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| Open AccessTransmission of tauopathy strains is independent of their isoform composition
Although normal human brains express 6 tau isoforms in equal ratio with 3 or 4 microtubule-binding repeat domains (3R and 4R), tau inclusions from different human tauopathy brains, now considered as different strains, have distinct isoform compositions and strain properties and the relationship between these two parts is unclear. Here the authors generate a new transgenic mouse line expressing 6 human tau isoforms with equal 3R and 4R ratios, recapitulate distinct human tau strains in mouse brains with similar isoform compositions and cell type specificities, and further show the strain transmission pattern is independent of its isoform composition.
- Zhuohao He
- , Jennifer D. McBride
- & Virginia M. -Y. Lee
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Article
| Open AccessOptogenetic gamma stimulation rescues memory impairments in an Alzheimer’s disease mouse model
Slow gamma oscillations are associated with memory and have been reported to be disrupted in patients with Alzheimer’s disease. Here the authors show that optogenetic stimulation of medial septum parvalbumin neurons at 40 Hz rescues memory retrieval in the J20 mouse model of Alzheimer’s disease.
- Guillaume Etter
- , Suzanne van der Veldt
- & Sylvain Williams
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| Open AccessCryo-EM structure and polymorphism of Aβ amyloid fibrils purified from Alzheimer’s brain tissue
Alzheimer’s disease is characterised by the deposition of Aβ amyloid fibrils and tau protein neurofibrillary tangles. Here the authors use cryo-EM to structurally characterise brain derived Aβ amyloid fibrils and find that they are polymorphic and right-hand twisted, which differs from in vitro generated Aβ fibrils.
- Marius Kollmer
- , William Close
- & Marcus Fändrich
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Article
| Open AccessTau deposition is associated with functional isolation of the hippocampus in aging
Deposition of tau protein aggregates occurs during aging and Alzheimer disease. Here, the authors show that tau burden in the anterior-temporal memory network is associated with disrupted fMRI connectivity and functional isolation of the hippocampus from other memory network components.
- Theresa M. Harrison
- , Anne Maass
- & William J. Jagust
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Article
| Open AccessNon-invasive in vivo hyperspectral imaging of the retina for potential biomarker use in Alzheimer’s disease
The use of PET for detection of Aβ in the brain in AD has limitations; studies also indicate that retinal changes, including Aβ deposition, occur in AD. Here the authors demonstrate the potential to use in vivo retinal hyperspectral imaging as a surrogate for brain accumulation of Aβ.
- Xavier Hadoux
- , Flora Hui
- & Peter van Wijngaarden
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Article
| Open AccessImpaired mitochondrial calcium efflux contributes to disease progression in models of Alzheimer’s disease
Dysregulation of intracellular calcium is reported in Alzheimer’s disease. Here the authors show that loss of the mitochondrial Na+ /Ca2+ exchanger, NCLX – primary route of mitochondrial calcium efflux, precedes neuronal pathology in experimental models and contributes to Alzheimer’s disease progression.
- Pooja Jadiya
- , Devin W. Kolmetzky
- & John W. Elrod
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Article
| Open AccessInhibition of amyloid beta toxicity in zebrafish with a chaperone-gold nanoparticle dual strategy
Treating Alzheimer’s disease, one of the most common neurodegenerative diseases, is of wide interest. Here, the authors report on the development of casein coated gold nanoparticles which were able to cross the blood brain barrier and protect against amyloid beta toxicity in a zebrafish model.
- Ibrahim Javed
- , Guotao Peng
- & Sijie Lin
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Article
| Open AccessSustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model
Genetics implicate microglia in Alzheimer’s disease pathogenesis, but their roles remain unclear. Here, the authors find that microglial depletion in a mouse model of Alzheimer’s disease impairs plaque formation and that Aβ-induced changes in neuronal gene expression are microglia-mediated.
