Rajapaksha TW, Eimer WA, Bozza TC, Vassar R.
The Alzheimer's β-secretase enzyme BACE1 is required for accurate axon guidance of olfactory sensory neurons and normal glomerulus formation in the olfactory bulb.
Mol Neurodegener. 2011;6:88.
PubMed.
This study by Rajapaksha et al. provides novel, very interesting, and important insights to the role of BACE in Neurobiology. Rajapaksha and coauthors applied an elegant genetic approach to explore the role of BACE in the olfactory system. Analysis of BACE-/- mice revealed smaller olfactory bulbs and mistargeted olfactory sensory neurons (OSNs), suggesting that BACE is involved in the process of axonal guidance of OSNs. The data are intriguing and, as the authors state in the paper, it will be interesting to learn whether the neuronal phenotype also impacts olfactory function, whether BACE plays a similar role in other neuronal subtypes, and what are the substrates/signaling pathways involved that cause the phenotype. From other BACE gene targeting studies (1), we have learned that only a limited decrease in BACE activity (BACE+/- mice) is sufficient to affect the development of amyloid pathology. It will therefore be interesting to learn whether the OSN phenotype is also present in BACE+/- mice and, from a drug discovery perspective, whether small molecule-mediated inhibition of BACE, at doses efficacious in lowering Aβ production, has any impact on the sensory neuronal network of the olfactory system.
References:
McConlogue L, Buttini M, Anderson JP, Brigham EF, Chen KS, Freedman SB, Games D, Johnson-Wood K, Lee M, Zeller M, Liu W, Motter R, Sinha S.
Partial reduction of BACE1 has dramatic effects on Alzheimer plaque and synaptic pathology in APP Transgenic Mice.
J Biol Chem. 2007 Sep 7;282(36):26326-34.
PubMed.
This article by Mattsson et al. is authored by an outstanding group, which investigated the effects of BACE1 inhibitors on Aβ peptide forms in media secreted from cultured neurons and in CSF after in-vivo treatment of dogs. Interestingly, the data suggest that the BACE1 inhibitors result in an altered Aβ peptide pattern, with an increase in the ratio of Aβ5-40:Aβ1-34. However, several aspects of the study should be carefully considered. Firstly, the wide range of dog ages, and the few number of dogs per group, make conclusions from the data difficult, since it is known that Aβ levels in CSF differ depending on the age of the dog (Head et al., 2010). Secondly, because a cocktail of protease inhibitors was not included in sample preparations, it is not known if the profiles of Aβ peptides observed are from the endogenous condition or if they became degraded during the in-vitro methods. Thirdly, use of standards for quantitative mass spectrometry is typical in the field, but standards were not evident in this study. Fourthly, the cell culture data reflect only Aβ produced in the constitutive, and not regulated, secretory pathway; since a major portion of Aβ is released from the regulated secretory pathway, which utilizes cathepsin B for Aβ production (Klein et al., 2009), nothing can be inferred regarding the role of cathepsin B in producing Aβ from the study’s finding that an inhibitor of cathepsin B had no effect on constitutive Aβ secretion. Finally, the authors should indicate whether they, or other groups, have data indicating that BACE1 inhibitors improve memory deficits, the critical goal of Alzheimer’s therapeutics. It will be of interest for the authors to continue these studies to examine these important features of Aβ research.
References:
Head E, Pop V, Sarsoza F, Kayed R, Beckett TL, Studzinski CM, Tomic JL, Glabe CG, Murphy MP.
Amyloid-beta peptide and oligomers in the brain and cerebrospinal fluid of aged canines.
J Alzheimers Dis. 2010;20(2):637-46.
PubMed.
Klein DM, Felsenstein KM, Brenneman DE.
Cathepsins B and L differentially regulate amyloid precursor protein processing.
J Pharmacol Exp Ther. 2009 Mar;328(3):813-21.
PubMed.
BACE1 inhibitor developers should take note of this paper by Rajapaksha et al. It is a novel finding that raises valid questions about potential BACE1 inhibitor drugs. Rajapaksha and colleagues looked only into the olfactory system. It's a good start that provided very interesting results; however, investigators should look into effects of BACE1 in more critical areas of the brain.
