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| Open AccessMapping synaptic glutamate transporter dysfunction in vivo to regions surrounding Aβ plaques by iGluSnFR two-photon imaging
In Alzheimer’s disease (AD), neural hyperactivity has been shown to occur in the regions surrounding Aβ plaques. Here, the authors use in vivotwo-photon imaging in mouse models of AD and report abnormal glutamate dynamics in the vicinity of plaques which can be partially restored via GLT-1 upregulation through Ceftriaxone treatment.
- J. K. Hefendehl
- , J. LeDue
- & B. A. MacVicar
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Article
| Open AccessBasal forebrain degeneration precedes and predicts the cortical spread of Alzheimer’s pathology
Whether Alzheimer’s disease originates in basal forebrain or entorhinal cortex remains highly debated. Here the authors use structural magnetic resonance data from a longitudinal sample of participants stratified by cerebrospinal biomarker and clinical diagnosis to show that tissue volume changes appear earlier in the basal forebrain than in the entorhinal cortex.
- Taylor W. Schmitz
- , R. Nathan Spreng
- & Ansgar J. Furst
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| Open AccessThe neuritic plaque facilitates pathological conversion of tau in an Alzheimer’s disease mouse model
Alzheimer’s disease (AD) is pathologically characterized by the accumulation of neuritic plaques and neurofibrillary tangles but it is not known whether the neuritic plaque is necessary to drive the conversion of wild-type tau. Here the authors developed a mouse model in which wild-type tau is converted into pathological tau in a neuritic plaque-dependent manner.
- Tong Li
- , Kerstin E. Braunstein
- & Philip C. Wong
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Article
| Open AccessEarly role of vascular dysregulation on late-onset Alzheimer’s disease based on multifactorial data-driven analysis
Late-onset Alzheimer's disease (LOAD) is a complex multi-factorial disorder. Here, the authors perform a data-driven analysis of LOAD progression, including multimodal brain imaging, plasma and CSF biomarkers, and find vascular dysfunction is among the earliest and strongest altered events.
- Y. Iturria-Medina
- , R. C. Sotero
- & Ansgar J. Furst
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| Open AccessEarly synaptic deficits in the APP/PS1 mouse model of Alzheimer’s disease involve neuronal adenosine A2A receptors
Hippocampal synaptic dysfunctions are an early symptom of Alzheimer’s disease. Here, the authors find adenosine A2A receptors are up-regulated in APP/PS1 model mice and that deleting or blocking receptor activity helps alleviate plasticity and memory impairments.
- Silvia Viana da Silva
- , Matthias Georg Haberl
- & Christophe Mulle
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| Open AccessEarly detection of cryptic memory and glucose uptake deficits in pre-pathological APP mice
Identifying early signs of Alzheimer’s disease is important when it comes to diagnosis and treatment. Here, the authors identify subtle memory retrieval deficits and associated brain glucose uptake impairments in very young mouse models of Alzheimer’s, prior to plaque development.
- V. Beglopoulos
- , J. Tulloch
- & R. G. M. Morris
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| Open AccessDeregulation of mitochondrial F1FO-ATP synthase via OSCP in Alzheimer’s disease
F1FO ATP synthase is a critical enzyme for the maintenance of mitochondrial function. Here the authors demonstrate that loss of the F1FO-ATP synthase subunit OSCP and the interaction of OSCP with Aβ peptide in Alzheimer’s disease patients and mouse models lead to F1FO-ATP synthase deregulation and disruption of synaptic mitochondrial function.
- Simon J. Beck
- , Lan Guo
- & Heng Du
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| Open AccessIncreased amyloidogenic APP processing in APOE ɛ4-negative individuals with cerebral β-amyloidosis
Autosomal dominant Alzheimer's disease is thought to be caused by increased amyloidogenic APP processing. Mattson et al.show that association between brain Aβ and cerobrospinal fluid Aβ40 levels is stronger in APOE ɛ4 negative people, suggesting that increased processing may also underlie sporadic disease.
- Niklas Mattsson
- , Philip S. Insel
- & Oskar Hansson
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| Open AccessAntibody-based PET imaging of amyloid beta in mouse models of Alzheimer’s disease
Imaging tools for evaluating progression of Alzheimer’s disease have been lacking. Here the authors develop a blood brain barrier-permeable Aß probe based on a radiolabelled, anti-Aß antibody, and report age-dependent brain uptake visualized in vivo with PET in mouse models of the disease.
