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| Open AccessBrain proteomic analysis implicates actin filament processes and injury response in resilience to Alzheimer’s disease
Resilience to Alzheimer’s disease (RAD) is an uncommon combination of high disease burden without dementia. The authors perform proteomic analysis of RAD brains and show lower isocortical and hippocampal soluble Aβ levels, actin filament-based processes, cellular detoxification, and wound healing are significant features.
- Zhi Huang
- , Gennifer E. Merrihew
- & Thomas J. Montine
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Article
| Open AccessSingle-nucleus RNA-sequencing of autosomal dominant Alzheimer disease and risk variant carriers
Mutations in amyloid precursor protein (APP) and presenilin 1 (PSEN1) cause autosomal dominant AD (ADAD). Here, the authors perform single-nucleus RNA-sequencing of ADAD and other disease risk modifying variant carriers and report altered expression states of specific brain cell types.
- Logan Brase
- , Shih-Feng You
- & Oscar Harari
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Perspective
| Open AccessAn aging, pathology burden, and glial senescence build-up hypothesis for late onset Alzheimer’s disease
In this perspective, the authors hypothesise that glial senescence, requiring senescent microglia burden, perpetuates further aging, Alzheimer’s pathologies, and senescence. Increasing glial senescence is proposed as necessary to drive individuals from healthy cognition into cognitive decline and dementia.
- Victor Lau
- , Leanne Ramer
- & Marie-Ève Tremblay
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Article
| Open AccessImmunotherapy targeting plasma ASM is protective in a mouse model of Alzheimer’s disease
Acid sphingomyelinase (ASM) is a sphingolipid metabolizing enzyme that catalyzes the hydrolysis of sphingomyelin to ceramide, and previous work has shown it is upregulated in models of Alzheimer’s disease. Here the authors demonstrate in a mouse model of Alzheimer’s disease that antibody-based immunotherapy targeting plasma ASM resulted in attenuated neuropathological features by suppressing pathogenic Th17 cells.
- Byung Jo Choi
- , Min Hee Park
- & Jae-sung Bae
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Article
| Open AccessRescue of astrocyte activity by the calcium sensor STIM1 restores long-term synaptic plasticity in female mice modelling Alzheimer’s disease
Altered Ca2+ signaling is involved in the pathogenesis of Alzheimer’s disease. Here, the authors show Ca2+ hypoactivity in astrocytes at plaque deposition onset related to reduced expression of the Ca2+ sensor STIM1 and impaired synaptic plasticity that was rescued by STIM1 overexpression in astrocytes.
- Annamaria Lia
- , Gabriele Sansevero
- & Micaela Zonta
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Article
| Open AccessN-acetylneuraminic acid links immune exhaustion and accelerated memory deficit in diet-induced obese Alzheimer’s disease mouse model
Obesity and aging increase Alzheimer’s disease (AD) risk. Here, using an AD mouse model and high-fat diet, we suggest that immune exhaustion links the two risk factors, and identify a metabolite that can hasten immune dysfunction and memory deficit.
- Stefano Suzzi
- , Tommaso Croese
- & Michal Schwartz
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Article
| Open AccessSingle-cell RNA-sequencing identifies disease-associated oligodendrocytes in male APP NL-G-F and 5XFAD mice
Oligodendrocytes have been increasingly shown to be involved in Alzheimer’s disease (AD). Here, the authors perform single-cell RNA-sequencing on APP NL-G-F mice and describe a disease-associated oligodendrocyte (DAO) population. They find inhibition of Erk1/2 signaling in DAOs rescues impaired axonal myelination and cognitive decline in an AD mouse model.
- Hanseul Park
- , Byounggook Cho
- & Jongpil Kim
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Article
| Open AccessForecasting individual progression trajectories in Alzheimer’s disease
Accurate prediction of disease progression in Alzheimer’s disease (AD) is necessary for optimal recruitment of patients to clinical trials. Here, the authors present AD Course Map, a statistical model which helps to predict disease progression in participants, thus decreasing the required sample size for a hypothetical trial.
- Etienne Maheux
- , Igor Koval
- & Stanley Durrleman
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Article
| Open AccessInhibition of histone methyltransferase Smyd3 rescues NMDAR and cognitive deficits in a tauopathy mouse model
The study by Williams et al shows targeting the aberrant histone modifying enzyme Smyd3 rescues NMDAR and cognitive deficits in a mouse model of Alzheimer’s disease. It highlights the potential of epigenetic treatment in neurodegenerative diseases.
