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| Open AccessA machine learning approach to brain epigenetic analysis reveals kinases associated with Alzheimer’s disease
Array-based epigenome-wide association studies only test about 2% of the CpG sites in the genome. Here, the authors describe EWASplus, a supervised machine learning strategy that extends EWAS coverage to the entire genome, and use it to identify novel brain CpGs associated with Alzheimer’s disease.
- Yanting Huang
- , Xiaobo Sun
- & Zhaohui S. Qin
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Article
| Open AccessPhosphorylated tau181 in plasma as a potential biomarker for Alzheimer’s disease in adults with Down syndrome
Plasma tau phosphorylated at threonine 181 (p-tau181) predicts Alzheimer’s disease (AD) pathology. Here, the authors investigated whether plasma ptau181 could be a potential biomarker of AD in individuals with Down syndrome (DS) and find plasma p-tau181 can detect AD in DS adults.
- Alberto Lleó
- , Henrik Zetterberg
- & Juan Fortea
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| Open AccessCo-factor-free aggregation of tau into seeding-competent RNA-sequestering amyloid fibrils
The authors present a method for the conversion of full-length tau protein into seeding-competent amyloid fibrils without heparin or other negatively charged co-factors, which could be useful for studying the effects of post-translational modifications on Tau aggregation as well as to identify potential inhibitors of tau aggregation. Biochemical experiments and solid-state NMR spectroscopy measurements show that these co-factor-free tau fibrils have similar properties as amyloid fibrils isolated from brain tissue but differ from those of commonly used heparin-induced tau fibrils.
- Pijush Chakraborty
- , Gwladys Rivière
- & Markus Zweckstetter
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| Open AccessHigher CSF sTNFR1-related proteins associate with better prognosis in very early Alzheimer’s disease
Neuroinflammation is observed in Alzheimer’s disease. Here the authors show that 15 proteins related to inflammation found in CSF can potentially be used as a prognostic biomarker.
- William T. Hu
- , Tugba Ozturk
- & Gloria Chiang
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Article
| Open AccessKL-VS heterozygosity is associated with lower amyloid-dependent tau accumulation and memory impairment in Alzheimer’s disease
The KL-VS haplotype of the Klotho gene has been associated with reduced risk of Alzheimer’s disease and dementia. Here the authors show an association between the KL-VS haplotype and amyloid-dependent tau accumulation using PET data.
- Julia Neitzel
- , Nicolai Franzmeier
- & Michael Ewers
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| Open AccessPlasma biomarkers of Alzheimer’s disease improve prediction of cognitive decline in cognitively unimpaired elderly populations
Plasma biomarkers of amyloid, tau and neurodegeneration (ATN) need to be characterized in cognitively unimpaired (CU) elderly individuals. Here, the authors show plasma ATN biomarkers predict clinical deterioration and cognitive decline and show in a simulated clinical trial combining all three biomarkers reduced the required sample size.
- Nicholas C. Cullen
- , Antoine Leuzy
- & Oskar Hansson
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| Open AccessA meta-analysis of epigenome-wide association studies in Alzheimer’s disease highlights novel differentially methylated loci across cortex
Although epigenome-wide association studies of Alzheimer’s disease have highlighted neuropathology-associated DNA methylation differences, previous studies have been limited in sample size and brain region used. Here, the authors combine data from six DNA methylomic studies of Alzheimer’s disease (N = 1453 unique individuals) to identify differentially methylated loci across cortex.
- Rebecca G. Smith
- , Ehsan Pishva
- & Katie Lunnon
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Article
| Open AccessAβ receptors specifically recognize molecular features displayed by fibril ends and neurotoxic oligomers
PrPC, a receptor for Aβ oligomers, blocks polarized elongation of Aβ fibrils by binding to the rapidly growing end of each fibril. PrPC and other receptors may trap Aβ oligomers and protofibrils on the neuronal surface by binding to a common molecular determinant, initiating a neurotoxic signal.