- Dag Sehlin
- , Xiaotian T. Fang
- & Stina Syvänen
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| Open AccessToxic tau oligomer formation blocked by capping of cysteine residues with 1,2-dihydroxybenzene groups
Aggregation of microtubule associated protein tau is one of cause of neuronal loss in tauopathies including Alzheimer’s disease. Here, the authors show that compounds with a 1,2-dihydroxybenzene skeleton can modify cysteine residues in tau and block toxic tau aggregation.
- Yoshiyuki Soeda
- , Misato Yoshikawa
- & Akihiko Takashima
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| Open AccessEPPS rescues hippocampus-dependent cognitive deficits in APP/PS1 mice by disaggregation of amyloid-β oligomers and plaques
Amyloid-beta deposits are a pathological hallmark of Alzheimer’s disease, and have previously been targeted in immunisation therapies. Here, the authors show that oral administration of the small molecule EPPS reduces Aß plaque and oligomer load in APP/PS1 mice and improves learning and memory performance.
- Hye Yun Kim
- , Hyunjin Vincent Kim
- & YoungSoo Kim
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Article
| Open AccessDNA repair factor BRCA1 depletion occurs in Alzheimer brains and impairs cognitive function in mice
DNA repair deficits have been suggested to play a role in Alzheimer’s pathology. Here, the authors report reduced levels of the DNA repair factor BRCA1 in patient brains, and provide evidence that loss of BRCA1 in the dentate gyrus leads to spatial learning and memory deficits in mice.
- Elsa Suberbielle
- , Biljana Djukic
- & Lennart Mucke
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| Open AccessAβ-dependent reduction of NCAM2-mediated synaptic adhesion contributes to synapse loss in Alzheimer’s disease
Understanding how ß-amyloid contributes to synapse loss and dysfunction is a central goal of Alzheimer’s disease research. Here, Leshchyns’ka et al.identify a novel mechanism by which Aß disassembles hippocampal glutamatergic synapses via cleavage of a neural cell adhesion molecule 2 (NCAM2).
- Iryna Leshchyns’ka
- , Heng Tai Liew
- & Vladimir Sytnyk
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Article
| Open AccessTRPC6 specifically interacts with APP to inhibit its cleavage by γ-secretase and reduce Aβ production
Attempts to treat Alzheimer's disease by targeting γ-secretase cleavage of APP into Aß have been unsuccessful, partially due to off-target effects. Here, the authors identify TRPC6 as a novel γ-secretase modulator, showing that it interacts with APP to regulate Aß levels while sparing Notch cleavage.
- Junfeng Wang
- , Rui Lu
- & Yizheng Wang
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Article
| Open AccessDelta-secretase cleaves amyloid precursor protein and regulates the pathogenesis in Alzheimer’s disease
Age is the greatest risk factor for Alzheimer’s disease, yet how ageing regulates disease pathology is unclear. Here, the authors find that asparagine endopeptidase expression increases with age and cleaves APP, contributing to ß-amyloid production and cognitive defects in a transgenic mouse model.
- Zhentao Zhang
- , Mingke Song
- & Keqiang Ye
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| Open AccessNeuronal uptake and propagation of a rare phosphorylated high-molecular-weight tau derived from Alzheimer’s disease brain
In Alzheimer's disease, tau spreads throughout the brain, however the nature of the tau species propagating from one neuron to another is not known. Here, Takeda et al. identify a rare, high-molecular-weight tau as the primary species taken up and transferred between synaptically connected neurons.
- Shuko Takeda
- , Susanne Wegmann
- & Bradley T. Hyman
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| Open AccessBreaking immune tolerance by targeting Foxp3+ regulatory T cells mitigates Alzheimer’s disease pathology
Immunosuppression has been unsuccessful in treatment of Alzheimer’s disease. Here the authors show in a mouse model of the disease that transient inhibition of regulatory T cells mitigates amyloid plaque pathology and reverses cognitive decline, whereas augmenting these cells worsens the pathology.
- Kuti Baruch
- , Neta Rosenzweig
- & Michal Schwartz
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| Open AccessFerritin levels in the cerebrospinal fluid predict Alzheimer’s disease outcomes and are regulated by APOE
Brain-iron elevation is implicated in Alzheimer’s disease (AD), but the impact of the metal on disease outcomes has not been analysed in a longitudinal study. Here, the authors examine the association between the levels of ferritin, an iron storage protein, in the cerebrospinal fluid (CSF) of AD patients and show that CSF ferritin levels predict AD outcomes.
