AβPP-Selective BACE Inhibitors (ASBI): Novel Class of Therapeutic Agents for Alzheimer's Disease

Descamps, Olivier; Spilman, Patricia; Zhang, Qiang; Libeu, Clare Peters; Poksay, Karen S.; Gorostiza, Olivia; Campagna, Jesus; Jagodzinska, Barbara; Bredesen, Dale E.; John, Varghese

doi:10.3233/jad-130578

Cited by 23 publications

(17 citation statements)

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“…BACE inhibitor IV completely eliminated BACE1 cleavage of the APP-C140 substrate, in contrast to Gleevec, which had no effect at all concentrations tested, thus again ruling out a direct inhibitory effect of Gleevec on BACE1 or an indirect effect through interaction with APP. Interestingly, it has been reported that a series of benzofuran-containing compounds selectively inhibit BACE processing of APP in vitro by binding directly to APP around the BACE cleavage site (17), and another study involving two flavonoid compounds reported similar results (18). It is unlikely that Gleevec inhibits BACE cleavage of APP by the same mechanism, however.…”

Section: Resultsmentioning

confidence: 94%

Gleevec shifts APP processing from a β-cleavage to a nonamyloidogenic cleavage

Netzer

Bettayeb

Sinha

et al. 2017

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

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Neurotoxic amyloid-β peptides (Aβ) are major drivers of Alzheimer's disease (AD) and are formed by sequential cleavage of the amyloid precursor protein (APP) by β-secretase (BACE) and γ-secretase. Our previous study showed that the anticancer drug Gleevec lowers Aβ levels through indirect inhibition of γ-secretase activity. Here we report that Gleevec also achieves its Aβ-lowering effects through an additional cellular mechanism. It renders APP less susceptible to proteolysis by BACE without inhibiting BACE enzymatic activity or the processing of other BACE substrates. This effect closely mimics the phenotype of APP A673T, a recently discovered mutation that protects carriers against AD and age-related cognitive decline. In addition, Gleevec induces formation of a specific set of APP C-terminal fragments, also observed in cells expressing the APP protective mutation and in cells exposed to a conventional BACE inhibitor. These Gleevec phenotypes require an intracellular acidic pH and are independent of tyrosine kinase inhibition, given that a related compound lacking tyrosine kinase inhibitory activity, DV2-103, exerts similar effects on APP metabolism. In addition, DV2-103 accumulates at high concentrations in the rodent brain, where it rapidly lowers Aβ levels. This study suggests that long-term treatment with drugs that indirectly modulate BACE processing of APP but spare other BACE substrates and achieve therapeutic concentrations in the brain might be effective in preventing or delaying the onset of AD and could be safer than nonselective BACE inhibitor drugs.Alzheimer's disease | Gleevec | nonamyloidogenic | β-cleavage

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Section: Resultsmentioning

confidence: 94%

Gleevec shifts APP processing from a β-cleavage to a nonamyloidogenic cleavage

Netzer

Bettayeb

Sinha

et al. 2017

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

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“…Descamps et al [26] identified two bioflavonoids, rutin (1) (found in Fagopyrum esculentum Moench) and galangin (2) (found in Alpinia officinarum Hance), which have the ability to impair BACE1 cleavage by acting as βAPP-selective BACE1 inhibitors. Galangin in cell culture studies and AD transgenic mice studies (J20 mice) conducted (at dosages of 50 µM and 40 mg/kg, respectively) showed inhibition of BACE-dependent βAPP nuclear signalling, without affecting neuregulin.…”

Section: Flavonoids Having Potential Anti-beta-site Amyloid Precursormentioning

confidence: 99%

Natural Compounds with Anti-BACE1 Activity as Promising Therapeutic Drugs for Treating Alzheimerʼs Disease