- Elizabeth Spangenberg
- , Paul L. Severson
- & Kim N. Green
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Article
| Open AccessA human memory circuit derived from brain lesions causing amnesia
Memory is hypothesised to depend on different brain regions that interact in a network. Here, the authors use case studies of stroke patients with amnesia from the literature to identify brain regions that are part of this network.
- Michael A. Ferguson
- , Chun Lim
- & Michael D. Fox
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Article
| Open AccessStructure of amyloid-β (20-34) with Alzheimer’s-associated isomerization at Asp23 reveals a distinct protofilament interface
In patients with sporadic Alzheimer’s disease part of the Asp23 residues are isomerized to L-isoaspartate (L-isoAsp23). Here the authors present the MicroED structures of wild-type and L-isoAsp23 Aβ 20–34 amyloid fibrils that both form tightly packed cores and self-associate through two distinct interfaces with one of these interfaces being strengthened by the isoaspartyl modification.
- Rebeccah A. Warmack
- , David R. Boyer
- & Steven G. Clarke
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Article
| Open AccessNon-coding variability at the APOE locus contributes to the Alzheimer’s risk
Several studies show that APOE-ε4 coding variants are associated with Alzheimer’s disease (AD) risk. Here, Zhou et al. perform fine-mapping of the APOE region and find AD risk haplotypes with non-coding variants in the PVRL2 and APOC1 regions that are associated with relevant endophenotypes.
- Xiaopu Zhou
- , Yu Chen
- & Nancy Y. Ip
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Article
| Open AccessBrain somatic mutations observed in Alzheimer’s disease associated with aging and dysregulation of tau phosphorylation
The role of brain somatic mutations in neurodegenerative diseases such as Alzheimer’s disease (AD) is not well understood. Here the authors carry out high-depth exome sequencing ~500× on brain tissue from patients with AD and controls, and identify mutations in a number of genes that are known to contribute to phosphorylation and aggregation of tau, including PIN1.
- Jun Sung Park
- , Junehawk Lee
- & Jeong Ho Lee
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Article
| Open AccessFactors other than hTau overexpression that contribute to tauopathy-like phenotype in rTg4510 mice
The rTg4510 mosue line has a tauopathy-like phenotype which is attributed to overexpression of human tau in the frontal cortex. Here the authors identify potential confounding genetic factors that could contribute to the phenotype.
- Julia Gamache
- , Kellie Benzow
- & Michael D. Koob
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Article
| Open AccessAβ-induced vulnerability propagates via the brain’s default mode network
Amyloid-β (Aβ) deposition occurs in Alzheimer's disease but its relation to disease features such as local brain hypometabolism or cognitive decline is unclear. Here, the authors show that Aβ aggregation in the brain’s default mode network leads to hypometabolism in distant but functionally connected areas.
- Tharick A. Pascoal
- , Sulantha Mathotaarachchi
- & Pedro Rosa-Neto
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Article
| Open AccessTau binding protein CAPON induces tau aggregation and neurodegeneration
To understand the molecular processes that link Aβ amyloidosis, tauopathy and neurodegeneration, the authors screened for tau-interacting proteins. They demonstrated that a novel tau binding protein CAPON accelerates tau pathology and neuronal cell death in an Alzheimer’s disease mouse model.
- Shoko Hashimoto
- , Yukio Matsuba
- & Takashi Saito
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Article
| Open AccessThe viral protein corona directs viral pathogenesis and amyloid aggregation
The protein corona around artificial nanoparticles is known to influence activity and biological fate, the formation around viruses is less well understood. Here, the authors observe the formation of protein corona on viruses and study the effects this corona has on viral infectivity and on amyloid protein assembly.
- Kariem Ezzat
- , Maria Pernemalm
- & Samir EL Andaloussi
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Article
| Open AccessEpigenetic dysregulation of enhancers in neurons is associated with Alzheimer’s disease pathology and cognitive symptoms
Epigenetic control of enhancers may contribute to neurological disease. Here the authors carry out genome-wide analysis of DNA methylation in neurons isolated postmortem from patients with Alzheimer’s disease.