- Scott Ayton
- , Noel G. Faux
- & Ansgar J. Furst
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Microglia constitute a barrier that prevents neurotoxic protofibrillar Aβ42 hotspots around plaques
In Alzheimer’s disease (AD), β-amyloid plaques are tightly enveloped by microglia but the significance of this phenomenon is unknown. Here the authors used confocal and in vivotwo-photon imaging in AD mouse models and revealed that microglia constitute a barrier that seems to prevent the formation of neurotoxic hotspots of protofibrillar β-amyloid.
- Carlo Condello
- , Peng Yuan
- & Jaime Grutzendler
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Metabotropic P2Y1 receptor signalling mediates astrocytic hyperactivity in vivo in an Alzheimer’s disease mouse model
Astrocytic network alterations are seen in Alzheimer’s disease (AD) but the underlying mechanisms have remained undefined. Here the authors use in vivomulitphoton microscopy to monitor spontaneous network activity of astrocytes in a mouse model of AD, and find that astroglial hyperactivity was largely mediated by activation of the purinergic receptor P2Y1.
- Andrea Delekate
- , Martina Füchtemeier
- & Gabor C. Petzold
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The key role of transient receptor potential melastatin-2 channels in amyloid-β-induced neurovascular dysfunction
Amyloid-beta has been shown to induce cerebrovascular defects that may contribute to the progression of Alzheimer's dementia. Park et al.show that amyloid-beta impairs vascular function by upregulating oxidative stress-induced DNA damage, resulting in opening of TRPM2 channels.
- L. Park
- , G. Wang
- & C. Iadecola
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| Open AccessPICALM modulates autophagy activity and tau accumulation
The protein PICALM/CALM is implicated in Alzheimer’s disease (AD) pathology, but it is unclear how. In this study, the authors show that CALM regulates clearance of the protein tau, which is also implicated in AD pathology, by facilitating endocytosis-dependent autophagy.
- Kevin Moreau
- , Angeleen Fleming
- & David C. Rubinsztein
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Tonic inhibition in dentate gyrus impairs long-term potentiation and memory in an Alzheimer’s disease model
Altered GABAergic synaptic transmission is implicated in Alzheimer’s disease pathology. Here, Wu et al. show that GABA content is increased in brain samples from human patients and that in mouse models of the disease, the increase in GABA leads to an increase in tonic inhibition in the dentate gyrus.
- Zheng Wu
- , Ziyuan Guo
- & Gong Chen
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The FAM3 superfamily member ILEI ameliorates Alzheimer’s disease-like pathology by destabilizing the penultimate amyloid-β precursor
γ-secretase is a major target for treating Alzheimer’s disease (AD). Here, the authors screen various binding proteins against the γ-secretase complex and find that the evolutionarily conserved secretory protein ILEI interferes with γ-secretase-dependent production of β-amyloid, which is implicated in AD.
- Hiroshi Hasegawa
- , Lei Liu
- & Masaki Nishimura
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| Open AccessConformational targeting of intracellular Aβ oligomers demonstrates their pathological oligomerization inside the endoplasmic reticulum
Intracellular Aß oligomers have been linked to Alzheimer’s disease but details about their biosynthesis and function have been hard to obtain due to the lack of selective approaches for targeting them. Here, Meli et al.develop a strategy using recombinant antibodies to target Aß oligomers in the endoplasmic reticulum of cells, and perform mechanistic studies in cellular models of the disease.
- Giovanni Meli
- , Agnese Lecci
- & Antonino Cattaneo
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Nrf2 reduces levels of phosphorylated tau protein by inducing autophagy adaptor protein NDP52
Impaired clearance of aberrantly phosphorylated tau protein is implicated in Alzheimer’s Disease. Jo et al.show that nuclear factor Nrf2 participates in the clearance of phosphorylated tau protein in the brain by inducing the autophagy adaptor protein NDP52.
- Chulman Jo
- , Soner Gundemir
- & Gail V. W. Johnson
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Reelin delays amyloid-beta fibril formation and rescues cognitive deficits in a model of Alzheimer’s disease
Reelin is crucial for brain development and controls neurogenesis and synaptic plasticity in the adult brain. Here, Pujadas et al. reveal that Reelin slows the onset of Alzheimer’s disease in a mouse model by delaying the formation of amyloid fibrils and preventing neuronal loss and cognitive decline.