- Ladan Amin
- & David A. Harris
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Article
| Open AccessPhospholipids of APOE lipoproteins activate microglia in an isoform-specific manner in preclinical models of Alzheimer’s disease
Microglia can clear amyloid plaques in Alzheimer’s disease. Here, the authors show that specific isoforms of the phospholipid forming APOE lipoproteins activate microglia in pre-clinical mouse models of Alzheimer’s disease.
- Nicholas F. Fitz
- , Kyong Nyon Nam
- & Radosveta Koldamova
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Article
| Open AccessUBE4B, a microRNA-9 target gene, promotes autophagy-mediated Tau degradation
Hyperphosphorylated Tau accumulation promotes neurodegeneration in Alzheimer’s disease. Here, the authors screen a miRNA library in Drosophila and identify a conserved ubiquitin ligase that directs Tau for autophagic degradation, uncovering a potential target to treat Tau-mediated neurodegeneration.
- Manivannan Subramanian
- , Seung Jae Hyeon
- & Kweon Yu
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Article
| Open AccessNon-productive angiogenesis disassembles Aß plaque-associated blood vessels
Aß are extracellular deposits relevant in Alzheimer’s disease (AD). This study shows that Aß plaques are hubs of endothelial disassembly that induce non-productive angiogenesis. This process is aided by the microglia and unchained by reduced presenilin function, a trait of AD, in endothelial cells.
- Maria I. Alvarez-Vergara
- , Alicia E. Rosales-Nieves
- & Alberto Pascual
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| Open AccessTranscriptional signature in microglia associated with Aβ plaque phagocytosis
Microglia associated with Aβ plaques may have a distinct transcriptional signature compared to those in plaque-free areas of the brain in Alzheimer’s disease (AD) models. Here the authors show that amyloid plaque phagocytosis is associated with a specific microglia transcriptional signature in a mouse model of AD.
- Alexandra Grubman
- , Xin Yi Choo
- & Jose M. Polo
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| Open AccessIncreased excitatory to inhibitory synaptic ratio in parietal cortex samples from individuals with Alzheimer’s disease
Synaptic loss may disturb the excitatory to inhibitory balance (E/I ratio) in circuits vulnerable in Alzheimer’s disease (AD). The authors find reduced synaptic levels of PSD-95 and gephyrin and show that individuals with AD exhibit a pro-excitatory shift of postsynaptic densities and the electrophysiological synaptic E/I ratio in the parietal cortex.
- Julie C. Lauterborn
- , Pietro Scaduto
- & Agenor Limon
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| Open AccessGeneration of a humanized Aβ expressing mouse demonstrating aspects of Alzheimer’s disease-like pathology
Most instances of Alzheimer’s disease (AD) are sporadic or not associated with a particular mutation. Here, the authors develop knock-in mice that express wildtype human Aβ under control of the mouse App locus, which may have potential for modelling some aspects of sporadic late onset AD.
- David Baglietto-Vargas
- , Stefania Forner
- & Frank M. LaFerla
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| Open AccessTranscriptomic analysis to identify genes associated with selective hippocampal vulnerability in Alzheimer’s disease
Alzheimer’s disease (AD) is typically associated with hippocampal and cortical pathology, although hippocampal sparing and limbic predominant forms exist. The authors use transcriptomic analysis and neuropathology to identify genes associated with selective hippocampal vulnerability in AD.
- Angela M. Crist
- , Kelly M. Hinkle
- & Melissa E. Murray
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| Open AccessTherapeutic B-cell depletion reverses progression of Alzheimer’s disease
Alzheimer’s disease is characterized by progressive dementia and amyloid beta plaque deposition. Here the authors show in three relevant transgenic animal models that accumulation of activated B cells is central to AD pathology and depletion of B cells interferes with both histological and behavioural manifestations of the disease.
