The BACE1 inhibitor verubecestat (MK-8931) reduces CNS β-amyloid in animal models and in Alzheimer’s disease patients

Kennedy, Matthew; Stamford, Andrew W.; Chen, Xia; Cox, Kathleen; Cumming, Jared N.; Dockendorf, Marissa; Egan, Michael; Ereshefsky, Larry; Hodgson, Robert A.; Hyde, Lynn A.; Jhee, Stanford; Kleijn, Huub Jan; Kuvelkar, Reshma; Li, Wei; Mattson, Britta A.; Hong, Mei; Palcza, John; Scott, Jack D.; Tanen, Michael; Troyer, Matthew D.; Tseng, Jack; Stone, Julie A.; Parker, Eric M.; Forman, Mark S.

doi:10.1126/scitranslmed.aad9704

Cited by 370 publications

(365 citation statements)

References 43 publications

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“…Verubecestat (MK-8931) and Lanabecestat (AZD3293) are two representative BACE1 inhibitors under clinical trials. Although phase I and phase II data present exciting benefits on AD models, the preliminary results of phase III trial have failed to meet clinical significance for Verubecestat [324, 325]. Nevertheless, the other oral BACE1 inhibitor Lanabecestat has recently gained support from FDA to further expand its phase III trial, following the data analysis based on early results [326].…”

Section: Discussion and Perspectivementioning

confidence: 99%

Functional analyses of major cancer-related signaling pathways in Alzheimer's disease etiology

Guo

Cheng²,

North

2017

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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Alzheimer’s disease (AD) is an aging-related neurodegenerative disease and accounts for majority of human dementia. The hyper-phosphorylated tau-mediated intracellular neurofibrillary tangle and amyloid β-mediated extracellular senile plaque are characterized as major pathological lesions of AD. Different from the dysregulated growth control and ample genetic mutations associated with human cancers, AD displays damage and death of brain neurons in the absence of genomic alterations. Although various biological processes predominately governing tumorigenesis such as inflammation, metabolic alteration, oxidative stress and insulin resistance have been associated with AD genesis, the mechanistic connection of these biological processes and signaling pathways including mTOR, MAPK, SIRT, HIF, and the FOXO pathway controlling aging and the pathological lesions of AD are not well recapitulated. Hence, we performed a thorough review by summarizing the physiological roles of these key cancer-related signaling pathways in AD pathogenesis, comprising of the crosstalk of these pathways with neurofibrillary tangle and senile plaque formation to impact AD phenotypes. Importantly, the pharmaceutical investigations of anti-aging and AD relevant medications have also been highlighted. In summary, in this review, we discuss the potential role that cancer-related signaling pathways may play in governing the pathogenesis of AD, as well as their potential as future targeted strategies to delay or prevent aging-related diseases and combating AD.

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Section: Discussion and Perspectivementioning

confidence: 99%

Functional analyses of major cancer-related signaling pathways in Alzheimer's disease etiology

Guo

Cheng²,

North

2017

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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“…This is particularly interesting as BACE inhibitors are actively being explored as a therapeutic strategy in AD (Kennedy, et al 2016). Our detection of BACE2 in α cells is in contrast to reports indicating the highest pancreatic BACE2 expression is found within pancreatic β cells (Esterhazy et al 2011; Finzi, et al 2008).…”

Section: Discussionmentioning

confidence: 99%

Amyloid precursor protein in pancreatic islets

Kulas

Puig

Combs

2017

Journal of Endocrinology

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The amyloid precursor protein (APP) has been extensively investigated for its role in the production of amyloid beta (Aβ), a plaque forming peptide in Alzheimer’s disease (AD). Epidemiological evidence suggests type 2 diabetes is a risk factor for AD. The pancreas is an essential regulator of blood glucose levels through the secretion of the hormones insulin and glucagon. Pancreatic dysfunction is a well characterized consequence of type 1 and type 2 diabetes. In this study we have examined the expression and processing of pancreatic APP to test the hypothesis that APP may play a role in pancreatic function and the pathophysiology of diabetes. Our data demonstrates the presence of APP within the pancreas, including pancreatic islets in both mouse and human samples. Additionally, we report that the APP/PS1 mouse model of AD overexpresses APP within pancreatic islets, although this did not result in detectable levels of Aβ. We compared whole pancreas and islet culture lysates by western blot from C57BL/6 (WT), APP−/−, and APP/PS1 mice and observed APP-dependent differences in the total protein levels of GLUT4, IDE and BACE2. Immunohistochemistry for BACE2 detected high levels in pancreatic α cells. Additionally, both mouse and human islets processed APP to release sAPP into cell culture media. Moreover, sAPP stimulated insulin but not glucagon secretion from islet cultures. We conclude that APP and its metabolites are capable of influencing the basic physiology of the pancreas, possibly through the release of sAPP acting in an autocrine or paracrine manner.

