Targeting the β secretase BACE1 for Alzheimer's disease therapy

Yan, Riqiang; Vassar, Robert

doi:10.1016/s1474-4422(13)70276-x

Cited by 548 publications

(426 citation statements)

References 84 publications

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“…Pharmacologic inhibition of BACE by a nonselective inhibitor has the potential to affect numerous signaling pathways, given the large number of putative BACE substrates present in cells (16). In contrast, the APP protective mutation, A673T, reduces BACE processing of APP but presumably of no other protein.…”

Section: Resultsmentioning

confidence: 99%

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: 99%

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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“…Development of inhibitors of BACE1 and/or ␥-secretase activities has been pursued since these enzymes were identified (reviewed in Ref. 42). However, we believe that more attention should have been devoted to ␥-secretase inhibitors.…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, suppression of BACE1 activity specifically in the brain may be a practical means for treating AD patients (reviewed in Ref. 42). Our results show that cleavage of APP by excess BACE1 activity can degrade A␤ by cleaving APP at the ␤Ј-site.…”

Section: Discussionmentioning

confidence: 99%

Alternative Selection of β-Site APP-Cleaving Enzyme 1 (BACE1) Cleavage Sites in Amyloid β-Protein Precursor (APP) Harboring Protective and Pathogenic Mutations within the Aβ Sequence

Kimura¹,

Hata²,

Suzuki

2016

Journal of Biological Chemistry

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Edited by F. Anne Stephenson␤␤-Site APP-cleaving enzyme 1 (BACE1), 3 a type I transmembrane aspartic protease, was identified as the ␤-secretase that cleaves amyloid ␤-protein precursor (APP) to generate neurotoxic amyloid ␤ (A␤) (1-4). BACE1 cleaves APP at the peptide bond between Met 671 and Asp 672 (␤-site; sequence numbering refers to the APP770 isoform) (5, 6). This primary cleavage of APP generates the secreted form of the amino-terminal large fragment (sAPP␤) and the membrane-associated carboxyl-terminal fragment (CTF␤/C99) (reviewed in Ref. 7). Because CTF␤/C99 includes the complete amino acid sequence of the A␤ region, and subsequent cleavage of CTF␤/C99 by ␥-secretase generates the A␤(1-XX) peptides (A␤1 indicates the position of Asp 672 ), the ␤-site cleavage is referred to as amyloidogenic processing of APP (reviewed in Ref. 8). Alternatively, APP can also be cleaved by ␣-secretase (mainly ADAM10/17), at the peptide bond between Lys 687 and Leu 688 , generating sAPP␣ and CTF␣/C83 including the A␤(17-XX) region; accordingly, this cleavage is referred to as amyloidolytic processing of APP (9 -11). BACE1 also cleaves APP at another peptide bond between Tyr 681 and Gln 682 (␤Ј-site), resulting in generation of sAPP␤Ј and CTF␤Ј/C89 (12, 13). Cleavage of CTF␤Ј/C89 by ␥-secretase yields A␤(11-XX), which lacks the first 10 amino acids of the A␤ domain. This ␤Ј-site cleavage of APP is also thought to be amyloidolytic, because the structural analysis suggests that A␤(11-40) and A␤(11-42) are less toxic than A␤(1-40) and A␤(1-42) (14), and the A␤(11-42) showed reduced neurotoxicity compared with A␤(1-42) and A␤(3-42) in a study with transgenic fly (15), although the neurotoxicity of A␤(11-XX) in human brain is controversial (16).A␤ is the major protein component of senile plaques observed in the brain of Alzheimer's disease (AD) subjects, and soluble A␤ oligomer(s) are thought to impair synaptic functions prior to A␤ deposition in the brain (17)(18)(19). Therefore, to understand AD pathogenesis and develop effective AD ther-

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“…Relevant to this issue, BACE1-null mice are reported to be viable and to have a normal phenotype, suggesting that inhibition of this enzyme could be clinically feasible with few side effects (80 -82). By contrast, it should be noted that recent reports demonstrated that BACE1-null mice have several abnormalities (83)(84)(85)(86), raising a concern that complete inhibition or entire absence of BACE1 function may not be free of unwanted side effects. More to this point, it is known that MB is pleiotropic and targets other substrates, including monoamine oxidase A, NOS, guanylate cyclase, metHb, AChE, and disulfide reductases (45,46).…”

Section: Discussionmentioning

confidence: 99%

Methylene Blue Modulates β-Secretase, Reverses Cerebral Amyloidosis, and Improves Cognition in Transgenic Mice

Mori¹,

Naoki

Segawa

et al. 2014

Journal of Biological Chemistry

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Amyloid precursor protein (APP) proteolysis is required for production of amyloid-β (Aβ) peptides that comprise β-amyloid plaques in the brains of patients with Alzheimer disease (AD). Here, we tested whether the experimental agent methylene blue (MB), used for treatment of methemoglobinemia, might improve AD-like pathology and behavioral deficits. We orally administered MB to the aged transgenic PSAPP mouse model of cerebral amyloidosis and evaluated cognitive function and cerebral amyloid pathology. Beginning at 15 months of age, animals were gavaged with MB (3 mg/kg) or vehicle once daily for 3 months. MB treatment significantly prevented transgene-associated behavioral impairment, including hyperactivity, decreased object recognition, and defective spatial working and reference memory, but it did not alter nontransgenic mouse behavior. Moreover, brain parenchymal and cerebral vascular β-amyloid deposits as well as levels of various Aβ species, including oligomers, were mitigated in MB-treated PSAPP mice. These effects occurred with inhibition of amyloidogenic APP proteolysis. Specifically, β-carboxyl-terminal APP fragment and β-site APP cleaving enzyme 1 protein expression and activity were attenuated. Additionally, treatment of Chinese hamster ovary cells overexpressing human wild-type APP with MB significantly decreased Aβ production and amyloidogenic APP proteolysis. These results underscore the potential for oral MB treatment against AD-related cerebral amyloidosis by modulating the amyloidogenic pathway.

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Targeting the β secretase BACE1 for Alzheimer's disease therapy

Cited by 548 publications

References 84 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

Alternative Selection of β-Site APP-Cleaving Enzyme 1 (BACE1) Cleavage Sites in Amyloid β-Protein Precursor (APP) Harboring Protective and Pathogenic Mutations within the Aβ Sequence

Methylene Blue Modulates β-Secretase, Reverses Cerebral Amyloidosis, and Improves Cognition in Transgenic Mice

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