- Jamal B. Williams
- , Qing Cao
- & Zhen Yan
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Article
| Open AccessOptimal deep brain stimulation sites and networks for stimulation of the fornix in Alzheimer’s disease
Deep brain stimulation has been investigated as a potential treatment for cognitive impairments in Alzheimer’s disease. Here the authors carry out post hoc analysis of multi-center cohorts to investigate the anatomical and functional correlates of effective deep brain stimulation, and find that stimulating circuit of Papez, fornix and bed nucleus of the stria terminalis, and a multi-region functional network, were associated with clinical improvement.
- Ana Sofía Ríos
- , Simón Oxenford
- & Andreas Horn
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Article
| Open AccessCausal inference in medical records and complementary systems pharmacology for metformin drug repurposing towards dementia
Previous observational studies of the diabetes drugs metformin vs. sulfonylureas have yielded mixed results about whether metformin reduces the risk of dementia, relative to the sulfonylureas. Here, the authors apply a novel competing risks approach to emulate dementia-related target trials in electronic health records of diabetic patients and a complementary systems pharmacology evaluation on human neural cells.
- Marie-Laure Charpignon
- , Bella Vakulenko-Lagun
- & Mark W. Albers
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Article
| Open AccessAmyloid-associated increases in soluble tau relate to tau aggregation rates and cognitive decline in early Alzheimer’s disease
The interplay between amyloid and tau pathology in Alzheimer’s disease is still not well understood. Here, the authors show that amyloid-related increased in soluble p-tau is related to subsequent accumulation of tau aggregates and cognitive decline in early stage of the disease.
- Alexa Pichet Binette
- , Nicolai Franzmeier
- & Oskar Hansson
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Article
| Open AccessCholinergic basal forebrain degeneration due to sleep-disordered breathing exacerbates pathology in a mouse model of Alzheimer’s disease
Sleep-disordered breathing is a risk factor for Alzheimer’s disease. Here the authors use mesopontine tegmentum lesion to model sleep disordered breathing in a mouse model of Alzheimer’s disease, and find that some features of the Alzheimer’s disease-like phenotype are exacerbated.
- Lei Qian
- , Oliver Rawashdeh
- & Elizabeth J. Coulson
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Article
| Open AccessSingle cell transcriptomic profiling of a neuron-astrocyte assembloid tauopathy model
Single cell RNA-sequencing of the AstTau neuron-asteroid tau assembloid model reveals excitatory neuron inflammatory signatures and an astrocytic heat shock response similar to that occurring in the brains of individuals with tauopathies, which can be ameliorated with a neuroprotective HSP90 inhibitor.
- Hannah Drew Rickner
- , Lulu Jiang
- & Christine S. Cheng
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Article
| Open AccessPericyte remodeling is deficient in the aged brain and contributes to impaired capillary flow and structure
Using in vivo two-photon imaging, Berthiaume et al. demonstrate how pericyte loss during aging could contribute to deterioration of cerebral blood flow. They also show how pericyte remodeling reduces the deleterious effects of pericyte loss.
- Andrée-Anne Berthiaume
- , Franca Schmid
- & Andy Y. Shih
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Article
| Open AccessDNA methylation signatures of Alzheimer’s disease neuropathology in the cortex are primarily driven by variation in non-neuronal cell-types
Here the authors identify differences in cortical DNA methylation associated with Alzheimer’s disease pathology, and profiling nuclei from specific cell-types, find that most of these differences reflect variation occurring in non-neuronal cells.
- Gemma Shireby
- , Emma L. Dempster
- & Jonathan Mill
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Article
| Open AccessStructure-based discovery of small molecules that disaggregate Alzheimer’s disease tissue derived tau fibrils in vitro
Evidence suggests that fibrous aggregates of protein tau may be the proximal cause of Alzheimer’s disease. Here, using atomic structures of tau fibrils from brains of people with Alzheimer’s disease, the authors have found small-molecule drug leads that disaggregate tau fibrils in vitro.
- Paul M. Seidler
- , Kevin A. Murray
- & David S. Eisenberg
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Article
| Open AccessDesigned peptides as nanomolar cross-amyloid inhibitors acting via supramolecular nanofiber co-assembly
Amyloid self-assembly is linked to type 2 diabetes and Alzheimer’s disease. Here the authors designed constrained peptides which are nanomolar amyloid inhibitors of the key polypeptides IAPP and Aβ42 and act via supramolecular nanofiber co-assembly.
- Karin Taş
- , Beatrice Dalla Volta
- & Aphrodite Kapurniotu
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Article
| Open AccessEarlier Alzheimer’s disease onset is associated with tau pathology in brain hub regions and facilitated tau spreading
Individuals with young onset sporadic Alzheimer’s disease show faster pathological and clinical progression. Here the authors report that earlier symptom onset in Alzheimer’s disease is associated with higher tau pathology in globally connected brain hubs, accelerated connectivity-mediated tau spreading and faster cognitive decline.
