Bioactive lipids Regulate Adaptive Immune responses in Neurodegeneration: novel target for treatment?

Project Information

BRAIN

Grant agreement ID: 101097983

DOI

10.3030/101097983

EC signature date 8 June 2023

Start date 1 September 2023

End date 31 August 2028

Funded under

• European Research Council (ERC)

Total cost

€ 2 499 686,00

EU contribution

€ 2 499 686,00

Coordinated by

STICHTING AMSTERDAM UMC
Netherlands

Periodic Reporting for period 1 - BRAIN (Bioactive lipids Regulate Adaptive Immune responses in Neurodegeneration: novel target for treatment?)

Reporting period: 2023-09-01 to 2026-02-28

Summary of the context and overall objectives of the project

Traditionally, AD is regarded as a neurodegenerative disease and as such, the major focus has been on investigating and treating neurodegeneration and neuronal functioning. Only the last decade, it became apparent that AD pathogenesis strongly interferes with immunological processes and vice versa. Indeed, my novel findings show that the immune system in patients with early AD is already severely derailed and highlight a specific role for CD8+ T-cells. My exciting data also suggest the importance of bio-active lipids like sphingolipids and specialized pro-resolving mediators in early AD pathogenesis, possibly by controlling the immune system. The identification of how the altered lipid landscape underlies AD and affects immune homeostasis is essential to come to new insights into disease pathogenesis and to discover novel intervention strategies, the ultimate goal of the BRAIN project. I therefore here hypothesize that a misbalance in bioactive lipids plays a key role in the induction and propagation of the impaired immune homeostasis associated with AD progression, thereby forming a novel target for treatment. My key objectives are:
i) Unravel bioactive lipid signatures and define correlations with disease progression, sex, biomarkers and an unbalanced immune response in early AD,
ii) Elucidate the underlying mechanisms of uncontrolled lipid mediator balance and how this relates to the altered immune landscape,
iii) Identify key players in this process and perform proof of concept studies to define if restoring the lipid balance reinstates immune homeostasis and consequently cognition and disease pathogenesis in AD.
Together this study will provide in-depth understanding of how bio-active lipids affect immune mediated processes that underlie disease progression, investigate interaction thereof and decode underlying mechanisms to pave the way towards the development of improved prognostic/diagnostic tools and identification of novel therapeutic targets.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

Background:
Within this ERC-Advanced program, the major aim is to elucidate the role of the immune system in Alzheimer’s disease (AD) pathogenesis and define the role of bioactive lipids therein. Goals are: 1. Unravel bioactive lipid signatures and define correlations with disease progression, sex, ApoE status and an unbalanced immune response in early AD, 2. Elucidate mechanisms of uncontrolled lipid mediator balance and how this relates to the altered immune landscape, 3. Identify key players in this process. My results so far collectively demonstrate that the (peripheral and central) immune system is altered in AD and highlight a role for a dysfunctional blood-brain barrier (BBB), CD8 T-cells, aging and ApoE4 and point towards a role for poly-unsaturated fatty acids (PUFA) and ceramides in disease pathogenesis. Results within the first 24 months of ERC advanced BRAIN project are highlighted within the report.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Knowledge transfer
We continuously train our master students an PhD students in the topics ongoing within the ERC program, we have weekly meetings with the research team, where people present their work. Moreover, PhD students present findings at the meetings of the Doctoral School of the research institute (ONWAR), the departmental meeting and also at national meetings (GliaNed, BBBNedwork). Researchers within my team are frequently selected to orally present their work, selected from submitted abstract at relevant conferences (ESNI).
A number of the findings highlighted in the summary are currently published or submitted for publication. Based on the ERC program, I have been invited to various conferences to present our findings, such as the Gordon Research Conference Barriers of the CNS in 2024 as Keynote, the European Brain Barrier Meeting in Bern (2025) and the B4 Barcelona meeting (2025).
For the lay audience, I was invited to contribute to a major article in highly esteemed national newspaper NRC on the work ongoing in the ERC program. I also was interviewed for another national newspaper (De Volkskrant) again on the findings of this program. In January 2026, I will organize a science café in my home town to inform people on the role of the immune system in dementia in laymen style. This is next to the continuous dissemination of our findings to the general public via our website, the Alzheimer Center Amsterdam and the research institute Amsterdam Neuroscience.


Publications:
1. Hansen CE, Vacondio D, van der Molen L, Jüttner AA, Fung WK, Karsten M, van Het Hof B, Fontijn RD, Kooij G, Witte ME, Roks AJM, de Vries HE, Mulder I, de Wit NM. Endothelial-Ercc1 DNA repair deficiency provokes blood-brain barrier dysfunction. Cell Death Dis. 2025 Jan 3;16(1):1. doi: 10.1038/s41419-024-07306-0. PMID: 39753531; PMCID: PMC11698980.
2. van Olst L, Kamermans A, Halters S, van der Pol SMA, Rodriguez E, Verberk IMW, Verberk SGS, Wessels DWR, Rodriguez-Mogeda C, Verhoeff J, Wouters D, Van den Bossche J, Garcia-Vallejo JJ, Lemstra AW, Witte ME, van der Flier WM, Teunissen CE, de Vries HE. Adaptive immune changes associate with clinical progression of Alzheimer's disease. Mol Neurodegener. 2024 Apr 24;19(1):38. doi: 10.1186/s13024-024-00726-8. PMID: 38658964; PMCID: PMC11044380.
3. Hansen CE, Konings J, Toth G, Chornyi S, Karsten M, van Het Hof B, van der Pol SMA, Beekhuis-Hoekstra SD, Kok N, Fung WK, Dijksman NS, Baron W, Witte ME, Lanekoff I, de Vries HE, Kooij G. Spatial mapping of the AA-PGE2-EP axis in multiple sclerosis lesions. Acta Neuropathol. 2025 Apr 29;149(1):39. doi: 10.1007/s00401-025-02878-3. PMID: 40299057; PMCID: PMC12041062.
Dissemination
Media reports: I was invited to contribute to a major article in highly esteemed national newspaper NRC on the work ongoing in the ERC program. I also was interviewed for another national newspaper (De Volkskrant) again on the findings of this program.
Invited lectures: invited lectures increased (Gordon conference 2024; Keynote speaker, invited speaker at various conferences; PhD and postdocs from the group are more frequently invited from submitted abstracts)


A number of the findings in the summary above were unexpected, in which the findings that ApoE4 has such a large role in regulating the immune system is most unexpected and novel. In the recent year, I have focused more and more on the combination of studying progressive MS and the inflammatory processes and define either overlapping or distinct pathologies. In this way, we now investigate for instance demyelination in AD, based on technologies we developed for MS. Likewise, the studies on the immune cell trafficking come from MS related findings. In this way, we are advancing the research field by providing new leads for potential treatments.