What first interested you in a biomedical career, and how did you come to work on Alzheimer’s disease?

From my earliest memories, I recall wanting to be a doctor when I grew up.  My parents confirmed that this was something I had said by the time I was five or six.  I think one motivation for this is that I had a wonderful pediatrician, an older lady whose warm manner and knowledge of how the body worked must have attracted me to the profession.  It was really not a scientific motivation at that early age, but rather an emotional one.  After I entered medical school, I soon found a way of expressing my strong interest in the mind-brain relationship, namely by studying neurology and coming to understand the complexities of chronic neurological illness.  My particular focus on Alzheimer’s disease came as a result of my postdoctoral experience in neurochemistry and neuronal cell biology.  My postdoctoral advisor assigned me a project involving microtubule biochemistry.  It soon became apparent to me that the abnormal neurofibrillary tangles of Alzheimer’s disease (AD) were thought to be potentially composed of twisted microtubules.  This did not turn out to be quite so, but nevertheless, this theory was sufficient to pique my interest in linking protein function and dysfunction to the mechanisms of brain disease.

  Much of your work appears to center around the amyloid beta-protein. What exactly is this protein and how has our understanding of its role in Alzheimer’s disease progressed over the years?

After my postdoctoral experience, I focused the attention of my fledgling laboratory in the early 1980s on deciphering the composition of both the neurofibrillary tangles and the amyloid plaques.  It soon became apparent to me that a number of etiologically distinct diseases had abundant neurofibrillary tangles, whereas amyloid plaques seemed to be somewhat more specific for the Alzheimer’s syndrome (including Down’s syndrome).  As I read about amyloid diseases it seemed quite clear that the buildup of aggregated proteins could initiate disease and that Alzheimer’s might be similar.  This recognition preceded the seminal paper by George Glenner that reported the initial isolation of the amyloid ß-protein (Aß).  I had already begun attempting to isolate amyloid plaque cores from Alzheimer brain (as I had previously done for neurofibrillary tangles) and had obtained initial compositional analyses of plaques at the time that I saw Glenner’s publication in 1984.

The amyloid ß-protein is a 40-42 amino acid fragment of a large precursor protein (APP).  We discovered in 1992 that amyloid ß-protein was a normal product of cellular metabolism throughout life, and this led to the use of cultured cells to study the details of how Aß was cleaved out of its large precursor and how it was metabolized.

Based on the ability to study the natural conversion of APP to Aß in cultured cells and living animals, a large number of laboratories around the world have made enormous progress in understanding the biology and pathobiology of amyloid ß-protein.  The reason that this hypothesis has continued to garner so much attention is because many factors related to Alzheimer’s disease appear to impact the production, clearance, or aggregation of amyloid ß-protein.  Foremost among these factors are specific genetic mutations that can cause Alzheimer’s disease.  But even before this genetic evidence implicating Aß in the disease became known, a few investigators were already convinced that Aß could actually cause Alzheimer’s disease.  Nonetheless, this hypothesis remains somewhat controversial and is certainly not fully proven.

  In your March 2000 Journal of Neuroscience paper, it is suggested that naturally occurring substances can degrade and clear amyloid beta-protein from the brain. Is this being considered as a possible treatment for Alzheimer’s?

Even before our Journal of Neuroscience paper in 2000, my colleagues and I had become interested in the possibility that deficits in the degradation or clearance of Aß might contribute to AD, just as we already knew that overproduction of the peptide could do.  The role of Aß clearance and degradation has been less well studied than the production of this peptide from APP.  Nevertheless, genetic mutations that enhance production can explain only a very small fraction of all Alzheimer’s disease, even a small fraction of familial forms of the disease.  This leaves open the possibility that faulty degradation and clearance of the peptide could lead to its rise in the brains of typical Alzheimer’s subjects in late-life.

  What role do presenilins play in Alzheimer’s?

In my view, the presenilin proteins are absolutely central to the pathogenesis of Alzheimer’s disease.  This is because my colleagues and I, in particular Dr. Michael Wolfe, obtained evidence in 1998 that presenilin was the active site of the long-sought enzyme, γ-secretase.  γ-secretase is the second of two enzymes (the other one is ß-secretase) that normally cleave APP to release Aß.  Our concept that presenilin was an unprecedented intramembrane-cleaving aspartyl protease that cut APP (and as it turned out, numerous other substrates) within the phospholipid bilayer (membrane) of the cell, was initially quite controversial, but evidence from many laboratories has virtually sealed the debate at this juncture.  As the active site of a multi-protein complex that is the γ-secretase, presenilin is important in all forms of Alzheimer’s disease, in the sense that all cases are marked by excess accumulation of Aß in brain regions important for memory and cognition.  If we could somehow inhibit presenilin/γ-secretase modestly and safely, I believe this would be a very effective therapeutic strategy for Alzheimer’s disease.

  Can you describe the progress we have made toward understanding this disease?

As discussed earlier, there has been enormous progress in the last 20 years in elucidating the fundamental molecular mechanisms underlying Alzheimer’s disease.  While this field has enjoyed more than its share of controversy, I believe there is now a substantial consensus among a majority of investigators on the pathobiology of Alzheimer’s disease—that it represents an insidious accumulation of Aß and a complex cascade of downstream consequences thereof.

  What predictions would you make regarding the course of Alzheimer’s research over the next decade?

I believe we are now witnessing the movement of Alzheimer research from the bench into the clinic.  We appear to have made enough progress as a field in understanding the origins of Alzheimer’s disease to conceive of specific agents that could treat and perhaps even prevent the disease.  Therefore, I believe that much of the emphasis in the next 5-10 years will be on testing these concepts and actual compounds in patients with the disease.  The so-called amyloid, or Aß, hypothesis of Alzheimer’s disease will only be proven when a compound that lowers Aß levels in the brain results in slowing or stabilization of the clinical progression of the dementia.  This is now the great objective on further research on the disease, and skilled clinical investigators will increasingly play the major role in the final assault on Alzheimer’s.

  What lessons would you draw from your work to share with the next generation of researchers?

I believe my experience in biomedical research has taught me that focus is critical.  In other words, one needs to survey the available evidence about a problem—whether in normal biology or disease pathogenesis—and then consider where one thinks the solution may lie.  Once one has a concept of that solution, one must design and execute experiments that steadily prove or deny the concept.  It feels like this is what my colleagues and I have been at for now more than 20 years.  Focusing on a problem and defining and redefining it in more precise molecular terms appears to be a fruitful avenue for solving the problem.  And even when problems and controversies arise, one must attempt to keep one’s focus, while still keeping in mind that the best-laid hypotheses constantly need adjustment and revision.  Finally, I would say that understanding the molecular etiology of a disease that causes so much suffering represents a wonderful way to spend one’s career.

Dennis J. Selkoe, M.D.
Department of Neurology
Brigham and Women’s Hospital
Harvard Institutes of Medicine
Boston , MA , USA