- Lukas Frontzkowski
- , Michael Ewers
- & Nicolai Franzmeier
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Article
| Open AccessCross-tissue analysis of blood and brain epigenome-wide association studies in Alzheimer’s disease
DNA methylation differences in Alzheimer’s disease have been previously reported, although the interpretation of the differences is unclear. Here, the authors performed epigenome-wide meta-analyses of DNA methylation in blood and brain, and developed a methylation-based risk prediction model for AD.
- Tiago C. Silva
- , Juan I. Young
- & Lily Wang
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Article
| Open AccessMulti-cohort and longitudinal Bayesian clustering study of stage and subtype in Alzheimer’s disease
Different types of atrophy in Alzheimer’s disease may reflect different disease stages or biologically distinct subtypes. Here the authors use longitudinal neuroimaging data to demonstrate five distinct patterns of atrophy with different demographical and cognitive characteristics.
- Konstantinos Poulakis
- , Joana B. Pereira
- & Eric Westman
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Article
| Open AccessAβ42 oligomers trigger synaptic loss through CAMKK2-AMPK-dependent effectors coordinating mitochondrial fission and mitophagy
Loss of excitatory synapses occur prior to the formation of amyloid plaques in Alzheimer’s disease. Here the authors show in an animal model that the loss of synapses induced by amyloid-beta oligomers requires over-activation of a stress-response pathway inducing structural remodelling of mitochondria in dendrites of cortical and hippocampal neurons.
- Annie Lee
- , Chandana Kondapalli
- & Franck Polleux
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Article
| Open AccessShared mechanisms across the major psychiatric and neurodegenerative diseases
Studying the shared genetic etiology of disease can help improve diagnosis and treatment. Here, the authors find evidence for shared genetic and molecular pathophysiology between several common psychiatric and neurodegenerative diseases using results of 25 GWAS and large-scale human brain transcriptomic and proteomic sequencing.
- Thomas S. Wingo
- , Yue Liu
- & Aliza P. Wingo
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Article
| Open AccessDisruption of tubulin-alpha4a polyglutamylation prevents aggregation of hyper-phosphorylated tau and microglia activation in mice
Pathologic oligomerization of hyper-phosphorylated Tau is a hallmark of tauopathies. Here the authors show that the loss of tubulin a4 polyglutamylation reverses tau hyperphosphorylation, oligomerization and microglia activation in a tauopathy mouse.
- Torben Johann Hausrat
- , Philipp C. Janiesch
- & Matthias Kneussel
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Article
| Open Access[11C]Martinostat PET analysis reveals reduced HDAC I availability in Alzheimer’s disease
The link between amyloid and tau proteins with Alzheimer’s disease progression remains unclear. Here, the authors propose HDACs I downregulation as an element linking the deleterious effects of brain proteinopathies with disease progression.
- Tharick A. Pascoal
- , Mira Chamoun
- & Pedro Rosa-Neto
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Article
| Open AccessHsp multichaperone complex buffers pathologically modified Tau
Alzheimer’s disease is characterized by the accumulation of aggregated tau protein. Here the authors find that Hsp chaperones, which normally protect cell homeostasis, can assemble with co-chaperones in a “multichaperone machinery” to target tau aggregation.
- Antonia Moll
- , Lisa Marie Ramirez
- & Markus Zweckstetter
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Article
| Open AccessCyclic microchip assay for measurement of hundreds of functional proteins in single neurons
Current single-cell tools are limited by the number of proteins they can analyse. Here the authors report a single-cell cyclic multiplex in situ tagging (CycMIST) method for functional proteome profiling of single cells, allowing multiple rounds of multiplexing of the same single cells on a microchip.
- Liwei Yang
- , Avery Ball
- & Jun Wang
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Article
| Open AccessMultimodal deep learning for Alzheimer’s disease dementia assessment
Here the authors present a deep learning framework for dementia diagnosis, which can identify persons with normal cognition, mild cognitive impairment, Alzheimer’s disease, and dementia due to other etiologies.
- Shangran Qiu
- , Matthew I. Miller
- & Vijaya B. Kolachalama
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Article
| Open AccessFluent molecular mixing of Tau isoforms in Alzheimer’s disease neurofibrillary tangles
The tau protein in Alzheimer’s disease contains two isoforms. Using solid-state NMR and seeded growth of isotopically labeled tau, here the authors determined that the two isoforms mix fluently on the molecular level to propagate the AD tau structure.
