Alzheimer’s Field Loses Fred van Leeuwen, 71

Fred van Leeuwen, professor at the Maastricht University in the Netherlands, passed away Wednesday, January 13. Van Leeuwen is best known for his discovery of a faulty transcription mechanism, dubbed “molecular misreading,” in the neurons of people who had sporadic Alzheimer’s disease. He frequently contributed to Alzforum.

Fred van Leeuwen

Van Leeuwen’s seminal paper made the cover of Science in 1998 (van Leeuwen et al., 1998). He found that despite having normal DNA, neurons in some people ended up with fewer nucleotides in mRNAs for amyloid precursor protein (APP) and ubiquitin B (UBB). These deletions caused a 1-nucleotide frameshift that led to premature truncation of the two proteins (Apr 1999 news; van Leeuwen et al., 2000). The shortened proteins, dubbed APP+1 and UBB+1 to denote the frameshift, accumulated in plaques or clogged the proteasome, respectively (Dec 2004 conference news). Van Leewen’s work was featured in one of the earliest Alzforum webinars (May 1998 webinar). 

In cultured neurons, UBB+1 triggered cell death (De Vrij et al., 2001). APP+1 turned out to be secreted from neurons, but much less turned up in the CSF of people with Alzheimer’s compared to healthy controls, suggesting problems secreting the protein (Hol et al., 2003). Neuronal accumulations of APP+1 and UBB+1 were found in people with frontotemporal dementia, Pick's disease, progressive supranuclear palsy, and Huntington’s, but not Parkinson’s (van Leeuwen et al., 2006; Dennissen et al., 2010). 

Van Leeuwen created UBB+1 transgenic mice; they had dysfunctional proteasomes in their brains and performed poorly on memory tests (Fischer et al., 2009). His lab crossed the UBB+1 mice with the APPPS1 mouse model of amyloidosis. Paradoxically, the offspring had smaller plaque loads than their parents, but still had behavioral deficits (Verheijen et al., 2018). 

Van Leeuwen began his research career at the Netherlands Institute for Brain Research in 1974. He remained there for 32 years until he moved to Maastricht University in 2007. We invite friends and colleagues to celebrate his life by emailing tributes to tfagan@alzforum.org for posting on Alzforum.—Chelsea Weidman Burke

Comments

  1. It is with great sadness and dismay that we heard of the death of our valued cooperation partner and friend Fred van Leeuwen, Ph.D. Fred has shaped Alzheimer's research for decades with innovative ideas and unique concepts, pushing science forward to unravel and understand the complexity of Alzheimer's disease. In addition to his successful work in teaching, research and academic self-administration, promoting young researchers was very important to him. Fred, we will never forget you; your spirit lives on in our research.

    View all comments by Marcus O. W. Grimm View all comments by Tobias Hartmann

  2. Our roads crossed during the first years of my postdoctoral project. In hindsight, I think that Fred and I probably started working around the same time on ubiquitin, Fred as a principal investigator in Amsterdam and me as a postdoctoral fellow in Stockholm. In 1997 I had moved from the Netherlands, my native country, to Stockholm to start my postdoctoral project at the Karolinska Institute. While attending, a few years later, a conference back home in the Netherlands I met Fred, who had just published the discovery that an aberrant form of ubiquitin could be detected in brains from individuals with Alzheimer’s disease and Down’s syndrome. While Fred had stumbled into ubiquitin through his interest in neurodegenerative disorders, I would follow a few years later the same road in reverse. I think that it is fair to say that my encounter with Fred at that conference and the collaboration that we started immediately after accelerated my transition from virology to neurodegenerative disorders.

    Fred’s very sharp observation that aberrant ubiquitin could be found in patient material was very timely, as those were also the days that many researchers became intrigued by the possible role of a defective ubiquitin-proteasome system, which is responsible for recycling misfolded proteins, in the etiology of neurodegenerative disorders. Fred quickly realized that a reporter assay for the ubiquitin-proteasome system (UPS) that I had developed during my postdoctoral project could probably be used to address if the presence of the aberrant ubiquitin caused a defect in the UPS. The initiative to collaborate on this topic came entirely from Fred but I was keen to join. In the end it resulted in several joint publications and a line of research that was pursued by both our labs for many years. Even though we still do not know to what extent the aberrant ubiquitin is causing impairment of the UPS and whether it contributes to the etiology of these diseases, Fred’s observations inspired many researchers to have a closer look at this weird ubiquitin. In the end these studies taught us not only about the diseases but also gave seminal insights in the basic mechanisms for destruction of misfolded proteins by the UPS.