- Peipei Li
- , Lee Marshall
- & Viviane Labrie
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Article
| Open AccessAβ34 is a BACE1-derived degradation intermediate associated with amyloid clearance and Alzheimer’s disease progression
Aβ34 is generated from degradation of Aβ40 and Aβ42 by β-secretase. Here, the authors show that Aβ34 is a marker for amyloid clearance and is elevated in the CSF of patients that go on to convert from mild cognitive impairment to Alzheimer’s disease, suggesting it may be a useful biomarker.
- Filip Liebsch
- , Luka Kulic
- & Gerhard Multhaup
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| Open AccessInterpretable classification of Alzheimer’s disease pathologies with a convolutional neural network pipeline
Convolutional neural networks have been applied to various areas of medical imaging and histology. Here the authors develop an automated approach using interpretable neural networks to determine Alzheimer’s disease plaque and cerebral amyloid angiopathy burden in post-mortem human brain tissue.
- Ziqi Tang
- , Kangway V. Chuang
- & Brittany N. Dugger
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Article
| Open AccessSIRT3 mediates hippocampal synaptic adaptations to intermittent fasting and ameliorates deficits in APP mutant mice
Intermittent fasting has been shown to have beneficial effects on hippocampal function in rodents, but the underlying mechanism is not fully understood. Here the authors show that the mitochondrial protein SIRT3 contributes to the beneficial cognitive and synaptic effects of intermittent fasting in mice.
- Yong Liu
- , Aiwu Cheng
- & Mark P. Mattson
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Article
| Open AccessThe BIN1 rs744373 SNP is associated with increased tau-PET levels and impaired memory
The BIN1 SNP rs744373 is associated with higher CSF tau and phosphorylated tau levels. Here the authors show, using PET imaging, that this SNP is associated with tau accumulation in the brain as well as impaired memory in older individuals without dementia.
- Nicolai Franzmeier
- , Anna Rubinski
- & Ansgar J. Furst
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Article
| Open AccessLarge-scale proteomic analysis of human brain identifies proteins associated with cognitive trajectory in advanced age
Cognitive abilities tend to decline over time in advanced age, yet some individuals experience stable abilities or rapid decline. Here the authors present a proteome-wide association study of cognitive trajectory, and identify 38 proteins associated with cognitive resilience.
- Aliza P. Wingo
- , Eric B. Dammer
- & Thomas S. Wingo
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Article
| Open AccessSoluble TREM2 ameliorates pathological phenotypes by modulating microglial functions in an Alzheimer’s disease model
TREM2 is a genetic risk factor for Alzheimer’s disease, and soluble TREM2 (sTREM2) in the CSF correlates with AD progression. Here the authors study the role of sTREM2 in a mouse model of Alzheimer’s disease, and find it reduces amyloid accumulation and increases the numbers of plaque-associated microglia which correlates with improved behavioural function in the mice.
- Li Zhong
- , Ying Xu
- & Xiao-Fen Chen
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Article
| Open AccessAmyloid β oligomers suppress excitatory transmitter release via presynaptic depletion of phosphatidylinositol-4,5-bisphosphate
The underlying mechanism of amyloid β (Aβ) oligomer-induced aberrant neurotransmitter release remains unclear. Here, authors show that the release probability at the synapse between the Schaffer collateral and CA1 pyramidal neurons is significantly reduced at an early stage in mouse models of AD with elevated Aβ production and is mainly due to an mGluR5-mediated depletion of PIP2 in axons.
- Yang He
- , Mengdi Wei
- & Yu-Dong Zhou
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Article
| Open AccessPD-1/PD-L1 checkpoint blockade harnesses monocyte-derived macrophages to combat cognitive impairment in a tauopathy mouse model
Blocking the PD-1 pathway was shown to be effective in amyloid beta mouse models, yet little is known about its therapeutic potential in models of tauopathy. The authors show here that blocking PD-L1, a PD-1 ligand, is similarly effective, and that both treatments reversed cognitive deficiencies, and modified disease pathology not only in an animal model of AD, but also in the DM-hTAU mouse tauopathy model, through a mechanism that involves monocyte-derived macrophages.