- Ki Kim
- , Xin Wang
- & Arya Biragyn
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| Open AccessHuman-lineage-specific genomic elements are associated with neurodegenerative disease and APOE transcript usage
Knowledge of genomic features specific to humans may be important for understanding disease. Here the authors demonstrate a potential role for these human-lineage-specific sequences in brain development and neurological disease.
- Zhongbo Chen
- , David Zhang
- & Mina Ryten
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| Open AccessLoss of microglial SIRPα promotes synaptic pruning in preclinical models of neurodegeneration
Microglial SIRPα regulates synaptic pruning during development. Its role in neurodegeneration is unclear. Here, the authors show microglial SIRPα declines in the model of Alzheimer’s disease, leading to excessive microglia mediated synapse elimination as well as impaired cognitive function.
- Xin Ding
- , Jin Wang
- & Liang Li
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| Open AccessCryo-EM structure of amyloid fibrils formed by the entire low complexity domain of TDP-43
Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) patients have brain deposits with amyloid-like aggregates from large C-terminal fragments of the transactive response DNA-binding protein of 43 kDa (TDP-43). Here, the authors present the cryo-EM structure of amyloid fibrils generated from the complete C-terminal TDP-43 low complexity domain and they discuss the effects of disease-causing mutations and phosphorylation of specific Ser residues.
- Qiuye Li
- , W. Michael Babinchak
- & Witold K. Surewicz
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| Open AccessIntegration of Alzheimer’s disease genetics and myeloid genomics identifies disease risk regulatory elements and genes
This study integrates Alzheimer’s disease (AD) GWAS data with myeloid cell genomics, and reports that myeloid active enhancers are most burdened by AD risk alleles. The authors also nominate candidate causal regulatory elements, variants and genes that likely modulate the risk for AD.
- Gloriia Novikova
- , Manav Kapoor
- & Alison M. Goate
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| Open AccessMachine learning identifies candidates for drug repurposing in Alzheimer’s disease
Clinical trials of novel therapeutics for Alzheimer’s Disease (AD) have provided largely negative results, so far. Here, the authors present a machine learning framework that quantifies potential associations between the pathology of AD severity and gene-based molecular mechanisms to enable drug repurposing.
- Steve Rodriguez
- , Clemens Hug
- & Artem Sokolov
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| Open AccessAsymmetric thinning of the cerebral cortex across the adult lifespan is accelerated in Alzheimer’s disease
Cortical thickness is asymmetric, and cortical thinning occurs with age and in disease. Here the authors investigate if both cortices thin at the same rate or if the thicker hemisphere declines faster in aging and in Alzheimer’s disease.
- James M. Roe
- , Didac Vidal-Piñeiro
- & Michael Vacher
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| Open AccessA logical network-based drug-screening platform for Alzheimer’s disease representing pathological features of human brain organoids
Developing effective drugs for Alzheimer’s disease (AD), the most common cause of dementia, has been difficult because of complicated pathogenesis. Here, the authors report an efficient network-based drug-screening platform developed by integrating mathematical modeling and the pathological features of human cerebral organoids.
- Jong-Chan Park
- , So-Yeong Jang
- & Inhee Mook-Jung
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| Open AccessSingle cell RNA sequencing of human microglia uncovers a subset associated with Alzheimer’s disease
Imbalance of microglial phenotypes in the aging brain might underlie their involvement in late onset neurodegenerative diseases. Here we report the population structure of microglia in the aged human brain and the reduction of a particular microglia subset in individuals with Alzheimer’s disease .
- Marta Olah
- , Vilas Menon
- & Philip L. De Jager
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| Open AccessTDP-43 interacts with amyloid-β, inhibits fibrillization, and worsens pathology in a model of Alzheimer’s disease
TDP-43 inclusions are observed in Alzheimer’s disease. Here the authors show that TDP-43 interacts with amyloid-β and inhibits fibrillization in vitro and exacerbates Alzheimer’s disease pathology in animal models.
