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Researchers uncover function of key Alzheimer's enzyme
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Alistair Garratt/Max-Delbrück-Center for Molecular Medicine
Researchers uncover function of key Alzheimer’s enzyme
The printed journal includes an image merely for illustration Electron micrographic section through nerve fibres within the sciatic nerve After inactivation of BACE1 (right panel), axons (pink) are only poorly surrounded by myelin, generated by Schwann cells (blue). By contrast, nerve fibres in a control animal (left) are surrounded by thick myelin sheaths (dark rings).
Cleavage of amyloid precursor protein (APP) by the enzyme BACE1 is essential for the formation of amyloidβ peptide—the main constituent of plaques in Alzheimer’s disease—and many pharmaceutical companies are actively trying to develop drugs that target BACE1 function. However, the physiological function of BACE1, aside from its role in APP cleavage, is unclear, which means that any potential side-effects of BACE1 inhibitors are a mystery. In a new study, an international team of researchers reports that BACE1 is involved in the myelination of peripheral neurons. Michael Willem (Ludwig-Maximilians-University,
Munich, Germany) and co-workers found that BACE1 expression in mice was greatest during the early postnatal stages—the period when myelin formation occurs. Expression fell in the second postnatal week and declined to low levels in adult mice. They also found that BACE1 was co-expressed with type III neuregulin 1—a protein that is known to control myelination—in neurons that projected to the periphery. By use of electron microscropy, the researchers showed that the thickness of the myelin sheath in the peripheral nerves of BACE1 knockout mice was lower than in normal animals (figure). Additionally, knockout mice showed poor segregation of unmyelinated nerve fibres. This pattern of hypomyelination and altered sorting of axons was very similar to the changes seen in mice that have defects in type III neuregulin. In further experiments, the researchers showed that deficiency in BACE1 led to the accumulation of unprocessed neuregulin 1; this suggests that neuregulin 1 is a substrate for BACE1 and accumulation of the uncleaved neuregulin 1 is due to a loss of processing by BACE1 (Science 2006; published online Sept 21. DOI: 10.1126/science.1132341). “Our work establishes for the first time a crucial physiological
function of BACE1 in the mammalian organism: it is necessary to trigger efficient myelination of peripheral nerves”, one of the researchers, Alistair Garratt (Max-DelbrückCentre for Molecular Medicine, Berlin, Germany), told The Lancet Neurology. The demonstration of a function for BACE1 in myelination and the processing of neuregulin 1 should be taken into account in the design and testing of BACE1 inhibitors in clinical trials, adds Garratt, as knowledge of BACE1’s function will enable researchers to monitor any adverse events of BACE1-inhibitor treatment. “However, we do not envisage that blockage of BACE1 in adult animals or humans will be detrimental to peripheral nerve myelination, as this process is finished by that time.” “We know from genetics that blockage of neuregulin 1 signalling in adult Schwann cells, as would also presumably occur after pharmacological inhibiton of BACE1, has no effect on myelination in vivo. However the potential role of BACE1 in neuregulin 1 function, also in the mature nervous system, should not be disregarded”, he adds.
Helen Frankish
CatB changes its spots Cathepsin B (CatB), a proteinase associated with amyloid-β (Aβ) plaques in Alzheimer’s disease, may not contribute to pathogenesis as previously thought. In fact, findings in a mouse model of the disorder suggest that CatB may help prevent formation of Aβ aggregates by breaking down the plaque-forming Aβ1–42 into shorter peptides that are less prone to aggregation. “One remarkable finding is that CatB overexpression reduces amyloidosis even after the onset 904
of significant amyloid pathology”, says researcher Li Gan (University of California at San Francisco, USA). “We discovered that CatB is engaged in a novel catabolic pathway for regulating Aβ levels.” Previous studies had implicated CatB in Alzheimer’s disease pathogenesis, although the enzyme had been suggested to cleave amyloid-precursor protein (APP) to create plaqueforming Aβ1–42. Gan and colleagues decided to investigate the effects of CatB in hAPP transgenic mice, which
express human APP. In mice lacking the gene that codes for CatB, APP was unaffected; however, accumulation of Aβ1–42 in neurons was upregulated. “We were quite surprised to find that ablation of CatB actually increased Aβ deposition in hAPP mice”, Gan told The Lancet Neurology, “which led us to suspect that maybe the substrate of CatB is not the precursor, but the peptide itself.” The researchers then investigated the effects of CatB on Aβ1–42 in vitro and found that it cleaved single molecules, dimers, and
http://neurology.thelancet.com Vol 5 November 2006
Alistair Garratt/Max-Delbrück-Center for Molecular Medicine
Researchers uncover function of key Alzheimer’s enzyme
The printed journal includes an image merely for illustration Electron micrographic section through nerve fibres within the sciatic nerve After inactivation of BACE1 (right panel), axons (pink) are only poorly surrounded by myelin, generated by Schwann cells (blue). By contrast, nerve fibres in a control animal (left) are surrounded by thick myelin sheaths (dark rings).
