A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline

Jónsson, Thorlákur; Atwal, Jasvinder K.; Steinberg, Stacy; Snædal, Jón; Jónsson, Pálmi V.; Björnsson, Sigurbjörn; Stefánsson, Hreinn; Sulem, Patrick; Guðbjartsson, Daníel F.; Maloney, Janice; Hoyte, Kwame; Gustafson, Amy; Liu, Yichin; Lu, Yanmei; Bhangale, Tushar; Graham, Robert; Huttenlocher, Johanna; Björnsdóttir, Gyða; Andreassen, Ole A.; Jönsson, Erik G.; Palotie, Aarno; Behrens, Timothy W.; Magnússon, Ólafur Þ.; Kong, Augustine; Þorsteinsdóttir, Unnur; Watts, Ryan J.; Stefánsson, Kāri

doi:10.1038/nature11283

Cited by 1,520 publications

(1,355 citation statements)

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“…4 A more recent study reported a variant of the APP gene (APPA673T) at a site proximal to the BACE1 proteolytic site that confers protection against AD. 5 A673T substitution in APP results in reduced production of Aβ peptides secreted from heterologously transfected cells, further supporting the hypothesis that increases in Aβ may underlie the pathology of AD. Cleavage of APP by β-site APP cleaving enzyme-1 (BACE1) results in shedding of the APP ectodomain, and the remaining membrane bound C-terminal fragment, C99, is further processed by γ-secretase to produce Aβ.…”

supporting

confidence: 59%

Targeting the BACE1 Active Site Flap Leads to a Potent Inhibitor That Elicits Robust Brain Aβ Reduction in Rodents

Guernon

Yang

et al. 2016

ACS Med. Chem. Lett.

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By targeting the flap backbone of the BACE1 active site, we discovered 6-dimethylisoxazole-substituted biaryl aminothiazine 18 with 34-fold improved BACE1 inhibitory activity over the lead compound 1. The cocrystal structure of 18 bound to the active site indicated two hydrogen-bond interactions between the dimethylisoxazole and threonine 72 and glutamine 73 of the flap. Incorporation of the dimethylisoxazole substitution onto the related aminothiazine carboxamide series led to pyrazine-carboxamide 26 as a very potent BACE1 inhibitor (IC 50 < 1 nM). This compound demonstrated robust brain Aβ reduction in rat dose−response studies. Thus, compound 26 may be useful in testing the amyloid hypothesis of Alzheimer's disease.

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supporting

confidence: 59%

Targeting the BACE1 Active Site Flap Leads to a Potent Inhibitor That Elicits Robust Brain Aβ Reduction in Rodents

Guernon

Yang

et al. 2016

ACS Med. Chem. Lett.

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“…According to the prevailing amyloid‐cascade hypothesis, A β deposition in the brain triggers the hyperphosphorylation of tau and its accumulation as neurofibrillary tangles, activation of inflammatory cells and pathways, initiation of oxidative stress, and decline in synaptic and neuronal health and finally neurodegeneration 8. This view recently gained further support from the identification of a protective APP variant (A673T), which was later shown to reduce A β levels and protect against cognitive decline 9, 10. Physiologic functions of A β are not well‐established, but significant lines of evidence suggest that A β may have potential protective properties under certain conditions.…”

Section: Introductionmentioning

confidence: 99%

Decreased plasma C‐reactive protein levels in APOE ε4 allele carriers

Martiskainen

Takalo

Solomon

et al. 2018

Ann Clin Transl Neurol

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ObjectiveApolipoprotein E (APOE) ε4 allele is a well‐established risk factor in Alzheimer's disease (AD). Here, we assessed the effects of APOE polymorphism on cardiovascular, metabolic, and inflammation‐related parameters in population‐based cohorts.MethodsAssociation of cardiovascular, metabolic, and inflammation‐related parameters with the APOE polymorphism in a large Finnish Metabolic Syndrome in Men (METSIM) cohort and Finnish Geriatric Intervention study to prevent cognitive impairment and disability (FINGER) were investigated. Brain‐specific effects were addressed in postmortem brain samples.ResultsIndividuals carrying the APOE ε4 allele displayed significantly elevated serum/plasma LDL cholesterol and apolipoprotein B levels. APOE ε3ε4 and ε4ε4 significantly associated with lower levels of plasma high‐sensitivity C‐reactive protein (hs‐CRP). Plasma amyloid‐β 42 (Aβ42) and reduced hs‐CRP levels showed an association independently of the APOE status.InterpretationThese data suggest that the APOE ε4 allele associates with lower levels of hs‐CRP in individuals without dementia. Moreover, Aβ42 may encompass anti‐inflammatory effects reflected by reduced hs‐CRP levels.

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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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A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline

Cited by 1,520 publications

References 24 publications

Targeting the BACE1 Active Site Flap Leads to a Potent Inhibitor That Elicits Robust Brain Aβ Reduction in Rodents

Targeting the BACE1 Active Site Flap Leads to a Potent Inhibitor That Elicits Robust Brain Aβ Reduction in Rodents

Decreased plasma C‐reactive protein levels in APOE ε4 allele carriers

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

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