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“…Based on the high potency of BACE inhibitors in reducing brain Aβ levels (30), several compounds are currently either in preparation for or in use in clinical trials. Although these ongoing clinical trials have not reported any major safety issues so far, there remain some concerns about potential (and perhaps subtler) side effects.…”

Section: Discussionmentioning

confidence: 99%

BACE inhibition-dependent repair of Alzheimer’s pathophysiology

Keskin

Kekuš

Adelsberger

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

111

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Amyloid-β (Aβ) is thought to play an essential pathogenic role in Alzheimer´s disease (AD). A key enzyme involved in the generation of Aβ is the β-secretase BACE, for which powerful inhibitors have been developed and are currently in use in human clinical trials. However, although BACE inhibition can reduce cerebral Aβ levels, whether it also can ameliorate neural circuit and memory impairments remains unclear. Using histochemistry, in vivo Ca 2+ imaging, and behavioral analyses in a mouse model of AD, we demonstrate that along with reducing prefibrillary Aβ surrounding plaques, the inhibition of BACE activity can rescue neuronal hyperactivity, impaired long-range circuit function, and memory defects. The functional neuronal impairments reappeared after infusion of soluble Aβ, mechanistically linking Aβ pathology to neuronal and cognitive dysfunction. These data highlight the potential benefits of BACE inhibition for the effective treatment of a wide range of AD-like pathophysiological and cognitive impairments.A lzheimer´s disease (AD) is the most common cause of dementia globally, with an increasing impact on aging societies (1). Therefore, the prevention and treatment of AD is a major unmet medical need. The amyloid hypothesis posits that the abnormal accumulation of amyloid-β (Aβ) peptides in the brain, and their aggregation, is an essential feature of AD (2, 3); however, results from clinical studies using several Aβ-targeting compounds have called into question the existence of a direct link between a reduction in Aβ and improvement of brain function, particularly in more advanced disease stages (4-6). In addition, recent evidence obtained in mouse models carrying genetic mutations that cause AD in humans revealed that immunotherapy with antibodies against Aβ worsened rather than reversed neuronal dysfunction (7). Despite reducing plaque burden, the anti-Aβ antibodies caused a massive increase in cortical hyperactivity and promoted abnormal synchrony of neurons in a subset of the treated mice. In this context, it is noteworthy that another recent mouse study found an increased risk of sudden death after anti-Aβ antibody treatment, which was attributed to enhanced excitatory neuronal activity culminating in fatal convulsive seizures (8).To clarify the causal relationship between Aβ and pathophysiology in vivo, we made use of a novel compound that reduces Aβ by inhibiting the β-secretase BACE, the rate-limiting enzyme for Aβ production (9). This approach allowed us to determine how the inhibition of Aβ production affects neural circuit and memory impairments in APP23xPS45 transgenic mice overexpressing mutant human amyloid precursor protein (APP) and presenilin 1 (PS1). The combination of histochemistry, in vivo Ca 2+ imaging, and behavioral analysis allowed us to directly link the treatment-related changes in brain Aβ levels to changes in neuronal and cognitive functions in individual mice. ResultsIn this study, we used 6-to 8-mo-old APP23xPS45 transgenic mice that exhibit severe cerebral Aβ pathology, neur...

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The BACE1 inhibitor verubecestat (MK-8931) reduces CNS β-amyloid in animal models and in Alzheimer’s disease patients

Cited by 370 publications

References 43 publications

Functional analyses of major cancer-related signaling pathways in Alzheimer's disease etiology

Functional analyses of major cancer-related signaling pathways in Alzheimer's disease etiology

Amyloid precursor protein in pancreatic islets

BACE inhibition-dependent repair of Alzheimer’s pathophysiology

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