- Aurelio J. Dregni
- , Pu Duan
- & Mei Hong
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Article
| Open AccessPresenilin 2 N141I mutation induces hyperactive immune response through the epigenetic repression of REV-ERBα
Hyperimmunity is associated with Alzheimer disease. Here the authors show that the Presenilin 2 N141I mutation causes overproduction of clock-controlled cytokines and memory deficits through suppression of REV-ERBα gene by hypermethylation.
- Hyeri Nam
- , Younghwan Lee
- & Seong-Woon Yu
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Article
| Open AccessMicroglial NF-κB drives tau spreading and toxicity in a mouse model of tauopathy
Wang et al show that microglial NF-κB activation is essential for tau spreading and tau-mediated spatial learning and memory deficits in tauopathy mice. Inactivation of NF-κB reversed tau associated microglial states and rescued autophagy deficits.
- Chao Wang
- , Li Fan
- & Li Gan
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Article
| Open AccessA robust and interpretable machine learning approach using multimodal biological data to predict future pathological tau accumulation
The authors present a machine learning approach that combines baseline multimodal data to accurately predict individualised trajectories of future pathological tau accumulation at asymptomatic and mildly impaired stages of Alzheimer’s disease.
- Joseph Giorgio
- , William J. Jagust
- & Zoe Kourtzi
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Article
| Open AccessA computational model of neurodegeneration in Alzheimer’s disease
Low-dimensional representations of functional brain anatomy relevant for dementia syndromes may exist. Here the authors propose a computational model of mental functions to catalogue this anatomy in Alzheimer’s and related dementias.
- D. Jones
- , V. Lowe
- & C. Jack
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Article
| Open AccessLower novelty-related locus coeruleus function is associated with Aβ-related cognitive decline in clinically healthy individuals
Older individuals exhibiting diminished function of the locus coeruleus while learning new information show faster cognitive decline that is typical for Alzheimer’s disease.
- Prokopis C. Prokopiou
- , Nina Engels-Domínguez
- & Heidi I. L. Jacobs
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Article
| Open AccessDissociation of tau pathology and neuronal hypometabolism within the ATN framework of Alzheimer’s disease
In Alzheimer’s disease (AD) tau and neurodegeneration have complex regional relationships. Here, the authors show neuronal hypometabolism discordant with tau burden defines functional resilience or susceptibility to Alzheimer’s pathology via limbic/cortical axes. Susceptible groups have faster cognitive decline and evidence of non-Alzheimer’s pathologies.
- Michael Tran Duong
- , Sandhitsu R. Das
- & Ilya M. Nasrallah
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Article
| Open AccessATAD3A oligomerization promotes neuropathology and cognitive deficits in Alzheimer’s disease models
Disturbance in lipid metabolism is one of the major pathological events in Alzheimer’s disease (AD). Here, the authors identify ATAD3A oligomerization as a key mechanism causing impaired cholesterol metabolism and neuropathology in AD models.
- Yuanyuan Zhao
- , Di Hu
- & Xin Qi
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Article
| Open AccessAcetylcholine deficiency disrupts extratelencephalic projection neurons in the prefrontal cortex in a mouse model of Alzheimer’s disease
Short-term memory deficits are associated with prefrontal cortex dysfunction in Alzheimer’s disease. Here, the authors assessed extratelencephalic projection (ET) neurons and found reduced ET neural activity in the medial prefrontal cortex (mPFC) and showed ET neurons received fewer cholinergic inputs from the basal forebrain in 5×FAD mice which led to object recognition memory deficits.
- Qingtao Sun
- , Jianping Zhang
- & Qingming Luo
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Article
| Open AccessDisruption of the grid cell network in a mouse model of early Alzheimer’s disease
It remains poorly understood how the onset of Alzheimer’s disease affects spatial cognition. Here, the authors report that spatial coding in grid cells deteriorates over time in a mouse model of Alzheimer’s disease during the early stages of pathology while place cell and head direction coding remain intact.
- Johnson Ying
- , Alexandra T. Keinath
- & Mark P. Brandon
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Article
| Open AccessInferring protein expression changes from mRNA in Alzheimer’s dementia using deep neural networks
Protein changes in a brain with Alzheimer’s are not often accompanied by transcriptional differences. Here, using a deep neural network that predicts protein abundance from mRNA expression, the authors track the early protein changes in Alzheimer’s dementia.
- Shinya Tasaki
- , Jishu Xu
- & Chris Gaiteri
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Article
| Open AccessAltered succinylation of mitochondrial proteins, APP and tau in Alzheimer’s disease
Succinylation is a metabolism-associated post-translational protein modification. Here the authors describe changes to the succinylation of proteins in the brain of individuals with Alzheimer’s disease.
