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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

Immunohistochemistry for deposited Aβ of APP51/16 mice; a-c examples of mouse cerebral cortex. a Baseline, b vehicle, c: NB-360-treated mice. d Illustration of the separation of large plaques, small plaques and intracellular granules; continuous arrow > large plaque; dashed arrow > small plaque; dotted arrow > granules. Size bar = 200 μm. e-g Quantification of cortex area stained positively with NT12 numbers are the sum of deposits in three adjacent sagittal sections, e large plaques, f small plaques, g small deposits
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Fig5: Immunohistochemistry for deposited Aβ of APP51/16 mice; a-c examples of mouse cerebral cortex. a Baseline, b vehicle, c: NB-360-treated mice. d Illustration of the separation of large plaques, small plaques and intracellular granules; continuous arrow > large plaque; dashed arrow > small plaque; dotted arrow > granules. Size bar = 200 μm. e-g Quantification of cortex area stained positively with NT12 numbers are the sum of deposits in three adjacent sagittal sections, e large plaques, f small plaques, g small deposits

Mentions: For histological analysis, brain cortical slices were stained with our in house Aβ antiserum NT12. The total area of the cortical region of interest that stained positively for NT12 was significantly higher in the vehicle group (0.754 ± 0.074 %, mean ± SEM), compared to the baseline (0.323 ± 0.031 %, p = 0.0012). There was no statistical difference between the baseline and NB-360 treatment group (0.209 ± 0.054 %, p = 0.093 vs baseline, p <0.0001 vs vehicle). For a more detailed analysis, Aβ deposits were categorized into large plaques, small plaques and small, mainly intracellular granules, and each size group was analyzed separately and expressed as the number of structures per 3 para-sagittal cortical sections. Irrespective of the deposit size, the vehicle-treated animals showed a substantial increase, compared to baseline, and again the NB-360 treated animals were indistinguishable from baseline (Fig. 5).Fig. 5


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)

Immunohistochemistry for deposited Aβ of APP51/16 mice; a-c examples of mouse cerebral cortex. a Baseline, b vehicle, c: NB-360-treated mice. d Illustration of the separation of large plaques, small plaques and intracellular granules; continuous arrow > large plaque; dashed arrow > small plaque; dotted arrow > granules. Size bar = 200 μm. e-g Quantification of cortex area stained positively with NT12 numbers are the sum of deposits in three adjacent sagittal sections, e large plaques, f small plaques, g small deposits
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig5: Immunohistochemistry for deposited Aβ of APP51/16 mice; a-c examples of mouse cerebral cortex. a Baseline, b vehicle, c: NB-360-treated mice. d Illustration of the separation of large plaques, small plaques and intracellular granules; continuous arrow > large plaque; dashed arrow > small plaque; dotted arrow > granules. Size bar = 200 μm. e-g Quantification of cortex area stained positively with NT12 numbers are the sum of deposits in three adjacent sagittal sections, e large plaques, f small plaques, g small deposits
Mentions: For histological analysis, brain cortical slices were stained with our in house Aβ antiserum NT12. The total area of the cortical region of interest that stained positively for NT12 was significantly higher in the vehicle group (0.754 ± 0.074 %, mean ± SEM), compared to the baseline (0.323 ± 0.031 %, p = 0.0012). There was no statistical difference between the baseline and NB-360 treatment group (0.209 ± 0.054 %, p = 0.093 vs baseline, p <0.0001 vs vehicle). For a more detailed analysis, Aβ deposits were categorized into large plaques, small plaques and small, mainly intracellular granules, and each size group was analyzed separately and expressed as the number of structures per 3 para-sagittal cortical sections. Irrespective of the deposit size, the vehicle-treated animals showed a substantial increase, compared to baseline, and again the NB-360 treated animals were indistinguishable from baseline (Fig. 5).Fig. 5

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