However, inhibition of BACE1 could have negative consequences if other molecules that are physiologically important require cleavage by BACE1.
In fact, Martin Citron from Amgen reported that over 100 patents have been filed for BACE1 inhibitors. Since inhibition of β-secretase should decrease Aβ levels in the brain, it is an attractive therapeutic target. Sequential cleavage of amyloid precursor protein by β-secretase and then γ-secretase produces the amyloid β-peptide (Aβ). The discovery of PGRN mutations is a major advance in our understanding of FTD and will undoubtedly inspire intense research to discover the mechanism by which progranulin deficiency leads to FTD.Īnother interesting story from the conference involved BACE1, the major β-secretase in the brain. Additionally, the ubiquitin-positive inclusions in the brains of affected individuals do not stain with anti-progranulin antibodies, leaving the identity of the ubiquitinated protein an intriguing mystery. Interestingly, all the PRGN mutations that were reported are dominant and effectively create null alleles, meaning that the FTD phenotype results from decreased levels of progranulin in affected individuals. In one patient series, PGRN mutations accounted for at least 11% of all FTD cases and 26% of familial FTD cases. Geneticists then sequenced genes near MAPT and were rewarded by finding mutations in the progranulin gene ( PGRN), which is located a mere 1.7 Mb away from MAPT. It seemed likely that difficult-to-find mutations in MAPT accounted for these FTD cases, but the mutations could not be found despite heroic efforts. Since 1998, when mutations in the microtubule-associated protein tau ( MAPT) gene on chromosome 17 were found to cause FTD with parkinsonism, geneticists have been stymied by families with FTD linked to the same region on chromosome 17 but having no MAPT mutations. Both groups found mutations in the gene encoding progranulin that cause a form of frontotemporal dementia (FTD), the second most common form of dementia in individuals younger than 65 years old. Perhaps the biggest news came from two independent groups of researchers at the Mayo Clinic and the University of Antwerp in Belgium. It is hoped that imaging will identify patients at risk for AD and differentiate patients with amyloid-β deposition from patients with other types of pathology.Īlthough there were hundreds of presentations at ICAD, a few stood out because of their importance and novelty. William Klunk from the University of Pittsburgh estimated that over 500 patients at 12 institutions have undergone PET scans using PiB, which appears to be a reliable marker of amyloid deposition. There were also several reports on brain PET imaging using the Pittsburgh compound B (PiB). Frank-Erik De Leeuw from UMC-Stradboud in the Netherlands reported that the extent of white matter lesions correlates with medial temporal atrophy in late-onset but not early-onset AD, suggesting that late-onset and early-onset AD may have some different pathological pathways.
There was particular interest in white matter lesions, which several scientists noted were closely correlated with AD.
Using a wide variety of methods, investigators showed correlations between AD or aging and different imaging measures. The main conference was preceded by an imaging consortium on Alzheimer's disease (AD). Flamenco dancers, banjo players, and plenty of sangria created a festive beginning for the conference. The welcome reception at Palacio Negralejo, a sprawling estate on the outskirts of Madrid, allowed attendees to meet collaborators and friends and sample some typical Spanish food: Iberic ham, seafood paella, grilled veal and various tapas. More than 5,000 researchers, students and clinicians came to Madrid to present their research and learn about the findings of others. The 10 th International Conference on Alzheimer's Disease (ICAD) and Related Disorders was held in the Spanish capitol of Madrid from July 15–20, 2006.
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