    During the first years of our collaboration, Fred and I had frequent contact and intense and productive projects. Fred hosted several of my students for visits in his lab in Amsterdam and several of Fred’s students spent time in my research group at the Karolinska Institute performing experiments. I myself also had the pleasure of spending some time in Fred’s lab. When he moved to Maastricht I had the honor to be invited by Fred for the special occasion when Nobel laureate Aaron Ciechanover received an honorary doctorate at the University of Maastricht. Even though the contacts became less frequent and more by phone and e-mail and less in person during recent years, it was always inspiring to talk with Fred. In many respects, Fred is an example for future generations of scientists. The story of his discovery of the aberrant ubiquitin testifies to an extremely sharp mind and exceptional eye for detail. It is the kind of scientific detective story that fascinates scientist and nonscientist alike. I think that many of us would have disregarded the vasopressin immunoreactive signal in the Brattleboro rat that was not supposed to be there. Easy to pass it off as an artefact, cross-reactivity of the antibody, or another trivial, boring explanation. But for Fred it became the start of a career-long journey to understand the cause and consequence of this unexpected signal.

     Fred was not only a great teacher but also never stopped learning himself. The student in him was always there. The genuine curiosity to understand never faded. One of my strongest memories comes from the short time that I spent in his lab. After a long day, when I was almost on my way to the hotel, he called me into his office, where he was sitting behind a dual-head teaching microscope. He asked me to take a seat and started to show me human brain sections from his collection that had been stained for the aberrant ubiquitin that he discovered. It was clear that the material that he was showing me was dear to him. The master and the student. There are not many researchers who truly made a discovery, but with the finding of “molecular misreading” Fred was one of those few, and with that he left his mark in science. 

    View all comments by Nico Dantuma

  3. Fred van Leeuwen: From vasopressin to Alzheimer’s disease.

    From the beginning of his scientific life, Fred’s field of expertise has been immunohistochemistry. At that time (the mid ’70s) this technique was still in a pioneering phase in neuroscience. Fred used it intensively to study the anatomy of vasopressin and oxytocin systems in the hypothalamus, working with Dick Swaab at the Netherlands Institute of Neuroscience, Amsterdam. Doing molecular research myself on the neuropeptide system in Utrecht, I found a great collaborator and friend in Fred. His observations that the Brattleboro rat, a genetic mutant strain that fails to produce vasopressin due to a single-nucleotide deletion, mysteriously acquires vasopressin-expressing neurons over age intrigued us enormously. It was the reason for a joint project. The solution of this mystery was eventually Fred’s entrance to the field of Alzheimer’s disease.

    We found that the restoration of vasopressin synthesis resulted from further deletion of two nucleotides from the mutant transcript (Evans et al., 1994). The -1 and -2 deletions together put the reading frame of the mRNA on the correct track again, and thus resulted in vasopressin expression. The finding that the dinucleotide deletion occurred at a particular motif prompted us to look for the same event in other brain mRNAs carrying this motif. We chose to study a couple of interesting genes in normal and diseased human brains, like the glial protein GFAP, ubiquitin, and the Alzheimer protein, APP. Here Fred’s expertise in designing robust antisera against protein sequences predicted by dinucleotide deletion and then getting them to work in immunohistochemistry on human brain sections appeared to be crucial. It eventually changed his life from a neuropeptide neuroanatomist to an Alzheimer researcher.

    The seminal paper of the findings in Alzheimer’s disease brain held the promise of a totally new mechanism underlying the protein problems in this form of dementia and perhaps others (van Leeuwen et al., 1998). To realize this potential defined Fred’s new mission and second scientific life. Meanwhile, having moved to Maastricht he remained fully engaged with “+1 proteins” molecular misreading and proteasome dysfunction, all in search for mechanisms of protein aggregation as a hallmark of Alzheimer’s disease.

    Fred’s perseverance, enthusiasm, and eagerness to collaborate were decisive for the progress in this new direction for almost 20 years. It brought a lot of new valuable science, but no solution for Alzheimer’s disease. Fred will be missed as a person and scientist in the Alzheimer’s field.

    References:

    Evans DA, van der Kleij AA, Sonnemans MA, Burbach JP, van Leeuwen FW. Frameshift mutations at two hotspots in vasopressin transcripts in post-mitotic neurons. Proc Natl Acad Sci U S A. 1994 Jun 21;91(13):6059-63. PubMed.

    van Leeuwen FW, de Kleijn DP, van den Hurk HH, Neubauer A, Sonnemans MA, Sluijs JA, Köycü S, Ramdjielal RD, Salehi A, Martens GJ, Grosveld FG, Peter J, Burbach H, Hol EM. Frameshift mutants of beta amyloid precursor protein and ubiquitin-B in Alzheimer's and Down patients. Science. 1998 Jan 9;279(5348):242-7. PubMed.