- Neta Rosenzweig
- , Raz Dvir-Szternfeld
- & Michal Schwartz
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Article
| Open AccessCRISPR/Cas9 editing of APP C-terminus attenuates β-cleavage and promotes α-cleavage
Gene editing strategies are typically designed to correct mutant genes, but most neurodegenerative diseases are sporadic. Here the authors describe a strategy to selectively edit the C-terminus of APP and attenuate amyloid-β production, while upregulating neuroprotective α-cleavage.
- Jichao Sun
- , Jared Carlson-Stevermer
- & Subhojit Roy
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Article
| Open AccessPresenilin-mediated cleavage of APP regulates synaptotagmin-7 and presynaptic plasticity
Mutations in presenilin, which cleaves amyloid precursor protein, cause familial Alzheimer’s Disease. Here, the authors show that loss of presenilin leads to loss of synaptotagmin 7, leading to impaired presynaptic release.
- Gaël Barthet
- , Tomàs Jordà-Siquier
- & Christophe Mulle
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Article
| Open AccessAPOE ε2 is associated with increased tau pathology in primary tauopathy
The APOE ε4 allele is a strong genetic risk factor for Alzheimer’s disease, whereas the APOE ε2 allele is protective. Here the authors show that mice expressing the human APOE ε2/ε2 genotype have increased tau pathology and related behavioral deficits; they also find that the APOE ε2 allele is associated with an increased burden of tau pathology in postmortem human brains with progressive supranuclear palsy.
- Na Zhao
- , Chia-Chen Liu
- & Guojun Bu
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Article
| Open AccessCaspase-1 inhibition alleviates cognitive impairment and neuropathology in an Alzheimer’s disease mouse model
Caspase-1, activated by stress in immune cells and in CNS human neurons, may contribute to neuronal degeneration. Here, the authors investigate the therapeutic potential of a Caspase-1 inhibitor in a mouse model of Alzheimer’s disease.
- Joseph Flores
- , Anastasia Noël
- & Andréa C. LeBlanc
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| Open AccessOverexpression of endophilin A1 exacerbates synaptic alterations in a mouse model of Alzheimer’s disease
Endophilin A1 protein is known to be elevated in Alzheimer’s disease (AD). Here the authors show that endophilin A1 overexpression exacerbates synaptic deficits in a mouse model of AD.
- Qing Yu
- , Yongfu Wang
- & Shirley ShiDu Yan
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Article
| Open AccessBlood–brain barrier opening in Alzheimer’s disease using MR-guided focused ultrasound
Magnetic resonance-guided focused ultrasound with injected microbubbles has been used to temporarily open the blood–brain barrier (BBB) in animal models of Alzheimer's disease (AD). Here, the authors use this technology to non-invasively open the BBB in 5 patients with mild-to-moderate AD in a phase I trial, and show that the procedure is safe.
- Nir Lipsman
- , Ying Meng
- & Sandra E. Black
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Article
| Open AccessIntroduction of pathogenic mutations into the mouse Psen1 gene by Base Editor and Target-AID
CRISPR-guided cytidine deaminases, including BE3 (Base Editor 3) and Target-AID (activation-induced cytidine deaminase), can covert C:G base pairs to T:A at target site. Here, the authors generate missense mutations of mouse Psen1 gene and find BE3 has higher editing efficiency than Target-AID.
- Hiroki Sasaguri
- , Kenichi Nagata
- & Takaomi C. Saido
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Article
| Open AccessDirect reprogramming of fibroblasts into neural stem cells by single non-neural progenitor transcription factor Ptf1a
Fibroblasts can be reprogrammed into induced neural stem cells (iNSCs) using transcription factors expressed in neural progenitors. Here the authors show that Ptf1a, which is normally expressed in postmitotic neurons, can reprogram fibroblasts to iNSCs through Notch independent interaction with Rbpj.
