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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 treatment on the number of GFAP-positive astrocytes and Iba-1 positive microglia cell clusters illustrating accumulation of astrocytes and microglia in the vicinity of amyloid plaques. a Triple staining of cerebral cortex for aggregated Aβ (blue), GFAP (red) and Iba-1 (green). b Quantitative analysis of GFAP+ and Iba-1+ clusters in cortex. Shown are mean ± SEM, **p < 0.01 (Dunnett’s multiple comparisons test) c: correlation of total Aβ stained area in cortex with GFAP+ clusters. d Correlation of total stained Aβ area in cortex with Iba-1+ clusters. Solid line represents the linear fit, and dashed lines the 95 % confidence interval
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Fig6: Effect of NB-360 treatment on the number of GFAP-positive astrocytes and Iba-1 positive microglia cell clusters illustrating accumulation of astrocytes and microglia in the vicinity of amyloid plaques. a Triple staining of cerebral cortex for aggregated Aβ (blue), GFAP (red) and Iba-1 (green). b Quantitative analysis of GFAP+ and Iba-1+ clusters in cortex. Shown are mean ± SEM, **p < 0.01 (Dunnett’s multiple comparisons test) c: correlation of total Aβ stained area in cortex with GFAP+ clusters. d Correlation of total stained Aβ area in cortex with Iba-1+ clusters. Solid line represents the linear fit, and dashed lines the 95 % confidence interval

Mentions: We investigated activated microglia cells (stained with anti-Iba1) and astrocytes (stained with anti-GFAP) in APP51/16 cerebral cortex. Triple staining for Aβ deposits and activated astrocytes/microglia cells showed activated cells were present in the vicinity of large, but also small Aβ deposits in the cortex (Fig. 6a). During the 6 weeks treatment period, clusters of neuroinflammation increased substantially in the vehicle compared to the baseline group (Fig. 6b). The number of GFAP positive and Iba-1 positive cell clusters in the cortex was substantially lower in NB-360 treated APP51/16 mice relative to vehicle-treated mice, reaching values comparable to the baseline group. We also investigated a possible correlation between total plaque load, and the Iba1+ and GFAP+ cell clusters and determined a significant correlation (r2 = 0.77 and 0.70 respectively, p < 0.0001). As shown in Fig. 6c and 6d, the number of activated innate immune cells in the brain correlated with the extent of amyloid deposition.Fig. 6


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 treatment on the number of GFAP-positive astrocytes and Iba-1 positive microglia cell clusters illustrating accumulation of astrocytes and microglia in the vicinity of amyloid plaques. a Triple staining of cerebral cortex for aggregated Aβ (blue), GFAP (red) and Iba-1 (green). b Quantitative analysis of GFAP+ and Iba-1+ clusters in cortex. Shown are mean ± SEM, **p < 0.01 (Dunnett’s multiple comparisons test) c: correlation of total Aβ stained area in cortex with GFAP+ clusters. d Correlation of total stained Aβ area in cortex with Iba-1+ clusters. Solid line represents the linear fit, and dashed lines the 95 % confidence interval
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig6: Effect of NB-360 treatment on the number of GFAP-positive astrocytes and Iba-1 positive microglia cell clusters illustrating accumulation of astrocytes and microglia in the vicinity of amyloid plaques. a Triple staining of cerebral cortex for aggregated Aβ (blue), GFAP (red) and Iba-1 (green). b Quantitative analysis of GFAP+ and Iba-1+ clusters in cortex. Shown are mean ± SEM, **p < 0.01 (Dunnett’s multiple comparisons test) c: correlation of total Aβ stained area in cortex with GFAP+ clusters. d Correlation of total stained Aβ area in cortex with Iba-1+ clusters. Solid line represents the linear fit, and dashed lines the 95 % confidence interval
Mentions: We investigated activated microglia cells (stained with anti-Iba1) and astrocytes (stained with anti-GFAP) in APP51/16 cerebral cortex. Triple staining for Aβ deposits and activated astrocytes/microglia cells showed activated cells were present in the vicinity of large, but also small Aβ deposits in the cortex (Fig. 6a). During the 6 weeks treatment period, clusters of neuroinflammation increased substantially in the vehicle compared to the baseline group (Fig. 6b). The number of GFAP positive and Iba-1 positive cell clusters in the cortex was substantially lower in NB-360 treated APP51/16 mice relative to vehicle-treated mice, reaching values comparable to the baseline group. We also investigated a possible correlation between total plaque load, and the Iba1+ and GFAP+ cell clusters and determined a significant correlation (r2 = 0.77 and 0.70 respectively, p < 0.0001). As shown in Fig. 6c and 6d, the number of activated innate immune cells in the brain correlated with the extent of amyloid deposition.Fig. 6

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