    View all comments by J.P.H. Burbach

  4. Some years ago, after Fred had given a wonderful talk on Alzheimer’s disease, I wrote to him to ask if I could use some of his diagrams. He responded by sending all his carefully drawn slides, saying we could use them without restriction.

    That is so unusual in this modern competitive world. What a lovely colleague!

    View all comments by Richard Lathe

  5. Fred, during his master's biology at the Free University Amsterdam, was a trainee at the Netherlands Institute for Brain Research in Amsterdam, an institute of the Royal Netherlands Academy of Arts and Sciences. In 1975 he was appointed in the neuroendocrinology group of Prof. Dick Swaab, where Fred made important contributions to the development of specific and validated immunocytochemistry of neuropeptides in the brain and added to the discovery of extrahypothalamic pathways of vasopressins (VPs).

    View all comments by Gerard J. Boer

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References

News Citations

  1. Making Dirty RNA from Clean DNA
  2. Conformation Rules Part 1: News, Common Threads, Debate from San Diego Conference

Webinar Citations

  1. Frameshift Mutants of β Amyloid Precursor Protein and Ubiquitin-B in Alzheimer's and Down's Syndrome Patients

Paper Citations

  1. van Leeuwen FW, de Kleijn DP, van den Hurk HH, Neubauer A, Sonnemans MA, Sluijs JA, Köycü S, Ramdjielal RD, Salehi A, Martens GJ, Grosveld FG, Peter J, Burbach H, Hol EM. Frameshift mutants of beta amyloid precursor protein and ubiquitin-B in Alzheimer's and Down patients. Science. 1998 Jan 9;279(5348):242-7. PubMed.
  2. van Leeuwen FW, Fischer DF, Kamel D, Sluijs JA, Sonnemans MA, Benne R, Swaab DF, Salehi A, Hol EM. Molecular misreading: a new type of transcript mutation expressed during aging. Neurobiol Aging. 2000 Nov-Dec;21(6):879-91. PubMed.
  3. De Vrij FM, Sluijs JA, Gregori L, Fischer DF, Hermens WT, Goldgaber D, Verhaagen J, Van Leeuwen FW, Hol EM. Mutant ubiquitin expressed in Alzheimer's disease causes neuronal death. FASEB J. 2001 Dec;15(14):2680-8. PubMed.
  4. Hol EM, van Dijk R, Gerez L, Sluijs JA, Hobo B, Tonk MT, de Haan A, Kamphorst W, Fischer DF, Benne R, Van Leeuwen FW. Frameshifted beta-amyloid precursor protein (APP+1) is a secretory protein, and the level of APP+1 in cerebrospinal fluid is linked to Alzheimer pathology. J Biol Chem. 2003 Oct 10;278(41):39637-43. PubMed.
  5. Van Leeuwen FW, van Tijn P, Sonnemans MA, Hobo B, Mann DM, Van Broeckhoven C, Kumar-Singh S, Cras P, Leuba G, Savioz A, Maat-Schieman ML, Yamaguchi H, Kros JM, Kamphorst W, Hol EM, De Vos RA, Fischer DF. Frameshift proteins in autosomal dominant forms of Alzheimer disease and other tauopathies. Neurology. 2006 Jan 24;66(2 Suppl 1):S86-92. PubMed.
  6. Dennissen FJ, Kholod N, Steinbusch HW, Van Leeuwen FW. Misframed proteins and neurodegeneration: a novel view on Alzheimer's and Parkinson's diseases. Neurodegener Dis. 2010;7(1-3):76-9. PubMed.
  7. Fischer DF, van Dijk R, van Tijn P, Hobo B, Verhage MC, van der Schors RC, Li KW, van Minnen J, Hol EM, Van Leeuwen FW. Long-term proteasome dysfunction in the mouse brain by expression of aberrant ubiquitin. Neurobiol Aging. 2009 Jun;30(6):847-63. PubMed.
  8. Verheijen BM, Stevens JA, Gentier RJ, van 't Hekke CD, van den Hove DL, Hermes DJ, Steinbusch HW, Ruijter JM, Grimm MO, Haupenthal VJ, Annaert W, Hartmann T, van Leeuwen FW. Paradoxical effects of mutant ubiquitin on Aβ plaque formation in an Alzheimer mouse model. Neurobiol Aging. 2018 Dec;72:62-71. Epub 2018 Aug 18 PubMed.

Other Citations

  1. tfagan@alzforum.org

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