Comments
AstraZeneca
This study by Rajapaksha et al. provides novel, very interesting, and important insights to the role of BACE in Neurobiology. Rajapaksha and coauthors applied an elegant genetic approach to explore the role of BACE in the olfactory system. Analysis of BACE-/- mice revealed smaller olfactory bulbs and mistargeted olfactory sensory neurons (OSNs), suggesting that BACE is involved in the process of axonal guidance of OSNs. The data are intriguing and, as the authors state in the paper, it will be interesting to learn whether the neuronal phenotype also impacts olfactory function, whether BACE plays a similar role in other neuronal subtypes, and what are the substrates/signaling pathways involved that cause the phenotype. From other BACE gene targeting studies (1), we have learned that only a limited decrease in BACE activity (BACE+/- mice) is sufficient to affect the development of amyloid pathology. It will therefore be interesting to learn whether the OSN phenotype is also present in BACE+/- mice and, from a drug discovery perspective, whether small molecule-mediated inhibition of BACE, at doses efficacious in lowering Aβ production, has any impact on the sensory neuronal network of the olfactory system.
References:
McConlogue L, Buttini M, Anderson JP, Brigham EF, Chen KS, Freedman SB, Games D, Johnson-Wood K, Lee M, Zeller M, Liu W, Motter R, Sinha S. Partial reduction of BACE1 has dramatic effects on Alzheimer plaque and synaptic pathology in APP Transgenic Mice. J Biol Chem. 2007 Sep 7;282(36):26326-34. PubMed.
University of California, San Diego
This article by Mattsson et al. is authored by an outstanding group, which investigated the effects of BACE1 inhibitors on Aβ peptide forms in media secreted from cultured neurons and in CSF after in-vivo treatment of dogs. Interestingly, the data suggest that the BACE1 inhibitors result in an altered Aβ peptide pattern, with an increase in the ratio of Aβ5-40:Aβ1-34. However, several aspects of the study should be carefully considered. Firstly, the wide range of dog ages, and the few number of dogs per group, make conclusions from the data difficult, since it is known that Aβ levels in CSF differ depending on the age of the dog (Head et al., 2010). Secondly, because a cocktail of protease inhibitors was not included in sample preparations, it is not known if the profiles of Aβ peptides observed are from the endogenous condition or if they became degraded during the in-vitro methods. Thirdly, use of standards for quantitative mass spectrometry is typical in the field, but standards were not evident in this study. Fourthly, the cell culture data reflect only Aβ produced in the constitutive, and not regulated, secretory pathway; since a major portion of Aβ is released from the regulated secretory pathway, which utilizes cathepsin B for Aβ production (Klein et al., 2009), nothing can be inferred regarding the role of cathepsin B in producing Aβ from the study’s finding that an inhibitor of cathepsin B had no effect on constitutive Aβ secretion. Finally, the authors should indicate whether they, or other groups, have data indicating that BACE1 inhibitors improve memory deficits, the critical goal of Alzheimer’s therapeutics. It will be of interest for the authors to continue these studies to examine these important features of Aβ research.
References:
Head E, Pop V, Sarsoza F, Kayed R, Beckett TL, Studzinski CM, Tomic JL, Glabe CG, Murphy MP. Amyloid-beta peptide and oligomers in the brain and cerebrospinal fluid of aged canines. J Alzheimers Dis. 2010;20(2):637-46. PubMed.
Klein DM, Felsenstein KM, Brenneman DE. Cathepsins B and L differentially regulate amyloid precursor protein processing. J Pharmacol Exp Ther. 2009 Mar;328(3):813-21. PubMed.
View all comments by Vivian HookBACE1 inhibitor developers should take note of this paper by Rajapaksha et al. It is a novel finding that raises valid questions about potential BACE1 inhibitor drugs. Rajapaksha and colleagues looked only into the olfactory system. It's a good start that provided very interesting results; however, investigators should look into effects of BACE1 in more critical areas of the brain.
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