- Yao-Hsiang Shih
- , Ling-Hsien Tu
- & Yun-Ru Chen
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| Open AccessPharmacological targeting of MCL-1 promotes mitophagy and improves disease pathologies in an Alzheimer’s disease mouse model
Previous work suggests that mitophagy in neurons is could be therapeutic in Alzheimer’s disease (AD). Here, the authors screen a library of drugs and identify UMI-77, a mitophagy inducer with beneficial effects in an AD mouse model, by binding MCL-1, which they identify as a mitophagy receptor.
- Xufeng Cen
- , Yanying Chen
- & Hongguang Xia
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Article
| Open AccessAPOE4 exacerbates synapse loss and neurodegeneration in Alzheimer’s disease patient iPSC-derived cerebral organoids
APOE4 is a strong genetic risk factor for late-onset Alzheimer’s disease. Here, the authors show that APOE4 is associated with AD features in hiPSCs-derived cerebral organoids. Isogenic conversion of APOE4 to APOE3 attenuates the AD-associated phenotype.
- Jing Zhao
- , Yuan Fu
- & Guojun Bu
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| Open AccessGene expression and functional deficits underlie TREM2-knockout microglia responses in human models of Alzheimer’s disease
Mutations in TREM2 alter risk for Alzheimer’s disease, though the mechanisms underlying risk in human cells are unclear. Here, the authors use iPS-microglia and chimeric mice to highlight altered survival, phagocytosis, migration, and transcriptional programs in microglia lacking TREM2.
- Amanda McQuade
- , You Jung Kang
- & Mathew Blurton-Jones
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| Open AccessRisk prediction of late-onset Alzheimer’s disease implies an oligogenic architecture
Despite the identification of genetic risk loci for late-onset Alzheimer’s disease (LOAD), the genetic architecture and prediction remains unclear. Here, the authors use genetic risk scores for prediction of LOAD across three datasets and show evidence suggesting oligogenic variant architecture for this disease.
- Qian Zhang
- , Julia Sidorenko
- & Peter M. Visscher
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| Open AccessChiral gold nanoparticles enantioselectively rescue memory deficits in a mouse model of Alzheimer’s disease
Nanoparticles are being explored as a potential method to target Aβ aggregation in Alzheimer’s disease. Here, the authors develop gold nanoparticles that were capped with chiral L or D-glutathione which has been shown to improve BBB permeability and demonstrate their ability to improve cognitive function in a mouse model of AD.
- Ke Hou
- , Jing Zhao
- & Zhiyong Tang
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| Open AccessPre-symptomatic Caspase-1 inhibitor delays cognitive decline in a mouse model of Alzheimer disease and aging
Previous work showed that the caspase 1 inhibitor VX-765 rescued cognitive deficits in the J20 mouse model of Alzheimer’s disease, and this may occur via reduced inflammation. Here the authors show that administration of the drug prior to onset of cognitive deficits and pathology in mice delays the onset of deficits.
- Joseph Flores
- , Anastasia Noël
- & Andréa C. LeBlanc
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| Open AccessPharmacologically reversible zonation-dependent endothelial cell transcriptomic changes with neurodegenerative disease associations in the aged brain
Blood–brain barrier dysfunction occurs in ageing and in neurodegenerative diseases. Here, the authors use scRNA-seq to identify transcriptomic changes in endothelial cell subtypes in the aged mouse brain, some of which may generalize to human and can be reversed by treatment with a GLP-1R agonist.
- Lei Zhao
- , Zhongqi Li
- & Ho Ko
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Article
| Open AccessRNA-binding proteins Musashi and tau soluble aggregates initiate nuclear dysfunction
The Musashi family of RNA binding proteins are found in an oligomeric state in the brains of patients with Alzheimer’s disease. Here the authors show that Mushashi1 and Musashi2 interact with tau protein in patient tissue and in models of tauopathy.
