Featured
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Article
| Open AccessA single-cell and spatial RNA-seq database for Alzheimer’s disease (ssREAD)
A systematic collection for single-cell and spatial transcriptomics is critical for in-depth analysis and novel discovery in AD. Here, authors show ssREAD which covers over 7 million cells and 381 spatial samples from human and mouse, providing a comprehensive resource for AD research.
- Cankun Wang
- , Diana Acosta
- & Qin Ma
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Article
| Open AccessPostmortem imaging reveals patterns of medial temporal lobe vulnerability to tau pathology in Alzheimer’s disease
Using high-resolution ex vivo MRI and serial histology, Ravikumar et al. characterise 3D tau spread across histologically defined medial temporal lobe subregions thus providing a postmortem reference for in vivo studies on early Alzheimer’s disease.
- Sadhana Ravikumar
- , Amanda E. Denning
- & Paul A. Yushkevich
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Article
| Open AccessNeuromodulatory subcortical nucleus integrity is associated with white matter microstructure, tauopathy and APOE status
The isodendritic core is a group of neuromodulatory nuclei with diffuse projections. Here the authors describe associations between the microstructural integrity of the isodendritic core and whole-brain white matter in humans, and its relationship to Apolipoprotein-E4 carrier status.
- Alfie Wearn
- , Stéfanie A. Tremblay
- & R. Nathan Spreng
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Article
| Open AccessApo and Aβ46-bound γ-secretase structures provide insights into amyloid-β processing by the APH-1B isoform
Incomplete proteolysis of amyloid-β (Aβ) peptides by γ-secretases is linked to Alzheimer’s disease. Using cryo-EM and functional analyses, this study uncovers the γ-secretase – Aβ46 structure and unveils key interactions for efficient Aβ cleavage.
- Ivica Odorčić
- , Mohamed Belal Hamed
- & Rouslan G. Efremov
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Article
| Open AccessEffects of SPI1-mediated transcriptome remodeling on Alzheimer’s disease-related phenotypes in mouse models of Aβ amyloidosis
Although SPI1 gene was identified as a risk factor for Alzheimer’s disease, its role in the disease remains unclear. Here, the authors show that decreasing SPI1 level exacerbates disease symptoms, whereas increasing its level ameliorates phenotypes.
- Byungwook Kim
- , Luke Child Dabin
- & Jungsu Kim
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Article
| Open AccessMetabolic phenotyping reveals an emerging role of ammonia abnormality in Alzheimer’s disease
Metabolic implications in AD are unclear. Here, authors found significant correlations between cognitive impairment and metabolic features in a Chinese aging cohort (n = 1397). The study highlights ammonia disturbance as a potential therapeutic target for AD.
- Tianlu Chen
- , Fengfeng Pan
- & Wei Jia
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Article
| Open AccessCerebrospinal fluid reference proteins increase accuracy and interpretability of biomarkers for brain diseases
CSF biomarker concentrations may be influenced by non-disease related interindividual variability. Here, the authors show that reference proteins can capture this variability and enhance the accuracy of Alzheimer’s disease biomarkers.
- Linda Karlsson
- , Jacob Vogel
- & Oskar Hansson
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Article
| Open AccessPlasma brain-derived tau is an amyloid-associated neurodegeneration biomarker in Alzheimer’s disease
The authors investigated associations of brain-derived-tau (BD-tau) with Aβ pathology, changes in cognition and MRI signatures. Staging Aβ-pathology according to neurodegeneration, using BD-tau, identifies individuals at risk of near-term cognitive decline and atrophy.
- Fernando Gonzalez-Ortiz
- , Bjørn-Eivind Kirsebom
- & Kaj Blennow
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Article
| Open AccessNative-state proteomics of Parvalbumin interneurons identifies unique molecular signatures and vulnerabilities to early Alzheimer’s pathology
Native state proteomics of PV interneurons revealed unique molecular features of high translational and metabolic activity, and enrichment of Alzheimer’s risk genes. Early amyloid pathology exerted unique effects on mitochondria, mTOR signaling and neurotransmission in PV neurons.
- Prateek Kumar
- , Annie M. Goettemoeller
- & Srikant Rangaraju
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Article
| Open AccessSKA2 regulated hyperactive secretory autophagy drives neuroinflammation-induced neurodegeneration
Secretory autophagy (SA) plays a crucial role in neuroinflammation-driven neurodegeneration, through SKA2 and FKBP5. SKA2 regulation of SA can inhibit IL-1β release. Its dysfunction leads to neurodegeneration, and is linked to Alzheimer’s disease.