- Yun Yang
- , Victor Tapias
- & Gary E. Gibson
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Article
| Open AccessReactive astrocytes acquire neuroprotective as well as deleterious signatures in response to Tau and Aß pathology
Alzheimer’s disease is associated with changes in astrocytes. Here the authors investigated the astrocyte translatome associated with amyloid-ß and tau pathology.
- Zoeb Jiwaji
- , Sachin S. Tiwari
- & Giles E. Hardingham
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Article
| Open AccessA deep learning framework identifies dimensional representations of Alzheimer’s Disease from brain structure
Alzheimer’s disease is heterogeneous in its neuroimaging and clinical phenotypes. Here the authors present a semi-supervised deep learning method, Smile-GAN, to show four neurodegenerative patterns and two progression pathways providing prognostic and clinical information.
- Zhijian Yang
- , Ilya M. Nasrallah
- & Balebail Ashok Raj
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Article
| Open AccessAtlas of RNA editing events affecting protein expression in aged and Alzheimer’s disease human brain tissue
Resources reporting RNA editing sites from brain tissue have been published. Here, the authors provide an atlas of RNA editing events found in the aged and Alzheimer’s disease human brain tissue resulting in changes at protein level.
- Yiyi Ma
- , Eric B. Dammer
- & Philip L. De Jager
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Article
| Open AccessA national cohort study (2000–2018) of long-term air pollution exposure and incident dementia in older adults in the United States
Air pollution has been linked to neurodegenerative disease. Here the authors carried out a population-based cohort study to investigate the association between long-term exposure to PM2.5, NO2, and warm-season O3 on dementia and Alzheimer’s disease incidence in the United States.
- Liuhua Shi
- , Kyle Steenland
- & Joel Schwartz
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Article
| Open AccessTau activates microglia via the PQBP1-cGAS-STING pathway to promote brain inflammation
Brain inflammation generally accelerates neurodegeneration but the mechanisms of this are not fully characterised. Here the authors show that PQBP1 in microglia is important for sensing extrinsic Tau 3 R/4 R proteins and triggers an innate immune response through cGAS and STING resulting in cognitive impairment.
- Meihua Jin
- , Hiroki Shiwaku
- & Hitoshi Okazawa
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Article
| Open AccessAn immune response characterizes early Alzheimer’s disease pathology and subjective cognitive impairment in hydrocephalus biopsies
Specific transcriptional changes in microglia associated with Alzheimer’s disease have been reported. Here, the authors show that transcriptional analysis of human hydrocephalus biopsies identifies changes in immune response genes associated with early AD pathology, including cognitive decline.
- Wenrui Huang
- , Anne Marie Bartosch
- & Andrew F. Teich
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Article
| Open AccessAccelerated functional brain aging in pre-clinical familial Alzheimer’s disease
Alzheimer’s disease has been associated with increased structural brain aging. Here the authors describe a model that predicts brain aging from resting state functional connectivity data, and demonstrate this is accelerated in individuals with pre-clinical familial Alzheimer’s disease.
- Julie Gonneaud
- , Alex T. Baria
- & Etienne Vachon-Presseau
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Article
| Open AccessImproved modeling of human AD with an automated culturing platform for iPSC neurons, astrocytes and microglia
Human induced pluripotent stem cell (iPSC) cells have been used to model disease in specific cell types. Here, the authors develop an automated long-term culturing platform of human iPSC neurons, astrocytes, and microglia and use it to model some cellular aspects of Alzheimer’s disease.
- Reina Bassil
- , Kenneth Shields
- & Ben Chih
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Article
| Open AccessEndo-lysosomal Aβ concentration and pH trigger formation of Aβ oligomers that potently induce Tau missorting
Aβ oligomers (AβO) are thought to represent the main toxic species in Alzheimer’s disease but very high Aβ concentrations are required to study them in vitro and it remains unknown what role these off-pathway oligomers play in vivo. Here, the authors use a dimeric variant of Aβ termed dimAβ, where two Aβ40 units are linked, which facilitates to study AβO formation kinetics and they observe that Aβ off-pathway oligomer formation is strongly accelerated at endo-lysosomal pH, while amyloid fibril formation is delayed. Furthermore, the authors demonstrate that dimAβ is a disease-relevant model construct for pathogenic AβO formation by showing that dimAβ AβOs target dendritic spines and induce AD-like somatodendritic Tau missorting.
- Marie P. Schützmann
- , Filip Hasecke
- & Wolfgang Hoyer