The Lundbeck Foundation announced March 6 that Bart De Strooper, Michel Goedert, John Hardy, and Christian Haass would share the 2018 Brain Prize of €1 million. The foundation recognized the quartet for their groundbreaking research into the genetic and molecular bases of Alzheimer’s disease. The prize will be awarded at a ceremony in Copenhagen on March 9.
The prize has been awarded annually since 2011, when Péter Somogyi, Tamás Freund, and György Buzsáki were recognized for helping elucidate how cortical and hippocampal circuitry form memories. This is the first time the award has gone to AD research.
Alzforum closely covers the work of the four researchers, who, in turn, contribute commentary and advice to the research community via Alzforum.
Hardy co-discovered amyloid precursor protein (APP) mutations that cause early onset familial AD, tau mutations that cause frontotemporal dementia (Goate et al., 1991; Research Timeline). He helped formulate the amyloid hypothesis, which places the Aβ peptide ahead of tau and into a pathological cascade leading to AD (Hardy and Alsop, 1991; Hardy et al., 1998; Research Timeline). Hardy has made seminal discoveries across neurogenetics, including of tau mutations causing frontotemporal dementia and α-synuclein triplication as a cause of early onset Parkinson’s disease (Hutton et al., 1998; Singleton et al., 2003). At University College London, Hardy’s team co-discovered that rare variants in TREM2 drive up risk for Alzheimer’s and other neurodegenerative diseases, magnifying global research interest into this microglial receptor (Nov 2012 news). In essence, Hardy’s work helped inspire the cell and molecular biology research being done on APP, tau, and TREM2.
Haass co-discovered that the generation of Aβ from APP is part and parcel of normal cellular biology, and subsequently dissected the molecular mechanisms and consequences of APP processing by the enzyme complex γ-secretase (Haass et al., 1992; Research Timeline; Haass et al., 1992). His lab pinpointed how mutations in APP accelerate its cleavage by the enzyme β-secretase, explored additional substrates of BACE, and in the process advanced the field of regulated intramembrane proteolysis, aka RIP (e.g. Haass et al., 1995; Willem et al., 2006). Haass discovered APP fragments that modulate neuronal activity (Willem at al., 2015). Recently, the lab focused on elucidating the processing and function of TREM2, and discovered that the concentration of a soluble piece of TREM2 rises in the CSF of people in the prodromal phase who are approaching Alzheimer’s dementia (e.g. Suárez-Calvet et al., 2016).
De Strooper directs the new U.K. Dementia Research Institute. In his early career, he helped unravel how β- and γ-secretases orchestrate the release of Aβ from APP and how they process other substrates, including Notch (De Strooper et al., 1998; Research Timeline; De Strooper et al., 1999; Research Timeline). By uncovering subtle changes in BACE knockout mice, De Strooper alerted the field to potential adverse effects of targeting β-secretase therapeutically (Dominguez et al., 2005; Research Timeline). Linking presenilin mutations to the production of Aβ43, a toxic peptide, De Strooper’s group helped solidify the amyloid cascade as the driving force in early onset familial AD (Veugelen et al., 2016). His recent review on the cellular phase of AD is considered a blueprint for exploring the molecular underpinnings of the prodromal decade of AD, and for broadening the amyloid hypothesis to integrate compensatory and dynamic cell biology process during those years (Mar 2016 webinar).
Goedert was recognized for his contributions to the study of the second major pathological hallmark of AD, neurofibrillary tangles comprised of tau. Goedert cloned this microtubule-binding protein and went on to show how phosphorylation increased its propensity to aggregate (Goedert et al., 1988; Research Timeline; Goedert et al., 1992). He figured out how multiple isoforms of tau factor into pathology, and his transgenic mouse models of human tau mutations helped the field understand the complexity of tauopathies (Goedert et al., 1989; Allen et al., 2002; Research Timeline). Goedert’s work helped establish the concept that tau spreads through the brain in a prion-like manner (Jun 2009 news; Research Timeline). Most recently he teamed up with colleagues at the MRC Laboratory of Molecular Biology in Cambridge to solve the structure of tau filaments isolated from the brain of an AD patient (Jul 2017 news).—Tom Fagan
- Enter the New Alzheimer’s Gene: TREM2 Variant Triples Risk
- Traveling Tau—A New Paradigm for Tau- and Other Proteinopathies?
- Tau Filaments from the Alzheimer’s Brain Revealed at Atomic Resolution
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