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Beta Secretase

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Robert Vassar – 1st expert on this subject based on the ideXlab platform

  • Beta–Secretase, APP and ABeta in Alzheimer’s disease.
    Sub-cellular biochemistry, 2020
    Co-Authors: Robert Vassar

    Abstract:

    Amyloid plaques, hallmark neuropathological lesions in Alzheimer’s disease (AD) brain, are composed of the Beta-amyloid peptide (ABeta). A large body of evidence suggests ABeta is central to the pathophysiology of AD and is likely to start this intractable neurodegenerative disorder. Mutations in three genes (amyloid precursor protein/APP, presenilin1, presenilin2) cause early on-set familial AD by increasing synthesis of the toxic 42 amino acid species of ABeta (ABeta42). Fibrillar ABeta in amyloid plaques appears to cause neurodegeneration, although recent studies suggest soluble ABeta oligomers may also be neurotoxic. Regardless, given the strong correlation between ABeta and AD, therapeutic strategies to lower cerebral ABeta levels should prove beneficial for the treatment of AD. ABeta is derived from APP via cleavage by two proteases, Beta– and gamma-Secretase. Beta–Secretase, recently identified as the novel aspartic protease BACEI, initiates the formation of ABeta. Consequently, BACE1 in principle is an excellent therapeutic target for strategies to reduce the production of ABeta in AD. However, the discovery of the homologue BACE2 raised the question of whether it too may be a Beta–Secretase. To settle this issue, our group and others have used gene targeting to generate BACE1 deficient (knockout) mice. These BACEI knockout mice have been instrumental in validating BACEI as the authentic Beta–Secretase in vivo. Here, I review the roles of BACE1, APP, and ABeta in AD and discuss the implications of therapeutic approaches that target BACE1 for the treatment of AD.

  • BACE1, the Alzheimer’s Beta–Secretase enzyme, in health and disease.
    Molecular Neurodegeneration, 2012
    Co-Authors: Robert Vassar

    Abstract:

    The Beta-amyloid (ABeta) peptide is the major constituent of amyloid plaques in Alzheimer’s disease (AD) brain and is likely to play a central role in the pathogenesis of this devastating neurodegenerative disorder. The Beta–Secretase, Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1; also called Asp2, memapsin 2), is the enzyme responsible for initiating the generation of ABeta. Thus, BACE1 is a prime drug target for the therapeutic inhibition of ABeta production for the treatment or prevention of AD. Since its discovery over 10 years ago, much has been learned about BACE1. This seminar will describe BACE1 properties, physiological functions, and dysregulation in AD. The therapeutic potential of BACE1 inhibitors for AD will also be considered. Particular focus will be placed upon our novel results demonstrating a role of BACE1 in the axon guidance of olfactory sensory neuron axons to specific odorant receptor glomeruli in the olfactory bulb and the therapeutic implications of these findings.

  • bace1 the alzheimer s Beta Secretase enzyme in health and disease
    Molecular Neurodegeneration, 2012
    Co-Authors: Robert Vassar

    Abstract:

    The Beta-amyloid (ABeta) peptide is the major constituent of amyloid plaques in Alzheimer’s disease (AD) brain and is likely to play a central role in the pathogenesis of this devastating neurodegenerative disorder. The Beta–Secretase, Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1; also called Asp2, memapsin 2), is the enzyme responsible for initiating the generation of ABeta. Thus, BACE1 is a prime drug target for the therapeutic inhibition of ABeta production for the treatment or prevention of AD. Since its discovery over 10 years ago, much has been learned about BACE1. This seminar will describe BACE1 properties, physiological functions, and dysregulation in AD. The therapeutic potential of BACE1 inhibitors for AD will also be considered. Particular focus will be placed upon our novel results demonstrating a role of BACE1 in the axon guidance of olfactory sensory neuron axons to specific odorant receptor glomeruli in the olfactory bulb and the therapeutic implications of these findings.

Ping He – 2nd expert on this subject based on the ideXlab platform

  • PET imaging of Beta–Secretase 1 in the human brain: radiation dosimetry, quantification, and test-retest examination of [^18F]PF-06684511
    European Journal of Nuclear Medicine and Molecular Imaging, 2020
    Co-Authors: Ryosuke Arakawa, Akihiro Takano, Per Stenkrona, Vladimir Stepanov, Mahabuba Jahan, Per Grybäck, Martin Bolin, Laigao Chen, Lei Zhang, Ping He

    Abstract:

    Purpose Beta–Secretase 1 (BACE1) enzyme is implicated in the pathophysiology of Alzheimer’s disease. [^18F]PF-06684511 is a positron emission tomography (PET) radioligand for imaging BACE1. Despite favorable brain kinetic properties, the effective dose (ED) of [^18F]PF-06684511 estimated in non-human primates was relatively high. This study was therefore designed to evaluate the whole-body distribution, dosimetry, quantification, and test-retest reliability of imaging brain BACE1 with [^18F]PF-06684511 in healthy volunteers. Methods Five subjects were studied for the dosimetry study. Whole-body PET was performed for 366 min with 4 PET-CT sessions. Estimates of the absorbed radiation dose were calculated using the male adult model. Eight subjects participated in the test-retest study. Brain PET measurements were conducted for 123 min with an interval of 5 to 19 days between test and retest conditions. The total distribution volume ( V _T) was estimated with one-tissue (1T), two-tissue (2T), compartment model (CM), and graphical analysis. Test-retest variability (TRV) and intraclass correlation coefficient (ICC) of V _T were calculated as reliability measures. Results In the dosimetry study, the highest uptake was found in the liver (25.2 ± 2.3 %ID at 0.5 h) and the largest dose was observed in the pancreas (92.9 ± 52.2 μSv/MBq). The calculated ED was 24.7 ± 0.8 μSv/MBq. In the test-retest study, 2TCM described the time-activity curves well. V _T (2TCM) was the highest in the anterior cingulate cortex (6.28 ± 1.09 and 6.85 ± 0.81) and the lowest in the cerebellum (4.23 ± 0.88 and 4.20 ± 0.75). Mean TRV and ICC of V _T (2TCM) were 16.5% (12.4–20.5%) and 0.496 (0.291–0.644). Conclusion The ED of [^18F]PF-06684511 was similar to other ^18F radioligands, allowing repeated PET measurements. 2TCM was the most appropriate quantification method. TRV of V _T was similar to other radioligands without a reference region, albeit with lower ICC. These data indicated that [^18F]PF-06684511 is a suitable radioligand to measure BACE1 level in the human brain. Trial registration EudraCT 2016-001110-19 (registered 2016-08-08)

  • pet imaging of Beta Secretase 1 in the human brain radiation dosimetry quantification and test retest examination of 18f pf 06684511
    European Journal of Nuclear Medicine and Molecular Imaging, 2020
    Co-Authors: Ryosuke Arakawa, Akihiro Takano, Per Stenkrona, Vladimir Stepanov, Mahabuba Jahan, Per Grybäck, Martin Bolin, Laigao Chen, Lei Zhang, Ping He

    Abstract:

    PURPOSE: Beta–Secretase 1 (BACE1) enzyme is implicated in the pathophysiology of Alzheimer’s disease. [18F]PF-06684511 is a positron emission tomography (PET) radioligand for imaging BACE1. Despite favorable brain kinetic properties, the effective dose (ED) of [18F]PF-06684511 estimated in non-human primates was relatively high. This study was therefore designed to evaluate the whole-body distribution, dosimetry, quantification, and test-retest reliability of imaging brain BACE1 with [18F]PF-06684511 in healthy volunteers. METHODS: Five subjects were studied for the dosimetry study. Whole-body PET was performed for 366 min with 4 PET-CT sessions. Estimates of the absorbed radiation dose were calculated using the male adult model. Eight subjects participated in the test-retest study. Brain PET measurements were conducted for 123 min with an interval of 5 to 19 days between test and retest conditions. The total distribution volume (VT) was estimated with one-tissue (1T), two-tissue (2T), compartment model (CM), and graphical analysis. Test-retest variability (TRV) and intraclass correlation coefficient (ICC) of VT were calculated as reliability measures. RESULTS: In the dosimetry study, the highest uptake was found in the liver (25.2 ± 2.3 %ID at 0.5 h) and the largest dose was observed in the pancreas (92.9 ± 52.2 μSv/MBq). The calculated ED was 24.7 ± 0.8 μSv/MBq. In the test-retest study, 2TCM described the time-activity curves well. VT (2TCM) was the highest in the anterior cingulate cortex (6.28 ± 1.09 and 6.85 ± 0.81) and the lowest in the cerebellum (4.23 ± 0.88 and 4.20 ± 0.75). Mean TRV and ICC of VT (2TCM) were 16.5% (12.4-20.5%) and 0.496 (0.291-0.644). CONCLUSION: The ED of [18F]PF-06684511 was similar to other 18F radioligands, allowing repeated PET measurements. 2TCM was the most appropriate quantification method. TRV of VT was similar to other radioligands without a reference region, albeit with lower ICC. These data indicated that [18F]PF-06684511 is a suitable radioligand to measure BACE1 level in the human brain. TRIAL REGISTRATION: EudraCT 2016-001110-19 (registered 2016-08-08).