- Jakob Hartmann
- , Thomas Bajaj
- & Nils C. Gassen
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Article
| Open AccessPlasma p-tau212 antemortem diagnostic performance and prediction of autopsy verification of Alzheimer’s disease neuropathology
A range of blood-based biomarkers have shown high specificity for Alzheimer’s disease (AD) pathophysiology with phosphorylated-tau (p-tau) being the most promising test. Here, the authors show the utility of plasma p-tau212 in autopsy-confirmed AD and memory clinic patient cohorts.
- Przemysław R. Kac
- , Fernando González-Ortiz
- & Thomas K. Karikari
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Article
| Open AccessThe aldehyde dehydrogenase 2 rs671 variant enhances amyloid β pathology
Here, Wang et al. report that the ALDH2 rs671 variant exacerbates amyloid-β pathology in the human brain. Mechanistically, the variant leads to 4-HNE accumulation, adducting Lys53 of C99 and promoting the production of Aβ40.
- Xia Wang
- , Jiayu Wang
- & Wei Ge
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Article
| Open AccessA blood-based biomarker workflow for optimal tau-PET referral in memory clinic settings
A screening strategy with plasma p-tau217, evaluated in two independent cohorts from Sweden and Canada, showed that this biomarker may effectively streamline tau-PET referrals in memory clinic settings, optimizing the prognostic work-up of Alzheimer’s disease.
- Wagner S. Brum
- , Nicholas C. Cullen
- & Oskar Hansson
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Review Article
| Open AccessNeuropathogenesis-on-chips for neurodegenerative diseases
This review focuses on recent advances in on-chip platforms for patient-like in vitro modeling of the pathology of neurodegenerative diseases, including Alzheimer’s, Parkinson’s, and Huntington’s diseases as well as Amyotrophic lateral sclerosis. The authors advocate for broader usage of these human-relevant models in the academic and pharmaceutical fields.
- Sarnai Amartumur
- , Huong Nguyen
- & Chaejeong Heo
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Article
| Open AccessA single nuclear transcriptomic characterisation of mechanisms responsible for impaired angiogenesis and blood-brain barrier function in Alzheimer’s disease
Vascular pathology may play important early role in Alzheimer’s disease (AD). Here, the authors show that β-amyloid induces transcriptomic signatures associated with accelerated apoptosis, impaired function and AD risk in human brain microvasculature.
- Stergios Tsartsalis
- , Hannah Sleven
- & Paul M. Matthews
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Article
| Open AccessQuantitative live cell imaging of a tauopathy model enables the identification of a polypharmacological drug candidate that restores physiological microtubule interaction
In tauopathies, the microtubule-associated protein tau is hyperphosphorylated and aggregated. Here the authors identified a polypharmacological small molecule that inhibits aggregation, reduces phosphorylation, and restores microtubule interaction of tau.
- Luca Pinzi
- , Christian Conze
- & Roland Brandt
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Article
| Open AccessNon-invasive modulation of meningeal lymphatics ameliorates ageing and Alzheimer’s disease-associated pathology and cognition in mice
Meningeal lymphatic vessels have been associated with amyloid beta clearance, which is considered as a modulation target for Alzheimer’s disease (AD) treatment. Here, the authors show that transcranial light treatment can enhance meningeal lymphatic drainage in aged and AD model mice and improve AD-associated pathology and cognitive function.
- Miao Wang
- , Congcong Yan
- & Feifan Zhou
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Article
| Open AccessThe structure of tyrosine-10 favors ionic conductance of Alzheimer’s disease-associated full-length amyloid-β channels
The structural basis of membrane permeabilization by Alzheimer’s disease-related amyloid β (Aβ) peptides is elucidated. Membrane insertion of tyrosine-10 supports the most effective ionic conductance of the full-length Aβ1-42 compared to other isoforms.
- Abhijith G. Karkisaval
- , Rowan Hassan
- & Suren A. Tatulian
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Article
| Open AccessEarly onset diagnosis in Alzheimer’s disease patients via amyloid-β oligomers-sensing probe in cerebrospinal fluid
In this work, the authors characterize a small molecule fluorescent probe pioneering early diagnosis of Alzheimer’s disease through identification of amyloid-β oligomers in patients’ cerebrospinal fluid, demonstrating potential for clinical application.
- Jusung An
- , Kyeonghwan Kim
- & Jong Seung Kim
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Article
| Open AccessIdentification of potential aggregation hotspots on Aβ42 fibrils blocked by the anti-amyloid chaperone-like BRICHOS domain
This study identifies potential aggregation hotspots on the fibril surface of Alzheimer’s disease associated Aβ42 fibrils, which are blocked by the anti-amyloid chaperone-like domain BRICHOS.