Cleavage of amyloid precursor protein (APP) by the enzyme BACE1 is essential for the formation of amyloidβ peptide—the main constituent of plaques in Alzheimer’s disease—and many pharmaceutical companies are actively trying to develop drugs that target BACE1 function. However, the physiological function of BACE1, aside from its role in APP cleavage, is unclear, which means that any potential side-effects of BACE1 inhibitors are a mystery. In a new study, an international team of researchers reports that BACE1 is involved in the myelination of peripheral neurons. Michael Willem (Ludwig-Maximilians-University,
Munich, Germany) and co-workers found that BACE1 expression in mice was greatest during the early postnatal stages—the period when myelin formation occurs. Expression fell in the second postnatal week and declined to low levels in adult mice. They also found that BACE1 was co-expressed with type III neuregulin 1—a protein that is known to control myelination—in neurons that projected to the periphery. By use of electron microscropy, the researchers showed that the thickness of the myelin sheath in the peripheral nerves of BACE1 knockout mice was lower than in normal animals (figure). Additionally, knockout mice showed poor segregation of unmyelinated nerve fibres. This pattern of hypomyelination and altered sorting of axons was very similar to the changes seen in mice that have defects in type III neuregulin. In further experiments, the researchers showed that deficiency in BACE1 led to the accumulation of unprocessed neuregulin 1; this suggests that neuregulin 1 is a substrate for BACE1 and accumulation of the uncleaved neuregulin 1 is due to a loss of processing by BACE1 (Science 2006; published online Sept 21. DOI: 10.1126/science.1132341). “Our work establishes for the first time a crucial physiological
function of BACE1 in the mammalian organism: it is necessary to trigger efficient myelination of peripheral nerves”, one of the researchers, Alistair Garratt (Max-DelbrückCentre for Molecular Medicine, Berlin, Germany), told The Lancet Neurology. The demonstration of a function for BACE1 in myelination and the processing of neuregulin 1 should be taken into account in the design and testing of BACE1 inhibitors in clinical trials, adds Garratt, as knowledge of BACE1’s function will enable researchers to monitor any adverse events of BACE1-inhibitor treatment. “However, we do not envisage that blockage of BACE1 in adult animals or humans will be detrimental to peripheral nerve myelination, as this process is finished by that time.” “We know from genetics that blockage of neuregulin 1 signalling in adult Schwann cells, as would also presumably occur after pharmacological inhibiton of BACE1, has no effect on myelination in vivo. However the potential role of BACE1 in neuregulin 1 function, also in the mature nervous system, should not be disregarded”, he adds.
Helen Frankish
CatB changes its spots Cathepsin B (CatB), a proteinase associated with amyloid-β (Aβ) plaques in Alzheimer’s disease, may not contribute to pathogenesis as previously thought. In fact, findings in a mouse model of the disorder suggest that CatB may help prevent formation of Aβ aggregates by breaking down the plaque-forming Aβ1–42 into shorter peptides that are less prone to aggregation. “One remarkable finding is that CatB overexpression reduces amyloidosis even after the onset 904
of significant amyloid pathology”, says researcher Li Gan (University of California at San Francisco, USA). “We discovered that CatB is engaged in a novel catabolic pathway for regulating Aβ levels.” Previous studies had implicated CatB in Alzheimer’s disease pathogenesis, although the enzyme had been suggested to cleave amyloid-precursor protein (APP) to create plaqueforming Aβ1–42. Gan and colleagues decided to investigate the effects of CatB in hAPP transgenic mice, which
express human APP. In mice lacking the gene that codes for CatB, APP was unaffected; however, accumulation of Aβ1–42 in neurons was upregulated. “We were quite surprised to find that ablation of CatB actually increased Aβ deposition in hAPP mice”, Gan told The Lancet Neurology, “which led us to suspect that maybe the substrate of CatB is not the precursor, but the peptide itself.” The researchers then investigated the effects of CatB on Aβ1–42 in vitro and found that it cleaved single molecules, dimers, and
http://neurology.thelancet.com Vol 5 November 2006