Ryosuke Arakawa – 3rd expert on this subject based on the ideXlab platform

  • PET imaging of Beta–Secretase 1 in the human brain: radiation dosimetry, quantification, and test-retest examination of [^18F]PF-06684511
    European Journal of Nuclear Medicine and Molecular Imaging, 2020
    Co-Authors: Ryosuke Arakawa, Akihiro Takano, Per Stenkrona, Vladimir Stepanov, Mahabuba Jahan, Per Grybäck, Martin Bolin, Laigao Chen, Lei Zhang, Ping He

    Abstract:

    Purpose Beta–Secretase 1 (BACE1) enzyme is implicated in the pathophysiology of Alzheimer’s disease. [^18F]PF-06684511 is a positron emission tomography (PET) radioligand for imaging BACE1. Despite favorable brain kinetic properties, the effective dose (ED) of [^18F]PF-06684511 estimated in non-human primates was relatively high. This study was therefore designed to evaluate the whole-body distribution, dosimetry, quantification, and test-retest reliability of imaging brain BACE1 with [^18F]PF-06684511 in healthy volunteers. Methods Five subjects were studied for the dosimetry study. Whole-body PET was performed for 366 min with 4 PET-CT sessions. Estimates of the absorbed radiation dose were calculated using the male adult model. Eight subjects participated in the test-retest study. Brain PET measurements were conducted for 123 min with an interval of 5 to 19 days between test and retest conditions. The total distribution volume ( V _T) was estimated with one-tissue (1T), two-tissue (2T), compartment model (CM), and graphical analysis. Test-retest variability (TRV) and intraclass correlation coefficient (ICC) of V _T were calculated as reliability measures. Results In the dosimetry study, the highest uptake was found in the liver (25.2 ± 2.3 %ID at 0.5 h) and the largest dose was observed in the pancreas (92.9 ± 52.2 μSv/MBq). The calculated ED was 24.7 ± 0.8 μSv/MBq. In the test-retest study, 2TCM described the time-activity curves well. V _T (2TCM) was the highest in the anterior cingulate cortex (6.28 ± 1.09 and 6.85 ± 0.81) and the lowest in the cerebellum (4.23 ± 0.88 and 4.20 ± 0.75). Mean TRV and ICC of V _T (2TCM) were 16.5% (12.4–20.5%) and 0.496 (0.291–0.644). Conclusion The ED of [^18F]PF-06684511 was similar to other ^18F radioligands, allowing repeated PET measurements. 2TCM was the most appropriate quantification method. TRV of V _T was similar to other radioligands without a reference region, albeit with lower ICC. These data indicated that [^18F]PF-06684511 is a suitable radioligand to measure BACE1 level in the human brain. Trial registration EudraCT 2016-001110-19 (registered 2016-08-08)

  • pet imaging of Beta Secretase 1 in the human brain radiation dosimetry quantification and test retest examination of 18f pf 06684511
    European Journal of Nuclear Medicine and Molecular Imaging, 2020
    Co-Authors: Ryosuke Arakawa, Akihiro Takano, Per Stenkrona, Vladimir Stepanov, Mahabuba Jahan, Per Grybäck, Martin Bolin, Laigao Chen, Lei Zhang, Ping He

    Abstract:

    PURPOSE: Beta–Secretase 1 (BACE1) enzyme is implicated in the pathophysiology of Alzheimer’s disease. [18F]PF-06684511 is a positron emission tomography (PET) radioligand for imaging BACE1. Despite favorable brain kinetic properties, the effective dose (ED) of [18F]PF-06684511 estimated in non-human primates was relatively high. This study was therefore designed to evaluate the whole-body distribution, dosimetry, quantification, and test-retest reliability of imaging brain BACE1 with [18F]PF-06684511 in healthy volunteers. METHODS: Five subjects were studied for the dosimetry study. Whole-body PET was performed for 366 min with 4 PET-CT sessions. Estimates of the absorbed radiation dose were calculated using the male adult model. Eight subjects participated in the test-retest study. Brain PET measurements were conducted for 123 min with an interval of 5 to 19 days between test and retest conditions. The total distribution volume (VT) was estimated with one-tissue (1T), two-tissue (2T), compartment model (CM), and graphical analysis. Test-retest variability (TRV) and intraclass correlation coefficient (ICC) of VT were calculated as reliability measures. RESULTS: In the dosimetry study, the highest uptake was found in the liver (25.2 ± 2.3 %ID at 0.5 h) and the largest dose was observed in the pancreas (92.9 ± 52.2 μSv/MBq). The calculated ED was 24.7 ± 0.8 μSv/MBq. In the test-retest study, 2TCM described the time-activity curves well. VT (2TCM) was the highest in the anterior cingulate cortex (6.28 ± 1.09 and 6.85 ± 0.81) and the lowest in the cerebellum (4.23 ± 0.88 and 4.20 ± 0.75). Mean TRV and ICC of VT (2TCM) were 16.5% (12.4-20.5%) and 0.496 (0.291-0.644). CONCLUSION: The ED of [18F]PF-06684511 was similar to other 18F radioligands, allowing repeated PET measurements. 2TCM was the most appropriate quantification method. TRV of VT was similar to other radioligands without a reference region, albeit with lower ICC. These data indicated that [18F]PF-06684511 is a suitable radioligand to measure BACE1 level in the human brain. TRIAL REGISTRATION: EudraCT 2016-001110-19 (registered 2016-08-08).