- Lluís Pujadas
- , Daniela Rossi
- & Eduardo Soriano
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| Open AccessmGlu5 receptors and cellular prion protein mediate amyloid-β-facilitated synaptic long-term depression in vivo
In Alzheimer's disease, the soluble amyloid beta peptide is known to modulate synaptic function by forming a complex with prion proteins and metabotropic glutamate receptors. Here, Hu et al.show that amyloid beta signalling via this complex facilitates the induction of long-term depression at synapses.
- Neng-Wei Hu
- , Andrew J. Nicoll
- & Michael J. Rowan
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Transition-metal-substituted polyoxometalate derivatives as functional anti-amyloid agents for Alzheimer’s disease
Beta amyloid aggregation, a process implicated in Alzheimer’s disease pathology, is inhibted by polyoxometalate with a Wells–Dawson structure. Gao et al.show that transition metal-functionalized derivatives are more effective at inhibiting beta amyloid aggregation than non-functionalized derivatives.
- Nan Gao
- , Hanjun Sun
- & Xiaogang Qu
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Decreased CALM expression reduces Aβ42 to total Aβ ratio through clathrin-mediated endocytosis of γ-secretase
CALM is an adaptor protein required for clathrin-mediated endocytosis, and is a protective factor in Alzheimer’s disease. Here, Kanatsu et al.show that CALM can reduce the production of toxic Aß42 protein by driving clathrin-mediated endocytosis of γ-secretase.
- Kunihiko Kanatsu
- , Yuichi Morohashi
- & Takeshi Iwatsubo
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Familial Alzheimer’s mutations within APPTM increase Aβ42 production by enhancing accessibility of ε-cleavage site
In Alzheimer’s disease, familial mutations of the amyloid precursor protein (APP) can increase the production of the toxic cleavage product Aß42. Here, Chen et al. show that mutations within the transmembrane domain of APP favour Aß42 production by increasing the accessibility of the ε-cleavage site.
- Wen Chen
- , Eric Gamache
- & Chunyu Wang
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Article
| Open AccessRETRACTED ARTICLE: Pericyte loss influences Alzheimer-like neurodegeneration in mice
Pericytes are cells in the blood–brain barrier that degenerate with the onset of Alzheimer's disease. Here, Sagare et al. show that pericyte loss contributes to disease onset by promoting amyloid-beta accumulation, tau pathology and early loss of neuronal cells.
- Abhay P. Sagare
- , Robert D. Bell
- & Berislav V. Zlokovic
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Lysosomal NEU1 deficiency affects amyloid precursor protein levels and amyloid-β secretion via deregulated lysosomal exocytosis
The enzyme NEU1 negatively regulates lysosomal exocytosis in various cell types. Annunziata et al.show that mice deficient in NEU1 display Alzheimer’s disease-like pathology and that direct brain administration of NEU1 reduces pathology in an Alzheimer’s disease mouse model.
- Ida Annunziata
- , Annette Patterson
- & Alessandra d’Azzo
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| Open AccessSubstrate ectodomain is critical for substrate preference and inhibition of γ-secretase
γ-Secretase inhibitors are studied for their potential to treat Alzheimer’s disease, but their use is limited by side effects. Funamoto et al.show that γ-secretase preferentially cleaves substrates with short ectodomains and that inhibitors based on these ectodomains reduce disease-like pathology in mice.
- Satoru Funamoto
- , Toru Sasaki
- & Yasuo Ihara
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| Open AccessAmyloid-β nanotubes are associated with prion protein-dependent synaptotoxicity
Prion protein has been suggested to bind toxic amyloid-ß oligomers. Nicollet al.demonstrate that binding to prion protein and prion protein-dependent synaptotoxicity correlate with the presence of a tubular form of amyloid-ß with a defined triple helical structure.
- Andrew J. Nicoll
- , Silvia Panico
- & John Collinge
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Alzheimer’s disease mutations in APP but not γ-secretase modulators affect epsilon-cleavage-dependent AICD production
Clinical trials of γ-secretase inhibitors to treat Alzheimer’s disease show that side effects occur from their non-selective action. Dimitrov et al.show that improved second generation γ-secretase modulators spare cleavage sites of substrate proteins that are implicated in the side effects.
- Mitko Dimitrov
- , Jean-René Alattia
- & Patrick C. Fraering
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Phosphatidylinositol-3-phosphate regulates sorting and processing of amyloid precursor protein through the endosomal system
Endosomal sorting is regulated by phosphatidylinositol-3-phosphate and anomalies in this process are implicated in Alzheimer’s disease. Here the authors show that deficiency of phosphatidylinositol-3-phosphate in vitroenhances the pathological trafficking and processing of amyloid precursor protein.