- Dongchang Xiao
- , Xiaoning Liu
- & Mengqing Xiang
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Article
| Open AccessAn in vitro paradigm to assess potential anti-Aβ antibodies for Alzheimer’s disease
The optimal Aβ species to target for the potential treatment of Alzheimer’s disease has not yet been established. Here, the authors describe an in vitro assay that uses extracts from brain tissue from patients with Alzheimer’s disease, and application to human iPSC-derived neurons, to compare the neuroprotective potential of several anti-Aβ antibodies.
- Ming Jin
- , Brian O’Nuallain
- & Dominic M. Walsh
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| Open AccessGeneration of App knock-in mice reveals deletion mutations protective against Alzheimer’s disease-like pathology
To date, only one mutation in the gene for amyloid-beta precursor protein APP has been suggested to be protective against Alzheimer’s disease. Here, authors found using gene editing of a mutant App knock-in mouse line that deletion of the 3’UTR region is protective against amyloid-β accumulation in vivo, and subsequently identify a 52-bp element in the 3’UTR region that is responsible for this effect.
- Kenichi Nagata
- , Mika Takahashi
- & Takaomi C. Saido
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Article
| Open AccessC/EBPβ regulates delta-secretase expression and mediates pathogenesis in mouse models of Alzheimer’s disease
Delta-secretase cleaves both APP and Tau, and contributes to Alzheimer’s disease-like pathology. Here the authors show that C/EBPβ, a regulator of inflammation, also regulates transcription of delta-secretase in an age-dependent manner and contributes to Alzheimer’s disease-like pathology in mouse models.
- Zhi-Hao Wang
- , Ke Gong
- & Keqiang Ye
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Article
| Open AccessNeuronal SphK1 acetylates COX2 and contributes to pathogenesis in a model of Alzheimer’s Disease
Sphingosine kinase (SphK) converts sphingosine into lipids, and is implicated in inflammation. Here the authors show that SphK1 functions as an acetyltransferase, regulates microglial phagocytosis and is reduced in a model of Alzheimer’s Disease, such that its restoration ameliorates pathology
- Ju Youn Lee
- , Seung Hoon Han
- & Hee Kyung Jin
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Article
| Open AccessA common mechanism of proteasome impairment by neurodegenerative disease-associated oligomers
Disruption of the ubiquitin proteasome system (UPS) is often associated with neurodegenerative diseases. Here the authors demonstrate the existence of a general mechanism of proteasomal impairment triggered by a specific protein oligomer structure, irrespective of its protein constituent.
- Tiffany A. Thibaudeau
- , Raymond T. Anderson
- & David M. Smith
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Article
| Open AccessDiscovery and characterization of stable and toxic Tau/phospholipid oligomeric complexes
The Alzheimer protein Tau interacts with biological membranes, but the role of these interactions in regulating Tau function in health and disease remains unexplored. Here, the authors report on the discovery and characterization of neurotoxic oligomeric protein/phospholipid complexes.
- Nadine Ait-Bouziad
- , Guohua Lv
- & Hilal A. Lashuel
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Article
| Open AccessImpairments of spatial memory in an Alzheimer’s disease model via degeneration of hippocampal cholinergic synapses
Cholinergic neurons in the diagonal band of Broca degenerate early in Alzheimer’s disease. Here the authors show that in healthy mice, these cholinergic inputs innervate newborn neurons in the hippocampus, and that loss of this innervation in an Alzheimer’s disease model leads to impairments in spatial memory.
- Houze Zhu
- , Huanhuan Yan
- & Youming Lu
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Article
| Open AccessER-associated degradation regulates Alzheimer’s amyloid pathology and memory function by modulating γ-secretase activity
Endoplasmic-reticulum associated degradation (ERAD) regulates protein homeostasis. Here the authors identify an ERAD component membralin, and show that it interacts with a member of the γ-secretase complex to regulate β-amyloid (Aβ) pathology and memory deficits in an Alzheimer’s disease model.