- Mauro Montalbano
- , Salome McAllen
- & Rakez Kayed
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| Open AccessLiquid-liquid phase separation induces pathogenic tau conformations in vitro
Tau plays an important role in tauopathies and undergoes liquid-liquid phase separation (LLPS). The authors show that disease-related P301L mutant and phosphomimic (S199E/S202E/T205E) tau enhance LLPS in vitro at physiological levels, and using specific antibodies, that tau LLPS leads to pathological conformations such as N-terminal exposure and oligomeric species.
- Nicholas M. Kanaan
- , Chelsey Hamel
- & Benjamin Combs
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| Open AccessSpread of pathological tau proteins through communicating neurons in human Alzheimer’s disease
The tau protein is theorized to spread transneuronally in Alzheimers disease, though this theory remains unproven in humans. Our simulations of epidemic-like protein spreading across human brain networks support this theory, and suggest the spreading dynamics are modified by β-amyloid
- Jacob W. Vogel
- , Yasser Iturria-Medina
- & Per Wollmer
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| Open AccessHDAC1 modulates OGG1-initiated oxidative DNA damage repair in the aging brain and Alzheimer’s disease
Defects in DNA repair have been linked to brain aging and neurodegenerative disorders. Here the authors reveal a role for HDAC1 in stimulating OGG1 activity to alleviate 8-oxoG lesions with implications in the aging brain and neurodegenerative diseases.
- Ping-Chieh Pao
- , Debasis Patnaik
- & Li-Huei Tsai
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| Open AccessN-AS-triggered SPMs are direct regulators of microglia in a model of Alzheimer’s disease
Neuronal sphingosine kinase 1 (SphK1) acetylates COX2 which is needed for microglial phagocytosis activity, and release of pro-resolving mediators (SPMs) from neurons. Here the authors examine how SphK1-mediates COX2 acetylation, and how this leads to increased secretion of SPMs from neurons in the context of Alzheimer’s disease models.
- Ju Youn Lee
- , Seung Hoon Han
- & Jae-sung Bae
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Article
| Open AccessIncreased mitochondrial calcium levels associated with neuronal death in a mouse model of Alzheimer’s disease
Calvo-Rodriguez et al. show elevated calcium levels in neuronal mitochondria in a mouse model of cerebral β-amyloidosis after plaque deposition, which precede rare neuron death events in this model. The mechanism involves toxic extracellular Aβ oligomers and the mitochondrial calcium uniporter.
- Maria Calvo-Rodriguez
- , Steven S. Hou
- & Brian J. Bacskai
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Article
| Open AccessCerebrospinal fluid p-tau217 performs better than p-tau181 as a biomarker of Alzheimer’s disease
Cerebrospinal fluid (CSF) p-tau181 (tau phosphorylated at threonine 181) is an established biomarker of Alzheimer’s disease (AD) reflecting abnormal tau metabolism in the AD brain. Here the authors demonstrate that CSF p-tau217 shows better performance as an AD biomarker than p-tau181.
- Shorena Janelidze
- , Erik Stomrud
- & Oskar Hansson
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Article
| Open AccessAmyloid-β42/40 ratio drives tau pathology in 3D human neural cell culture models of Alzheimer’s disease
The relationship between amyloid-β species and tau pathology in Alzheimer’s disease is not fully understood. Here, the authors show that it is the increased ratio of amyloid-β42 and 40 isoforms drives tau pathology in 3D human neural cell culture models of the disease.
- Sang Su Kwak
- , Kevin J. Washicosky
- & Doo Yeon Kim
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Article
| Open AccessSex and APOE ε4 genotype modify the Alzheimer’s disease serum metabolome
Sex and the APOE ε4 genotype are important risk factors for late-onset Alzheimer’s disease. In the current study, the authors investigate how sex and APOE ε4 genotype modify the association between Alzheimer’s disease biomarkers and metabolites in serum.