- Rakesh Kumar
- , Tanguy Le Marchand
- & Axel Abelein
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Article
| Open AccessA one-two punch targeting reactive oxygen species and fibril for rescuing Alzheimer’s disease
Toxic amyloid-beta plaque and harmful inflammation are two leading hallmarks of Alzheimer’s disease (AD), and precise AD therapy is elusive due to the lack of dual-targeting therapy function, limited blood-brain barrier penetration, and low imaging sensitivity. Here, the authors address these issues by designing a near-infrared-II aggregation-induced emission nanotheranostic for precise AD therapy.
- Jiefei Wang
- , Ping Shangguan
- & Ben Zhong Tang
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Article
| Open AccessEndothelial leakiness elicited by amyloid protein aggregation
This study reports endothelial leakiness in vitro, in silico and in vivo, where adherens junctions are disrupted by their exposure to the anionic oligomers and seeds of Alzheimer’s amyloid beta, preceding proinflammatory and pro-oxidative events.
- Yuhuan Li
- , Nengyi Ni
- & Pu Chun Ke
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Article
| Open AccessDeath Induced by Survival gene Elimination (DISE) correlates with neurotoxicity in Alzheimer’s disease and aging
Events that cause neurons to die in Alzheimer’s disease (AD) are poorly understood. Here, the authors provide evidence for a role of RNA interference in AD. Short RNAs causing neurotoxicity and DNA damage are seen in AD and aged brains, and are counteracted by nontoxic RNAs.
- Bidur Paudel
- , Si-Yeon Jeong
- & Marcus E. Peter
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Article
| Open AccessElevated CSF GAP-43 is associated with accelerated tau accumulation and spread in Alzheimer’s disease
Trans-synaptic tau spread drives neurodegeneration in Alzheimer’s disease. This study shows that GAP-43, a marker of synaptic abnormality, is linked to faster tau spread, showing that synaptic changes may contribute to tau spreading in Alzheimer’s disease.
- Nicolai Franzmeier
- , Amir Dehsarvi
- & Michael Schöll
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Article
| Open AccessANKS1A regulates LDL receptor-related protein 1 (LRP1)-mediated cerebrovascular clearance in brain endothelial cells
LRP1 plays a key role in the clearance of Aβ peptides across the blood-brain barrier. Here, the authors report that ANKS1A promotes the LRP1-mediated Aβ clearance in brain endothelium, providing insights into the pathology of Alzheimer’s disease.
- Jiyeon Lee
- , Haeryung Lee
- & Soochul Park
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Article
| Open AccessFatal iatrogenic cerebral β-amyloid-related arteritis in a woman treated with lecanemab for Alzheimer’s disease
A 79-year-old woman received three doses of lecanemab, an experimental drug for Alzheimer’s disease, and suffered a seizure and cerebral edema. Neuropathological evaluation showed severe cerebral amyloid angiopathy, arteritis and microhemorrhages.
- Elena Solopova
- , Wilber Romero-Fernandez
- & Matthew Schrag
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Article
| Open AccessAmplified fluorogenic immunoassay for early diagnosis and monitoring of Alzheimer’s disease from tear fluid
Accurate diagnosis of Alzheimer’s disease in its earliest stage can prevent the disease and delay the symptoms. Here the authors identify a potential Alzheimer’s biomarker from tear fluid, and develop a nanoparticle-based immunoassay for its detection, demonstrating potential in Alzheimer’s diagnosis.
- Sojeong Lee
- , Eunjung Kim
- & Seungjoo Haam
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Article
| Open AccessCell-type-specific Alzheimer’s disease polygenic risk scores are associated with distinct disease processes in Alzheimer’s disease
Alzheimer’s disease genetic risk is enriched in glial genes. Here, the authors derive cell-type-specific polygenic risk scores and link astrocytic genes with Aβ, and microglial genes with Aβ, tau, microglial activation, and cognitive decline.
- Hyun-Sik Yang
- , Ling Teng
- & Reisa A. Sperling
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Article
| Open AccessINPP5D regulates inflammasome activation in human microglia
INPP5D/SHIP1 is a microglial-expressed gene that has been associated with Alzheimer’s disease through genetic studies. This study reveals that reduction in INPP5D activity induces activation of the NLRP3-inflammasome in human microglia.
