Molecular Mechanisms of Alzheimer Disease Protection by the A673T Allele of Amyloid Precursor Protein

Maloney, Janice; Bainbridge, Travis W.; Gustafson, Amy; Zhang, Shuo; Kyauk, Roxanne; Steiner, Pascal; Brug, Marcel van der; Liu, Yichin; Ernst, James A.; Watts, Ryan J.; Atwal, Jasvinder K.

doi:10.1074/jbc.m114.589069

Cited by 167 publications

(196 citation statements)

References 33 publications

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“…23,24 As a note of caution against a too straightforward interpretation of these findings, it is worth mentioning that the above APP mutations might also affect the aggregation kinetics of Ab. 25,26 In view of its pathogenic impact, inhibition of BACE1 is considered a highly promising strategy against AD. Almost a decade before BACE1 has been identified as b-secretase, protease inhibition by competing peptides had been proposed.…”

Section: Role Of Bace1 In Admentioning

confidence: 99%

Ion channel regulation by β-secretase BACE1 – enzymatic and non-enzymatic effects beyond Alzheimer's disease

et al. 2016

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b-site APP-cleaving enzyme 1 (BACE1) has become infamous for its pivotal role in the pathogenesis of Alzheimer's disease (AD). Consequently, BACE1 represents a prime target in drug development. Despite its detrimental involvement in AD, it should be quite obvious that BACE1 is not primarily present in the brain to drive mental decline. In fact, additional functions have been identified. In this review, we focus on the regulation of ion channels, specifically voltage-gated sodium and KCNQ potassium channels, by BACE1. These studies provide evidence for a highly unexpected feature in the functional repertoire of BACE1. Although capable of cleaving accessory channel subunits, BACE1 exerts many of its physiologically significant effects through direct, non-enzymatic interactions with main channel subunits. We discuss how the underlying mechanisms can be conceived and develop scenarios how the regulation of ion conductances by BACE1 might shape electric activity in the intact and diseased brain and heart.

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Section: Role Of Bace1 In Admentioning

confidence: 99%

Ion channel regulation by β-secretase BACE1 – enzymatic and non-enzymatic effects beyond Alzheimer's disease

et al. 2016

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“…[3][4][5] Support for the amyloid cascade hypothesis was spurred by the identification of mutations in amyloid precursor protein (APP) that are associated with familial AD [6][7][8] or protection against amyloid pathology and age-related Alzheimer's disease. [9][10][11] In addition, it was discovered that overexpression of APP due to trisomy 21 in Downs disease was associated with a high incidence of AD in these individuals. [12][13][14] Today it is clear that the pathological tau also plays a vital role in the development of AD pathology and progression of this disease, 15 correlating better with the degree of dementia than Ab plaques.…”

Section: Introductionmentioning

confidence: 99%

Comparison of Efficacy of Preventive and Therapeutic Vaccines Targeting the N Terminus of β-Amyloid in an Animal Model of Alzheimer’s Disease

et al. 2017

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Previously, we reported that Alzheimer's disease (AD) epitope vaccines (EVs) composed of N-terminal b-amyloid (Ab 42 ) B cell epitope fused with universal foreign T helper (Th) epitope(s) were immunogenic, potent, and safe in different amyloid precursor protein (APP) transgenic mice with early AD-like pathology. However, developing an effective therapeutic vaccine is much more challenging, especially when a self-antigen such as Ab 42 is a target. Here, we directly compare the efficacy of anti-Ab 42 antibodies in Tg2576 mice with low or high levels of AD-like pathology at the start of immunizations: 6-6.5 months for preventive vaccinations and 16-19 months for therapeutic vaccinations. EV in a preventive setting induced high levels of anti-Ab antibodies, significantly reducing pathologic forms of Ab in the brains of Tg2576 mice. When used therapeutically for immunesenescent Tg2576 mice, EV induced low levels of antibodies not sufficient for clearing of AD-like pathology. Separately, we demonstrated that EV was also not effective in 11-11.5-month-old Tg2576 mice with moderate AD-like pathology. However, we augmented the titers of anti-Ab antibodies in transgenic (Tg) mice of the same age possessing the pre-existing memory Th cells and detected a significant decrease in diffuse and core plaques in cortical regions compared to control animals along with improved novel object recognition performance. INTRODUCTIONA critical goal of developing therapeutic interventions for Alzheimer's disease (AD) has been the identification of suitable targets. During the last two decades, the predominant theory of the etiology of AD was that Ab has a central role in the onset and progression of AD, as delineated in the amyloid cascade hypothesis. 1,2 According to this hypothesis, the accumulation of Ab peptide, either by overproduction or aberrant clearance, results in deposition of Ab in plaques, which leads to the formation of neurofibrillary tau tangles and cell death, resulting in dementia. Later on, the amyloid cascade hypothesis evolved to focus on oligomers and protofibrils of Ab as instigators in the destruction of synaptic function. [3][4][5] Support for the amyloid cascade hypothesis was spurred by the identification of mutations in amyloid precursor protein (APP) that are associated with familial AD 6-8 or protection against amyloid pathology and age-related Alzheimer's disease. [9][10][11] In addition, it was discovered that overexpression of APP due to trisomy 21 in Downs disease was associated with a high incidence of AD in these individuals. [12][13][14] Today it is clear that the pathological tau also plays a vital role in the development of AD pathology and progression of this disease, 15 correlating better with the degree of dementia than Ab plaques. Importantly, substantial data suggest that Ab pathology emerges many years prior to tau pathology and accelerates formation of toxic tau aggregates, [16][17][18] supporting the preventive rather than therapeutic potential of anti-amyloid therapies.Immunotherapies target...

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“…Most APP mutations result in increased production of amyloidogenic forms of Aβ peptides, mainly Aβ42 or an increased Aβ42/40 ratio (3), which increases the propensity for Aβ42 to form oligomers, leading to the accumulation of toxic fold variants of Aβ (4) and insoluble Aβ species that form amyloid plaques (5,6). Recently, an APP mutation (APP-A673T) that protects against the development of AD and age-related cognitive decline was identified in the Icelandic population (7,8). The mutation exerts a protective effect by rendering APP a less efficacious substrate of β-secretase (BACE), possibly as the result of lower catalytic turnover (8).…”

mentioning

confidence: 99%

“…Recently, an APP mutation (APP-A673T) that protects against the development of AD and age-related cognitive decline was identified in the Icelandic population (7,8). The mutation exerts a protective effect by rendering APP a less efficacious substrate of β-secretase (BACE), possibly as the result of lower catalytic turnover (8). The subsequent reduction in BACE processing of APP results in reduced production of Aβ and soluble APPβ (sAPPβ) but, as expected, no reported effect on the processing of other BACE substrates.…”

mentioning

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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Molecular Mechanisms of Alzheimer Disease Protection by the A673T Allele of Amyloid Precursor Protein

Cited by 167 publications

References 33 publications

Ion channel regulation by β-secretase BACE1 – enzymatic and non-enzymatic effects beyond Alzheimer's disease

Ion channel regulation by β-secretase BACE1 – enzymatic and non-enzymatic effects beyond Alzheimer's disease

Comparison of Efficacy of Preventive and Therapeutic Vaccines Targeting the N Terminus of β-Amyloid in an Animal Model of Alzheimer’s Disease

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

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