The β‐secretase (BACE) inhibitor NB‐360 in preclinical models: From amyloid‐β reduction to downstream disease‐relevant effects

Neumann, Ulf; Machauer, Rainer; Shimshek, Derya R.

doi:10.1111/bph.14582

Cited by 20 publications

(25 citation statements)

References 93 publications

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“…2e-h, Supplementary Table 4). To test whether increased Aβ levels also contribute to PV neuron hyperexcitability in vivo, APP/PS1-PV-Cre mice were treated for 6 weeks with NB-360, a potent BACE1 inhibitor that reduces Aβ levels and amyloid pathology and rescues neuronal network and behavioral deficits in mouse models of AD [39][40][41][42]. Mice were sacrificed directly following the treatment, at 15-17 weeks of age ( Fig.…”

Section: Early Hippocampal Pv Interneuron Hyperexcitability In App/psmentioning

confidence: 99%

Early restoration of parvalbumin interneuron activity prevents memory loss and network hyperexcitability in a mouse model of Alzheimer’s disease

et al. 2019

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Neuronal network dysfunction is increasingly recognized as an early symptom in Alzheimer's disease (AD) and may provide new entry points for diagnosis and intervention. Here, we show that amyloid-beta-induced hyperexcitability of hippocampal inhibitory parvalbumin (PV) interneurons importantly contributes to neuronal network dysfunction and memory impairment in APP/PS1 mice, a mouse model of increased amyloidosis. We demonstrate that hippocampal PV interneurons become hyperexcitable at~16 weeks of age, when no changes are observed yet in the intrinsic properties of pyramidal cells. This hyperexcitable state of PV interneurons coincides with increased inhibitory transmission onto hippocampal pyramidal neurons and deficits in spatial learning and memory. We show that treatment aimed at preventing PV interneurons from becoming hyperexcitable is sufficient to restore PV interneuron properties to wild-type levels, reduce inhibitory input onto pyramidal cells, and rescue memory deficits in APP/PS1 mice. Importantly, we demonstrate that early intervention aimed at restoring PV interneuron activity has long-term beneficial effects on memory and hippocampal network activity, and reduces amyloid plaque deposition, a hallmark of AD pathology. Taken together, these findings suggest that early treatment of PV interneuron hyperactivity might be clinically relevant in preventing memory decline and delaying AD progression.

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Section: Early Hippocampal Pv Interneuron Hyperexcitability In App/psmentioning

confidence: 99%

Early restoration of parvalbumin interneuron activity prevents memory loss and network hyperexcitability in a mouse model of Alzheimer’s disease

et al. 2019

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“…The BACEi NB-360 [71,72] was obtained from Novartis Institutes for BioMedical Research. It was added to bacon flavored chow (S7334, Rodent Diet, Grain-base (5053); Bio-Serv) at 0.5 g/kg chow.…”

Section: Bacei Treatmentmentioning

confidence: 99%

“…To further explore the relationship between functional abnormalities and APP metabolites, we treated J20 mice with a BACE1 inhibitor (NB-360) [71,72]. We selected the J20 line for this experiment because it consistently shows robust levels of network dysfunction and behavioral deficits.…”

Section: Bace1 Inhibition Does Not Reduce Functional Abnormalities Inmentioning

confidence: 99%

Behavioral and neural network abnormalities in human APP transgenic mice resemble those of App knock-in mice and are modulated by familial Alzheimer’s disease mutations but not by inhibition of BACE1

Johnson

et al. 2020

Mol Neurodegeneration

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Background Alzheimer’s disease (AD) is the most frequent and costly neurodegenerative disorder. Although diverse lines of evidence suggest that the amyloid precursor protein (APP) is involved in its causation, the precise mechanisms remain unknown and no treatments are available to prevent or halt the disease. A favorite hypothesis has been that APP contributes to AD pathogenesis through the cerebral accumulation of the amyloid-β peptide (Aβ), which is derived from APP through sequential proteolytic cleavage by BACE1 and γ-secretase. However, inhibitors of these enzymes have failed in clinical trials despite clear evidence for target engagement. Methods To further elucidate the roles of APP and its metabolites in AD pathogenesis, we analyzed transgenic mice overexpressing wildtype human APP (hAPP) or hAPP carrying mutations that cause autosomal dominant familial AD (FAD), as well as App knock-in mice that do not overexpress hAPP but have two mouse App alleles with FAD mutations and a humanized Aβ sequence. Results Although these lines of mice had marked differences in cortical and hippocampal levels of APP, APP C-terminal fragments, soluble Aβ, Aβ oligomers and age-dependent amyloid deposition, they all developed cognitive deficits as well as non-convulsive epileptiform activity, a type of network dysfunction that also occurs in a substantive proportion of humans with AD. Pharmacological inhibition of BACE1 effectively reduced levels of amyloidogenic APP C-terminal fragments (C99), soluble Aβ, Aβ oligomers, and amyloid deposits in transgenic mice expressing FAD-mutant hAPP, but did not improve their network dysfunction and behavioral abnormalities, even when initiated at early stages before amyloid deposits were detectable. Conclusions hAPP transgenic and App knock-in mice develop similar pathophysiological alterations. APP and its metabolites contribute to AD-related functional alterations through complex combinatorial mechanisms that may be difficult to block with BACE inhibitors and, possibly, also with other anti-Aβ treatments.

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“…No benefits and reported undesirable side effects could indicate the first. However, BACE1 inhibitors reduce Aβ brain load and associated inflammation [ 185 ]. According to Alzforum, people on the drug also scored better than placebo on language tests [ 133 ].…”

Section: Concluding Remarks and Future Perspectivesmentioning

confidence: 99%

Is It the Twilight of BACE1 Inhibitors?

Hrabinová

Pejchal

Kučera

et al. 2020

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: β-secretase (BACE1) has been regarded as a prime target for the development of amyloid beta (Aβ) lowering drugs in the therapy of Alzheimer´s disease (AD). Although the enzyme was discovered in 1991 and helped to formulate the Aβ hypothesis as one of the very important features of AD etiopathogenesis, progress in AD treatment utilizing BACE1 inhibitors has remained limited. Moreover, in the last years, major pharmaceutical companies have discontinued clinical trials of five BACE1 inhibitors that had been strongly perceived as prospective. In our review, the Aβ hypothesis, the enzyme, its functions, and selected substrates are described. BACE1 inhibitors are classified into four generations. Those that underwent clinical trials displayed adverse effects, including weight loss, skin rashes, worsening of neuropsychiatric symptoms, etc. Some inhibitors could not establish a statistically significant risk-benefit ratio, or even scored worse than placebo. We still believe that drugs targeting BACE1 may still hide some potential, but a different approach to BACE1 inhibition or a shift of focus to modulation of its trafficking and/or post-translational modification should now be followed.

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The β‐secretase (BACE) inhibitor NB‐360 in preclinical models: From amyloid‐β reduction to downstream disease‐relevant effects

Cited by 20 publications

References 93 publications

Early restoration of parvalbumin interneuron activity prevents memory loss and network hyperexcitability in a mouse model of Alzheimer’s disease

Early restoration of parvalbumin interneuron activity prevents memory loss and network hyperexcitability in a mouse model of Alzheimer’s disease

Behavioral and neural network abnormalities in human APP transgenic mice resemble those of App knock-in mice and are modulated by familial Alzheimer’s disease mutations but not by inhibition of BACE1

Is It the Twilight of BACE1 Inhibitors?

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