- Vicky Chou
- , Richard V. Pearse II
- & Tracy L. Young-Pearse
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Article
| Open AccessResting-state global brain activity affects early β-amyloid accumulation in default mode network
Why β-amyloid plaque initially accumulates in the default mode network of the cortex before Alzheimer’s disease diagnosis is not known. Here, the authors show that this accumulation is associated with a reduction of global brain activity in these regions.
- Feng Han
- , Xufu Liu
- & Xiao Liu
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Article
| Open AccessIntegrative analysis reveals a conserved role for the amyloid precursor protein in proteostasis during aging
The normal function of amyloid precursor protein (APP) implicated in Alzheimer’s disease is unclear. Here, authors use multi-omics to reveal the fly APP’s role in regulating proteostasis and validate using vertebrate and In-vivo tauopathy models.
- Vanitha Nithianandam
- , Hassan Bukhari
- & Mel B. Feany
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Article
| Open AccessA neurodegeneration checkpoint mediated by REST protects against the onset of Alzheimer’s disease
The mechanisms that underlie cognitive resilience during aging are poorly understood. Here, the authors describe a neurodegeneration checkpoint response mediated by the transcription factor REST that protects against the onset of Alzheimer’s disease.
- Liviu Aron
- , Chenxi Qiu
- & Bruce A. Yankner
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Article
| Open AccessDeep brain stimulation of thalamic nucleus reuniens promotes neuronal and cognitive resilience in an Alzheimer’s disease mouse model
The mechanisms that confer cognitive resilience to Alzheimer’s disease are not fully understood. Here, the authors uncover the role of the nucleus reuniens in promoting resilience through the suppression of hyperexcitability and the restoration of circuit-level homeostasis to prevent memory decline.
- Shiri Shoob
- , Nadav Buchbinder
- & Inna Slutsky
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Article
| Open AccessMultivalent Tau/PSD-95 interactions arrest in vitro condensates and clusters mimicking the postsynaptic density
Cognitive impairment in Alzheimer’s disease is associated with Tau at the postsynapse. We show that multivalent Tau interactions arrest in vitro condensates and clusters mimicking the postsynaptic density that may result in synaptic dysfunction.
- Zheng Shen
- , Daxiao Sun
- & Markus Zweckstetter
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Article
| Open AccessPlasma biomarkers predict Alzheimer’s disease before clinical onset in Chinese cohorts
Performance of plasma biomarkers of amyloid (A), tau (T) and neurodegeneration (N) for Alzheimer’s disease (AD) in Chinese cohorts is unknown. Here, the authors report that plasma ATN biomarkers can predict AD 8–10 years before symptoms in Chinese cohorts.
- Huimin Cai
- , Yana Pang
- & Longfei Jia
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Article
| Open AccessHealthy dietary patterns and the risk of individual chronic diseases in community-dwelling adults
Dietary patterns have been linked to a limited number of major chronic diseases. Here, the authors show greater adherence to healthy dietary patterns, especially Alternate Mediterranean Diet, is associated with a lower risk of most of the 48 tested chronic diseases.
- Xianwen Shang
- , Jiahao Liu
- & Mingguang He
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Article
| Open AccessSoluble TREM2 ameliorates tau phosphorylation and cognitive deficits through activating transgelin-2 in Alzheimer’s disease
In this study, the authors found that sTREM2 attenuates tau hyperphosphorylation by activating transgelin-2. They developed an active peptide that mimics the protective effect of sTREM2, which may be an innovative therapeutic intervention for AD.
- Xingyu Zhang
- , Li Tang
- & Zhentao Zhang
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Article
| Open AccessFSH and ApoE4 contribute to Alzheimer’s disease-like pathogenesis via C/EBPβ/δ-secretase in female mice
Follicle stimulating hormone (FSH) has been shown to Alzheimer’s disease like pathology in rodent models. Here the authors show using cellular and animal models that ApoE4 and FSH collectively act to trigger AD-like pathogenesis, by activating C/EBPβ/δ-secretase signalling.
- Jing Xiong
- , Seong Su Kang
- & Keqiang Ye
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Article
| Open AccessAcetylation discriminates disease-specific tau deposition
The authors show that acetylation enhances the aggregation of 3R tau, while blocking the aggregation of 4R tau, providing a molecular basis for disease- and isoform-specific tau deposition.
- Pijush Chakraborty
- , Gwladys Rivière
- & Markus Zweckstetter
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Article
| Open AccessHistidine modulates amyloid-like assembly of peptide nanomaterials and confers enzyme-like activity
In this work, the authors report that Histidine residues play a critical role in modulating amyloid-like assembly and building active sites for Fmoc–F–F and Aβ aggregates. Aβ1-42 filaments were found to perform peroxidase-like activity to enhance oxidative stress, which might also be ascribed to the interaction mode of His and F-F.