et al. 2019

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Alzheimerʼs disease is a neurodegenerative disease that leads to irreversible neuronal damage. Senile plaques, composed of amyloid beta peptide, is the principal abnormal characteristic of the disease. Among the factors involved, the secretase enzymes, namely, α secretase, beta-site amyloid precursor protein-cleaving enzyme, β secretase, and γ secretase, hold consequential importance. Beta-site amyloid precursor protein-cleaving enzyme 1 is considered to be the rate-limiting factor in the production of amyloid beta peptide. Research supporting the concept of inhibition of beta-site amyloid precursor protein-cleaving enzyme activity as one of the effective therapeutic targets in the mitigation of Alzheimerʼs disease is well accepted. The identification of natural compounds, such as β-amyloid precursor protein-selective beta-site amyloid precursor protein-cleaving enzyme inhibitors, and the idea of compartmentalisation of the beta-site amyloid precursor protein-cleaving enzyme 1 action have caused a dire need to closely examine the natural compounds and their effectiveness in the disease mitigation. Many natural compounds have been reported to effectively modulate beta-site amyloid precursor protein-cleaving enzyme 1. At lower doses, compounds like 2,2′,4′-trihydroxychalcone acid, quercetin, and myricetin have been shown to effectively reduce beta-site amyloid precursor protein-cleaving enzyme 1 activity. The currently used five drugs that are marketed and used for the management of Alzheimerʼs disease have an increased risk of toxicity and restricted therapeutic efficiency, hence, the search for new anti-Alzheimerʼs disease drugs is of primary concern. A variety of natural compounds having pure pharmacological moieties showing multitargeting activity and others exhibiting specific beta-site amyloid precursor protein-cleaving enzyme 1 inhibition as discussed below have superior biosafety. Many of these compounds, which are isolated from medicinal herbs and marine flora, have been long used for the treatment of various ailments since ancient times in the Chinese and Ayurvedic medical systems. The aim of this article is to review the available data on the selected natural compounds, giving emphasis to the inhibition of beta-site amyloid precursor protein-cleaving enzyme 1 activity as a mode of Alzheimerʼs disease treatment.

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“…More recent approaches to AD therapeutic development include re-purposing the anti-epileptic drug levetiracetam to address the seizure-like activity manifest in many AD patients [7,8], use of anti-diabetic drugs including intranasal insulin [9,10], and development of BACE inhibitors [11][12][13], including our own APP-selective BACE inhibitors [14], to name a few. It is hoped that some of these new approaches will provide benefit in AD, but it is very likely that truly effective treatment for AD will require multiple therapeutics working in concert -similar to the approach used for AIDS therapy -to address the many deficits in the disease.…”

Section: Introduction Therapeutics For Alzheimer's Disease (Ad)mentioning

confidence: 99%

Enhancement of sAPPα as a Therapeutic Strategy for Alzheimer’s and Other Neurodegenerative Diseases

John¹

2015

AND

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Citation: Spilman P, Jagodzinska B, Bredesen DE, John V (2015) Enhancement of sAPPα as a Therapeutic Strategy for Alzheimer's and Other Neurodegenerative Diseases. J Alzheimers Neurodegener Dis 1: 001. AbstractSoluble, secreted Amyloid Precursor Protein-α (sAPPα), a product of α-secretase (ADAM10) cleavage of Full Length-APP (FL-APP), is a trophic factor critical for synaptic complexity and maintenance. As cleavage at the α-site of APP precludes the β-site cleavage that is the first step in Amyloid β (Aβ) production, enhancing sAPPα production may not only support and restore neuronal health, but may also decrease the generation of anti-trophic Aβ. Over-production or reduced clearance of Aβ is a hallmark of Alzheimer's Disease (AD), and recent findings suggest it also plays a role in other neurodegenerative diseases and neurological conditions, such as Amyotrophic Lateral Sclerosis (ALS), Cerebral Amyloid Angiopathy (CAA), and Traumatic Brain Injury (TBI). Yet decades of focus on Aβ-lowering strategies alone including passive and active immunotherapy and γ-secretase and BACE1 (BACE) inhibition have yet to yield positive clinical results. Clinical trials of several BACE inhibitors are underway in AD patients, and although there is optimism about this strategy, there are also concerns about mechanism-based side-effects of these drugs. A truly effective therapy would not only slow the degenerative process underlying onset and progression of the disease, it should also restore healthy neuronal function. It is very likely this will comprise combination therapy utilizing more than one drug or intervention. Molecules that enhance sAPPα may be a safe, effective component of a multi-modal therapeutic approach to AD and other neurodegenerative diseases, and have the potential to increase neuronal health by providing trophic support and disrupting neurodegenerative mechanisms.

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AβPP-Selective BACE Inhibitors (ASBI): Novel Class of Therapeutic Agents for Alzheimer's Disease

Cited by 23 publications

References 50 publications

Gleevec shifts APP processing from a β-cleavage to a nonamyloidogenic cleavage

Gleevec shifts APP processing from a β-cleavage to a nonamyloidogenic cleavage

Natural Compounds with Anti-BACE1 Activity as Promising Therapeutic Drugs for Treating Alzheimerʼs Disease

Enhancement of sAPPα as a Therapeutic Strategy for Alzheimer’s and Other Neurodegenerative Diseases

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