the same in all three. These findings could eventually aid in identifying the correct treatment for AD patients carrying an ABCA7 variant.

The new epigenetic driver role of PPARα and mitochondria in metabolic dysfunction associated liver disease (MASLD), paving the way towards new therapeutics and diagnostic biomarkers - Claudia Theys (29/01/2024)

Claudia Theys

  • 29 January 2024, 4pm - 6pm
  • Promotiezaal, Q.002 (CDE)
  • Promoter: Wim Vanden Berghe


Metabolic dysfunction associated fatty liver disease (MASLD) is a global health burden. It consists of a spectrum of liver disorders ranging from steatosis, characterized by lipid accumulation in the liver, inducing inflammation and thereby progression into metabolic dysfunction associated steatohepatitis (MASH). MASH predisposes patients for further cirrhosis and hepatocarcinoma. Unfortunately, there is still no FDA-approved treatment due to the lack of biomarkers to correctly stratify patients and the multifactorial nature of the disease. Therefore changes in lifestyle including diet and exercise remain the current treatment strategy. However this is difficult to maintain, leading to a lot of relapsing patients. Thus, there is an urgent need for a full characterization of the molecular targets that have a key role in the progression of the disease.

The nuclear receptor PPARα and mitochondria have a key role in lipid metabolism and are also closely related to inflammation. Moreover, recent research, especially cancer research, has shown that mitochondrial DNA (mtDNA) methylation can be used as a biomarker and interactions of PPARα with epigenetic enzymes can regulate lipid metabolism in liver and colon, which makes them interesting targets.

PPARα is epigenetically downregulated in MASH patients, but previously tested agonists could not ameliorate the disease. Interestingly, we show that the loss of PPARα function by diet induces similar epigenetic and transcriptional changes towards a MASLD gene signature, as a genetic knock out. Moreover, in both mice models, the loss of this one PPARα hub induced a shockwave of changes in the transcriptome of several epigenetic enzymes, resulting in the epigenetic reprogramming of the lipid and bile acid metabolism towards ferroptotic and pyroptotic lipotoxicity that is closely related with fibrosis. This suggests an important indirect epigenetic protective function of PPARα towards its target genes, to maintain general lipid homeostasis and prevent progression of MASLD. Therefore combination therapies of PPARα agonists with epigenetic compounds should be explored.   

Due to the constant accumulation of lipids in the liver, MASH patients show an overactivation of the mitochondrial metabolism. However the exact molecular mechanisms leading to this overactivation and eventually shutdown are still largely unknown. We have shown that MASLD is associated with small changes of mtDNA methylation. Moreover, an artificial increase of 20% mitochondrial CpG or GpC methylation induced mitochondrial dysfunction and dysregulation of the bile acid metabolism by mito-nuclear communication as seen in MASLD progression. Therefore also mitochondrial methylation shows new opportunities for both MASLD biomarker and therapeutic research.