- Ye Yuan
- , Lei Chen
- & Lizeng Gao
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Article
| Open AccessC3N nanodots inhibits Aβ peptides aggregation pathogenic path in Alzheimer’s disease
In this work, the authors report the utilization of nano-inhibito C3N nanodots to inhibit Aβ peptides aggregation and fibrils disassembly, and show how they induce a cognitive enhancement in treated AD mice.
- Xiuhua Yin
- , Hong Zhou
- & Ruhong Zhou
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Article
| Open AccessCSF proteome profiling reveals biomarkers to discriminate dementia with Lewy bodies from Alzheimer´s disease
This study characterizes the CSF proteome changes underlying Dementia with Lewy Bodies (DLB) and identifies pathophysiological and diagnostic leads associated to this cause of dementia. Findings have been translated into a biomarker panel that could identify DLB patients with high accuracy across different cohorts.
- Marta del Campo
- , Lisa Vermunt
- & Charlotte E. Teunissen
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Article
| Open AccessBacteroides Fragilis in the gut microbiomes of Alzheimer’s disease activates microglia and triggers pathogenesis in neuronal C/EBPβ transgenic mice
Gut dysbiosis contributes to Alzheimer’s disease (AD) pathogenesis, and Bacteroides strains are commonly enriched in AD gut microbiota. Here, the authors show that Bacteroides fragilis and its metabolites 12-hydroxy-heptadecatrienoic acid (12-HHTrE) and Prostaglandin E2 (PGE2) can mediate activation of microglia and induce AD pathogenesis in neuronal C/EBPβ transgenic mice.
- Yiyuan Xia
- , Yifan Xiao
- & Keqiang Ye
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Article
| Open AccessMicroglial REV-ERBα regulates inflammation and lipid droplet formation to drive tauopathy in male mice
The circadian clock protein REV-ERBα has been implicated in neuroinflammation but mechanisms are poorly understood. Here, the authors show that microglial REV-ERBα regulates inflammatory signaling and lipid droplet formation to exert sex-specific effects on tau pathology in mice.
- Jiyeon Lee
- , Julie M. Dimitry
- & Erik S. Musiek
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Article
| Open AccessEffect of apolipoprotein genotype and educational attainment on cognitive function in autosomal dominant Alzheimer’s disease
PSEN1 E280A carriers develop dementia by midlife, but there is variability in disease trajectory. Cognitive decline is accelerated in E280A carriers who also have an APOE e4 allele. Educational attainment moderates the effect of APOE on cognition.
- Stephanie Langella
- , N. Gil Barksdale
- & Yakeel T. Quiroz
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Article
| Open AccessA brainstem to circadian system circuit links Tau pathology to sundowning-related disturbances in an Alzheimer’s disease mouse model
Sundowning in Alzheimer’s disease (AD) patients is characterized by agitation and aggression during their afternoon-to-evening transition and a phase delay in circadian rhythms. Here, the authors show that AD model mice develop a phase delay and increased aggression around their active-to-rest transition with Tau pathology in brainstem neurons that target the circadian system.
- Andrew E. Warfield
- , Pooja Gupta
- & William D. Todd
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Article
| Open AccessWhole genome deconvolution unveils Alzheimer’s resilient epigenetic signature
The authors present a deep learning method that deconvolutes ATAC-seq samples into cell type-specific chromatin accessibility profiles. Applied on 191 samples, the method unveils cell type-specific pathways and nominates potential epigenetic mediators underlying resilience to Alzheimer’s disease.
- Eloise Berson
- , Anjali Sreenivas
- & Thomas J. Montine
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Article
| Open AccessCompilation of reported protein changes in the brain in Alzheimer’s disease
Proteomic studies in Alzheimer’s disease may be useful for understanding disease mechanisms and potential therapeutic targets. Here the authors describe a resource collating known protein changes throughout the progression of Alzheimer’s disease in human brain tissue.
- Manor Askenazi
- , Tomas Kavanagh
- & Eleanor Drummond
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Article
| Open AccessExpanded vacuum-stable gels for multiplexed high-resolution spatial histopathology
Emerging high-plex imaging technologies are limited in resolving subcellular biomolecular features. Here, the authors propose a spatial histopathology tool that allows for high-plex protein staining and physical expansion, while retaining the lateral tissue expansion.
- Yunhao Bai
- , Bokai Zhu
- & Sizun Jiang