Last week, my colleague Francesco Rao (DC Biosciences’ CSO) and I travelled to Bonn to participate in a progress meeting for ADAPTED (Alzheimer’s Disease Apolipoprotein Pathology for Treatment Elucidation and Development).
Bonn, the birthplace of Beethoven (though everyone’s favourite tortured pre-romantic composer spent most of his years in Vienna), is a relatively small city (about 300,000 inhabitants).
Sadly, we did not really have the time to do much sightseeing, but Bonn feels like a quiet and unassuming place as it sits cosily on the side of the Rhine River’s lazy meanders. In fact, anyone who has read a bit of German history will notice that the city is rarely mentioned – especially compared with its close neighbour, Cologne. This relatively obscure status is allegedly the reason why post-WWII Chancellor Konrad Adenauer, a native of the area, suggested the city serve as temporary seat of the institutions of the German Federal Republic. The government did not want to give up Berlin, but since the historic capital was cut in two and its western part was entirely surrounded by the communist German Democratic Republic, a temporary solution had to be found. Bonn was chosen because more prominent German cities such as Hamburg or Frankfurt would too easily have become permanent capitals.
Now, back to business: ADAPTED is funded by the Innovative Medicines Initiative 2 Joint Undertaking, the European Union’s Horizon 2020 research and innovation programme and the European Federation of Pharmaceutical Industries and Associations. The consortium – to which DC Biosciences contributes its proteomics expertise – aims to leverage the diverse skills of the participating pharma and bio-tech companies to investigate the role of Apolipoprotein E in Alzheimer’s disease. This meeting was actually the second I had attended, the first one having taken place in Leiden (Netherlands) last April.
But, I hear you say, have scientists not been working on Alzheimer’s disease (AD) for decades now, with almost no progress? What makes us think that we can make a difference?
Well, I remember that during my studies, there were two main hypothesis to explain AD’s aetiology: the “β-amyloid hypothesis” and the “Tau hypothesis”. Most of the research into the causative mechanisms of AD performed in the last decades has concentrated on these two hypotheses. However, these hypotheses, especially the former, seem in recent years to be losing momentum.
A promising, alternate direction of investigation is that of the genetic component of AD. It is known that the probability of contracting AD is massively proposed direction of investigation is the role of the Apolipoprotein E (ApoE), a protein with about 30 documented amino acid polymorphisms, 2 of which (C130R and R176C) are relevant to AD. Based on which amino-acid is present at these positions, ApoE variants are classified into three main groups: ApoE3 (T-C, freq. ~78%), ApoE4 (C-C, freq. ~14%) and ApoE2 (T-T, ~8%). ApoE1 (C-T) also exists but is extremely rare. Interestingly, the ApoE2 allele has been shown to be protective against AD, while possession of the ApoE4 allele increases the risk of developing the disease.
Until recently, analysing the mechanism of ApoE’s involvement in the aetiology of AD was difficult. However, the consortium DC Biosciences is part of is aiming to use a use a variety of state of the art techniques to do just this. The biological material studied includes clinical samples, iPSC-derived neural cell types and tissue models, and murine AD-models. CRISPR-Cas9 gene editing is used to generate isogenic models with different ApoE backgrounds. The different groups are generating large amounts of metabolomics, genomics (GWAS), transcriptomics (GWES), and of course LC-MS/MS based proteomics datasets. Our hopes are that careful comparison of the data in each dataset should at the very least open up new avenues to understand the molecular mechanisms underlying AD. We only have three years, with the first already over, but judging from the exciting results shown at the meeting and the great collaborative atmosphere, we may actually find something exciting soon!