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A novel BACE inhibitor NB-360 shows a superior pharmacological profile and robust reduction of amyloid-β and neuroinflammation in APP transgenic mice.

Neumann U, Rueeger H, Machauer R, Veenstra SJ, Lueoend RM, Tintelnot-Blomley M, Laue G, Beltz K, Vogg B, Schmid P, Frieauff W, Shimshek DR, Staufenbiel M, Jacobson LH - Mol Neurodegener (2015)

Bottom Line: Current symptomatic treatments delay, but do not halt, disease progression.Data across species suggest similar treatment effects can possibly be achieved in humans.The reduced neuroinflammation upon amyloid reduction by NB-360 treatment supports the notion that targeting amyloid-β pathology can have beneficial downstream effects on the progression of Alzheimer's disease.

View Article: PubMed Central - PubMed

Affiliation: Neuroscience, Novartis Institutes for BioMedical Research (NIBR), Basel, Switzerland. ulf.neumann@novartis.com.

ABSTRACT

Background: Alzheimer's disease (AD) is the most common form of dementia, the number of affected individuals is rising, with significant impacts for healthcare systems. Current symptomatic treatments delay, but do not halt, disease progression. Genetic evidence points to aggregation and deposition of amyloid-β (Aβ) in the brain being causal for the neurodegeneration and dementia typical of AD. Approaches to target Aβ via inhibition of γ-secretase or passive antibody therapy have not yet resulted in substantial clinical benefits. Inhibition of BACE1 (β-secretase) has proven a challenging concept, but recent BACE1inhibitors can enter the brain sufficiently well to lower Aβ. However, failures with the first clinical BACE1 inhibitors have highlighted the need to generate compounds with appropriate efficacy and safety profiles, since long treatment periods are expected to be necessary in humans.

Results: Treatment with NB-360, a potent and brain penetrable BACE-1 inhibitor can completely block the progression of Aβ deposition in the brains of APP transgenic mice, a model for amyloid pathology. We furthermore show that almost complete reduction of Aβ was achieved also in rats and in dogs, suggesting that these findings are translational across species and can be extrapolated to humans. Amyloid pathology may be an initial step in a complex pathological cascade; therefore we investigated the effect of BACE-1 inhibition on neuroinflammation, a prominent downstream feature of the disease. NB-360 stopped accumulation of activated inflammatory cells in the brains of APP transgenic mice. Upon chronic treatment of APP transgenic mice, patches of grey hairs appeared.

Conclusions: In a rapidly developing field, the data on NB-360 broaden the chemical space and expand knowledge on the properties that are needed to make a BACE-1 inhibitor potent and safe enough for long-term use in patients. Due to its excellent brain penetration, reasonable oral doses of NB-360 were sufficient to completely block amyloid-β deposition in an APP transgenic mouse model. Data across species suggest similar treatment effects can possibly be achieved in humans. The reduced neuroinflammation upon amyloid reduction by NB-360 treatment supports the notion that targeting amyloid-β pathology can have beneficial downstream effects on the progression of Alzheimer's disease.

No MeSH data available.


Related in: MedlinePlus

Effect of NB-360 on APP metabolites in APP51/16 mice, measured in Triton X100 extract 4 and 24 h after the last dose of a 6 week study (100 μmol/kg/d p.o.). a Aβ40, Aβ42, and sAPPβ in CSF, b Aβ40 in plasma, c Example of forebrain samples on Western blot stained with C-terminal APP antibody (green) and N-terminal Aβ antibody (red). B: baseline, 14.5 mo, V: vehicle 16 mo, T: treatment with NB-360, d quantification of Western blot data for C83 and C99. e MSD-immunoassay results for full-length APP, sAPPα, and sAPPβ in TX-100 forebrain extract. Data are means ± SEM, n = 8-17, all comparisons done against vehicle group
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Fig4: Effect of NB-360 on APP metabolites in APP51/16 mice, measured in Triton X100 extract 4 and 24 h after the last dose of a 6 week study (100 μmol/kg/d p.o.). a Aβ40, Aβ42, and sAPPβ in CSF, b Aβ40 in plasma, c Example of forebrain samples on Western blot stained with C-terminal APP antibody (green) and N-terminal Aβ antibody (red). B: baseline, 14.5 mo, V: vehicle 16 mo, T: treatment with NB-360, d quantification of Western blot data for C83 and C99. e MSD-immunoassay results for full-length APP, sAPPα, and sAPPβ in TX-100 forebrain extract. Data are means ± SEM, n = 8-17, all comparisons done against vehicle group

Mentions: NB-360 exposure in APP51/16 mouse blood was 3.2 μM at 4 h after the last dose, and declined to 0.13 μM over the next 20 h. Concentrations of soluble APP metabolites in the CSF were determined at 4 and 24 h. The effect on the BACE-1 dependent APP metabolites correlated with exposure, with Aβ40 and Aβ42 showing > 90 % reduction 4 h after the dose, and about 60 % at 24 h. Soluble APPβ (sAPPβ) had a slightly different profile, with less pronounced reduction at 4 h, but stronger effect towards 24 h (Fig. 4a). As an overall measure of daily efficacy within a repeated dosing study, we calculated an approximate area under the effect curve for the 24 h period after the last dose (AUEC24h from 0, 4, 24 h time points). CSF Aβ40, Aβ42, and sAPPβ showed almost identical efficacy of approximately 75 % reduction. Plasma Aβ40 showed a lower efficacy at the 4 h time point, with an overall AUEC24h of 70 % reduction (Fig. 4b).Fig. 4


A novel BACE inhibitor NB-360 shows a superior pharmacological profile and robust reduction of amyloid-β and neuroinflammation in APP transgenic mice.

