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Origin of Alzheimer's| Researcher Profile | Zetterberg


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Henrik Zetterberg, M.D., Ph.D.


Henrik Zetterberg, M.D., Ph.D.
Institute of Laboratory Medicine, Department of Clinical Chemistry and Transfusion Medicine, The Sahlgrenska Academy at Göteborg University, Gothenburg, Sweden, recipient of a 2008 New Investigator Research Grant

In his own words, investigator Dr. Henrik Zetterberg, describes his research and what receiving Association funding has meant to his career.

Research focus


Alzheimer's disease is strongly linked to abnormal metabolism of beta-amyloid and its precursor, the amyloid precursor protein (APP). In addition to the 40- and 42-amino-acid-long forms of beta-amyloid, cerebrospinal fluid (CSF) and brain tissue contain a broad range of other beta-amyloid peptides. These beta-amyloid fragments result when enzymes called secretases clip APP. During the past year, we have confirmed earlier data suggesting that types of beta-amyloid fragments in CSF separate individuals with sporadic Alzheimer's disease from those without Alzheimer's with high accuracy. In addition to the well-established Alzheimer's biomarker beta-amyloid 1-42, those with Alzheimer's have high levels of the shorter fragment beta-amyloid 1-16, in CSF.

Impact of Association funding

The Alzheimer's Association grant was a true vitamin injection into our ongoing research examining methods to better understand the origins of Alzheimer's.

New pathway for APP processing


Experiments conducted in cell cultures and in mice show that this fragment is the result of alpha- and beta-secretase clipping the same APP molecule. This represents a previously unknown pathway in which APP is processed. We have recently verified this pathway in dogs. Further, we have shown that this pathway is strongly induced in response to the inhibition of the gamma-secretase enzyme in cell cultures, mice, dogs and humans. Since beta-amyloid 1-16 is water-soluble and not influenced by overall amounts of amyloid in the brain, we believe that this marker will be very useful in future studies of potential therapies that inhibit or change the behavior of gamma-secretase. We have also shown that beta-amyloid 1-16 does not have any acute toxic effect on synapses on its own.

Potential role of gamma-secretase


When comparing the beta-amyloid patterns in the CSF of people with sporadic Alzheimer's and those who are carriers of the Alzheimer's-causing genetic mutation PSEN1 A431E, the patterns separate the two groups completely. PSEN1 A431E mutation carriers have levels of beta-amyloid 1-40 and 1-42 that are similar to people with sporadic Alzheimer's, but mutation carriers have extremely low levels of beta-amyloid 1-37, 1-38 and 1-39. It is tempting to speculate that these fragments may inhibit the aggregation of individual beta-amyloid 1-42 peptides into multiple-peptide oligomers and that the key Alzheimer's-promoting effect of PSEN1 A431E, and possibly several other familial Alzheimer's disease-associated PSEN mutations, is gamma-secretase activity that results in loss of the protective beta-amyloid 1-37, 1-38 and 1-39 peptides. Modulating gamma-secretase function would in that case be a novel approach to prevent Alzheimer's-associated beta-amyloid aggregation.

Finally, we have discovered several previously unknown N-terminal fragments of APP and APP/beta-amyloid fragments. The results described above have thus far resulted in five publications.

Moving research forward


The Alzheimer's Association grant was a true vitamin injection into our ongoing research examining methods to better understand the origins of Alzheimer's. Some of these methods had been under development for quite a while. We realized their potential in shedding light on how amyloid metabolism might be changed in individuals with Alzheimer's disease or those at high risk of developing Alzheimer's and wrote a grant proposal describing how we would push the projects further. The reviewer comments were very positive and helpful, and the grant money was really needed. It is also notable that Alzheimer's Association funding is quite prestigious and very well recognized in the field.