- Bing Zhu
- , LuLin Jiang
- & Huaxi Xu
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Article
| Open AccessNeuronal hyperactivity due to loss of inhibitory tone in APOE4 mice lacking Alzheimer’s disease-like pathology
The APOE4 allele is the leading risk factor for late-onset Alzheimer’s disease, but how it might contribute to the disease is not clear. Here the authors show that a mouse expressing the human APOE4 allele displays hyperactivity in the entorhinal cortex due to a decreased inhibitory tone, which may in part explain accelerated Alzheimer’s pathology in APOE4 carriers.
- Tal Nuriel
- , Sergio L. Angulo
- & Karen E. Duff
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Article
| Open AccessIdentification of a peptide recognizing cerebrovascular changes in mouse models of Alzheimer’s disease
Cerebrovascular changes and astrogliosis occur in Alzheimer’s disease (AD). Using an in vivo phage display technique, the authors identified a peptide that upon systematic administration, can home to brain endothelial cells and astrocytes in mouse models of AD at the early stages of the disease.
- Aman P. Mann
- , Pablo Scodeller
- & Erkki Ruoslahti
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Article
| Open AccessEarliest accumulation of β-amyloid occurs within the default-mode network and concurrently affects brain connectivity
Abnormal levels of Aβ42 in the cerebrospinal fluid occur prior to a positive amyloid PET scan in the brain of individuals with Alzheimer’s disease and here the authors use this temporal pattern to identify individuals with very early stage AD. They show that Aβ fibrils start to accumulate in some of the regions of the default mode network and affect brain connectivity before neurodegeneration occurs.
- Sebastian Palmqvist
- , Michael Schöll
- & Oskar Hansson
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Article
| Open AccessSeed-induced acceleration of amyloid-β mediated neurotoxicity in vivo
Seeding of amyloid beta from one brain region to another is thought to contribute to the progression of Alzheimer’s disease, although to date most studies have depended on inoculation of animals with exogenous amyloid. Here the authors describe a genetic seed and target system in Drosophila which may be useful for the mechanistic study of seeding of amyloid in vivo.
- Ramona F. Sowade
- & Thomas R. Jahn
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Article
| Open AccessTau association with synaptic vesicles causes presynaptic dysfunction
Mislocalisation of tau occurs in several neurodegenerative diseases and is thought to contribute to synaptic function. The authors show that presynaptically, tau binds to synaptic vesicles via the N-terminus which contributes to synaptic dysfunction.
- Lujia Zhou
- , Joseph McInnes
- & Patrik Verstreken
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Article
| Open AccessDiurnal and seasonal molecular rhythms in human neocortex and their relation to Alzheimer’s disease
Diurnal and seasonal rhythms modulate brain function, but we do not know the genomic basis for these rhythms. Here, Limet al. show diurnal and seasonal rhythms of gene expression in the human brain, their relationship to histone acetylation and DNA methylation, and their disruption in Alzheimer’s disease.
- Andrew S. P. Lim
- , Hans-Ulrich Klein
- & Philip L. De Jager
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Article
| Open AccessDopamine neuronal loss contributes to memory and reward dysfunction in a model of Alzheimer’s disease
Dopaminergic dysfunction occurs in Alzheimer’s disease (AD). The authors show that in a mouse model of AD, loss of dopaminergic neurons in the ventral tegmental area, but not the substantia nigra, occurs at early pre-plaque stages, and may contribute to impaired cognition and reward processing.
- Annalisa Nobili
- , Emanuele Claudio Latagliata
- & Marcello D’Amelio
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Article
| Open AccessInhibition of delta-secretase improves cognitive functions in mouse models of Alzheimer’s disease
Delta-secretases are associated with Alzheimer’s disease (AD) as they cleave both amyloid precursor protein and tau. Here the authors develop a series of orally bioactive small molecule delta-secretase inhibitors and report its therapeutic effects in mouse models of AD.
- Zhentao Zhang
- , Obiamaka Obianyo
- & Keqiang Ye