Neumann U, Rueeger H, Machauer R, Veenstra SJ, Lueoend RM, Tintelnot-Blomley M, Laue G, Beltz K, Vogg B, Schmid P, Frieauff W, Shimshek DR, Staufenbiel M, Jacobson LH - Mol Neurodegener (2015)

Effect of NB-360 on APP metabolites in APP51/16 mice, measured in Triton X100 extract 4 and 24 h after the last dose of a 6 week study (100 μmol/kg/d p.o.). a Aβ40, Aβ42, and sAPPβ in CSF, b Aβ40 in plasma, c Example of forebrain samples on Western blot stained with C-terminal APP antibody (green) and N-terminal Aβ antibody (red). B: baseline, 14.5 mo, V: vehicle 16 mo, T: treatment with NB-360, d quantification of Western blot data for C83 and C99. e MSD-immunoassay results for full-length APP, sAPPα, and sAPPβ in TX-100 forebrain extract. Data are means ± SEM, n = 8-17, all comparisons done against vehicle group
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4559881&req=5

Fig4: Effect of NB-360 on APP metabolites in APP51/16 mice, measured in Triton X100 extract 4 and 24 h after the last dose of a 6 week study (100 μmol/kg/d p.o.). a Aβ40, Aβ42, and sAPPβ in CSF, b Aβ40 in plasma, c Example of forebrain samples on Western blot stained with C-terminal APP antibody (green) and N-terminal Aβ antibody (red). B: baseline, 14.5 mo, V: vehicle 16 mo, T: treatment with NB-360, d quantification of Western blot data for C83 and C99. e MSD-immunoassay results for full-length APP, sAPPα, and sAPPβ in TX-100 forebrain extract. Data are means ± SEM, n = 8-17, all comparisons done against vehicle group
Mentions: NB-360 exposure in APP51/16 mouse blood was 3.2 μM at 4 h after the last dose, and declined to 0.13 μM over the next 20 h. Concentrations of soluble APP metabolites in the CSF were determined at 4 and 24 h. The effect on the BACE-1 dependent APP metabolites correlated with exposure, with Aβ40 and Aβ42 showing > 90 % reduction 4 h after the dose, and about 60 % at 24 h. Soluble APPβ (sAPPβ) had a slightly different profile, with less pronounced reduction at 4 h, but stronger effect towards 24 h (Fig. 4a). As an overall measure of daily efficacy within a repeated dosing study, we calculated an approximate area under the effect curve for the 24 h period after the last dose (AUEC24h from 0, 4, 24 h time points). CSF Aβ40, Aβ42, and sAPPβ showed almost identical efficacy of approximately 75 % reduction. Plasma Aβ40 showed a lower efficacy at the 4 h time point, with an overall AUEC24h of 70 % reduction (Fig. 4b).Fig. 4

Bottom Line: Current symptomatic treatments delay, but do not halt, disease progression.Data across species suggest similar treatment effects can possibly be achieved in humans.The reduced neuroinflammation upon amyloid reduction by NB-360 treatment supports the notion that targeting amyloid-β pathology can have beneficial downstream effects on the progression of Alzheimer's disease.

View Article: PubMed Central - PubMed

Affiliation: Neuroscience, Novartis Institutes for BioMedical Research (NIBR), Basel, Switzerland. ulf.neumann@novartis.com.

ABSTRACT

Background: Alzheimer's disease (AD) is the most common form of dementia, the number of affected individuals is rising, with significant impacts for healthcare systems. Current symptomatic treatments delay, but do not halt, disease progression. Genetic evidence points to aggregation and deposition of amyloid-β (Aβ) in the brain being causal for the neurodegeneration and dementia typical of AD. Approaches to target Aβ via inhibition of γ-secretase or passive antibody therapy have not yet resulted in substantial clinical benefits. Inhibition of BACE1 (β-secretase) has proven a challenging concept, but recent BACE1inhibitors can enter the brain sufficiently well to lower Aβ. However, failures with the first clinical BACE1 inhibitors have highlighted the need to generate compounds with appropriate efficacy and safety profiles, since long treatment periods are expected to be necessary in humans.

Results: Treatment with NB-360, a potent and brain penetrable BACE-1 inhibitor can completely block the progression of Aβ deposition in the brains of APP transgenic mice, a model for amyloid pathology. We furthermore show that almost complete reduction of Aβ was achieved also in rats and in dogs, suggesting that these findings are translational across species and can be extrapolated to humans. Amyloid pathology may be an initial step in a complex pathological cascade; therefore we investigated the effect of BACE-1 inhibition on neuroinflammation, a prominent downstream feature of the disease. NB-360 stopped accumulation of activated inflammatory cells in the brains of APP transgenic mice. Upon chronic treatment of APP transgenic mice, patches of grey hairs appeared.

Conclusions: In a rapidly developing field, the data on NB-360 broaden the chemical space and expand knowledge on the properties that are needed to make a BACE-1 inhibitor potent and safe enough for long-term use in patients. Due to its excellent brain penetration, reasonable oral doses of NB-360 were sufficient to completely block amyloid-β deposition in an APP transgenic mouse model. Data across species suggest similar treatment effects can possibly be achieved in humans. The reduced neuroinflammation upon amyloid reduction by NB-360 treatment supports the notion that targeting amyloid-β pathology can have beneficial downstream effects on the progression of Alzheimer's disease.

No MeSH data available.


Related in: MedlinePlus