- Matthias Arnold
- , Kwangsik Nho
- & Gabi Kastenmüller
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| Open AccessExceptionally low likelihood of Alzheimer’s dementia in APOE2 homozygotes from a 5,000-person neuropathological study
APOE is the major genetic risk factor for Alzheimer’s disease. In a large number of neuropathologically confirmed cases and controls, the impact of different APOE genotypes on Alzheimer’s dementia risk was greater than previously thought and APOE2 homozygotes had an exceptionally low risk.
- Eric M. Reiman
- , Joseph F. Arboleda-Velasquez
- & Yi Zhao
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Article
| Open AccessCerebrospinal fluid lipocalin 2 as a novel biomarker for the differential diagnosis of vascular dementia
Diagnosis of vascular dementia is hampered by the lack of biochemical markers for this disease. Here, the authors show that vascular dementia is associated with increased lipocalin-2 in cerebrospinal fluid, compared to controls and patients with other forms of dementia.
- Franc Llorens
- , Peter Hermann
- & Inga Zerr
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Article
| Open AccessYAP-dependent necrosis occurs in early stages of Alzheimer’s disease and regulates mouse model pathology
The precise mechanisms of neuronal cell death in neurodegeneration are not fully understood. Here the authors show that YAP-mediated neuronal necrosis is increased in pre-symptomatic stages of Alzheimer’s disease and intervention to the necrosis rescues extracellular Aβ aggregation and symptoms in a mouse model.
- Hikari Tanaka
- , Hidenori Homma
- & Hitoshi Okazawa
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Article
| Open AccessFAM222A encodes a protein which accumulates in plaques in Alzheimer’s disease
In this study the authors identify a possible link between the gene FAM222A and brain atrophy. The protein it encodes is found to accumulate in plaques seen in Alzheimer’s disease, and functional analysis suggests it interacts with amyloid-beta.
- Tingxiang Yan
- , Jingjing Liang
- & Xinglong Wang
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Article
| Open AccessFunctional brain architecture is associated with the rate of tau accumulation in Alzheimer’s disease
Tau accumulation is associated with disease progression in Alzheimer’s disease. Here the authors use resting state fMRI and tau-PET to demonstrate that baseline connectivity in Alzheimer's disease is associated with tau spreading.
- Nicolai Franzmeier
- , Julia Neitzel
- & Balebail Ashok Raj
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Article
| Open AccessThe epichaperome is a mediator of toxic hippocampal stress and leads to protein connectivity-based dysfunction
The biology of Alzheimer’s disease (AD) remains unknown. We propose AD is a protein connectivity-based dysfunction disorder whereby a switch of the chaperome into epichaperomes rewires proteome-wide connectivity, leading to brain circuitry malfunction that can be corrected by novel therapeutics.
- Maria Carmen Inda
- , Suhasini Joshi
- & Gabriela Chiosis
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Article
| Open AccessPosterior basolateral amygdala to ventral hippocampal CA1 drives approach behaviour to exert an anxiolytic effect
Projections from the anterior and posterior basolateral amygdala (pBLA) to the ventral hippocampus CA1 (vCA1) are heterogenous. Here the authors show that activating the pathway from pBLA to vCA1 calbindin 1 positive neurons has an anxiolytic effect in approach-avoidance tasks in mice.
- Guilin Pi
- , Di Gao
- & Jian–Zhi Wang
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Article
| Open AccessClinically accurate diagnosis of Alzheimer’s disease via multiplexed sensing of core biomarkers in human plasma
Detection of Alzheimer’s disease (AD) biomarkers from patients’ blood is challenging because these are present in very low concentrations in the plasma. Here the authors develop a sensor array of densely aligned single-walled carbon nanotubes for clinically accurate detection of femtomolar AD biomarkers in human plasma samples.
- Kayoung Kim
- , Min-Ji Kim
- & Chan Beum Park