- Etienne Morel
- , Zeina Chamoun
- & Gilbert Di Paolo
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Scara1 deficiency impairs clearance of soluble amyloid-β by mononuclear phagocytes and accelerates Alzheimer’s-like disease progression
The scavenger receptor Scara1, expressed on microglia and macrophages, binds beta amyloid aggregates. In a mouse model of Alzheimer’s disease, the authors show that Scara1deficiency is associated with reduced clearance and increased deposition of aggregates in the brain, which results in early mortality.
- Dan Frenkel
- , Kim Wilkinson
- & Joseph El Khoury
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Caspase-2 is required for dendritic spine and behavioural alterations in J20 APP transgenic mice
Aberrant caspase signalling is implicated in Alzheimer’s disease. Pozueta et al.study a mouse model of Alzheimer’s disease that is deficient in caspase-2 and find that surprisingly, these mice don’t display impaired cognitive function, or the reduced dendritic spine density normally associated with the disease.
- Julio Pozueta
- , Roger Lefort
- & Michael Shelanski
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Smoking exacerbates amyloid pathology in a mouse model of Alzheimer’s disease
A link between smoking and the incidence of Alzheimer’s disease has been implicated in humans. In this study, transgenic mouse models of Alzheimer’s disease exposed to cigarette smoke display increased disease abnormalities in the brain, such as amyloidogenesis, neuroinflammation and tau phosphorylation.
- Ines Moreno-Gonzalez
- , Lisbell D. Estrada
- & Claudio Soto
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Phospho-dependent ubiquitination and degradation of PAR-1 regulates synaptic morphology and tau-mediated Aβ toxicity in Drosophila
PAR-1 inDrosophilahas been identified as a key physiological tau kinase. Lee and colleagues perform genetic screens for regulators of PAR-1 and find that it is targeted for ubiquitination and degradation by the ubiquitin ligase complex SCF(Slimb), and that this pathway modulates synaptic morphology.
- Seongsoo Lee
- , Ji-Wu Wang
- & Bingwei Lu
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Aβ alters the connectivity of olfactory neurons in the absence of amyloid plaques in vivo
The amyloid beta peptide can aggregate into insoluble plaques, which may indicate the onset of Alzheimer's disease. In a mouse model of Alzheimer's disease, Cao and colleagues report a phenotype of altered connectivity in the olfactory neuronal circuit that precedes amyloid plaque deposition.
- Luxiang Cao
- , Benjamin R. Schrank
- & Mark W. Albers
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Soluble amyloid precursor protein-α modulates β-secretase activity and amyloid-β generation
The loss of neurotrophic factors is responsible for key neurodegenerative processes in Alzheimer's disease. In this study, Obregon and colleagues treat amyloidogenic cells with the neurotrophin soluble amyloid precursor protein-α and find that it halts amyloidogenesis by interacting with the β-secretase BACE1.
- Demian Obregon
- , Huayan Hou
- & Jun Tan
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Article
| Open AccessStaged decline of neuronal function in vivo in an animal model of Alzheimer's disease
The amyloid-β-peptide is pivotal to the pathology of Alzheimer's disease, but its mechanism of action remains uncertain. This study utilizesin vivotwo-photon calcium imaging to investigate the effects of this peptide on single cortical neurons of the visual cortex in a mouse model of Alzheimer's disease.
- Christine Grienberger
- , Nathalie L. Rochefort
- & Arthur Konnerth
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| Open AccessInteraction between prion protein and toxic amyloid β assemblies can be therapeutically targeted at multiple sites
The ability of synthetic amyloid β-protein to bind to prion proteins and alter synaptic plasticity has been previously reported. Here the relevance of this binding is investigated in brains of Alzheimer's disease patients and the interaction is shown to be blocked by antibodies to two distinct regions of prion proteins.
- Darragh B. Freir
- , Andrew J. Nicoll
- & John Collinge
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Article
| Open AccessSubstrate docking to γ-secretase allows access of γ-secretase modulators to an allosteric site
γ-Secretase modulators have promise in the treatment of Alzheimer's disease, but their molecular target is uncertain. Here, fluorescence resonance energy transfer is used to determine that the γ-secretase allosteric site is within the γ-secretase complex and that substrate docking is required for modulators to access the site.
- Kengo Uemura
- , Katherine C. Farner
- & Oksana Berezovska