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Article
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Regional patterns of human cortex development correlate with underlying neurobiology
The neurobiology of human brain development and aging is hard to study in vivo. The authors report on distinct spatial associations between brain morphology and cellular as well as molecular brain properties throughout neurodevelopment and aging.
- Leon D. Lotter
- , Amin Saberi
- & Juergen Dukart
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| Open Access
The brain structure, inflammatory, and genetic mechanisms mediate the association between physical frailty and depression
Identifying modifiable risk factors that could prevent depression is important. Here, the authors show increased risks of incident depression in pre-frail and frail individuals and highlight the mediating role of brain structure and inflammation.
- Rongtao Jiang
- , Stephanie Noble
- & Dustin Scheinost
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Article
| Open Access
Repression of developmental transcription factor networks triggers aging-associated gene expression in human glial progenitor cells
Human glial progenitor cells (hGPCs) lose mitotic competence with age. Here, the authors show that with maturation, adult hGPCs acquire a set of transcriptional repressors that actively suppress developmental gene expression.
- John N. Mariani
- , Benjamin Mansky
- & Steven A. Goldman
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| Open Access
Intracellular magnesium optimizes transmission efficiency and plasticity of hippocampal synapses by reconfiguring their connectivity
How synapses at dendrites are organized to optimize information processing remains elusive. Here, the authors found that intracellular magnesium optimizes transmission, plasticity, and coding capacity of synapses by reconfiguring their connectivity at dendrites.
- Hang Zhou
- , Guo-Qiang Bi
- & Guosong Liu
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| Open Access
Brain asymmetries from mid- to late life and hemispheric brain age
The human brain is highly asymmetrical and increasingly so with age. Here the authors examine hemispheric brain age estimates, which provide additional insights into brain asymmetries.
- Max Korbmacher
- , Dennis van der Meer
- & Ivan I. Maximov
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| Open Access
Disruption of lysosomal proteolysis in astrocytes facilitates midbrain organoid proteostasis failure in an early-onset Parkinson’s disease model
The protein DJ1, encoded by the PARK7 gene, is causally linked to development of early-onset PD. Here the authors observed that the loss of DJ1 function in midbrain organoids led to astrocyte dysfunction, impairing protein clearance, accumulation of α-synuclein.
- Gustavo Morrone Parfitt
- , Elena Coccia
- & Tim Ahfeldt
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| Open Access
Mitochondrial malfunction and atrophy of astrocytes in the aged human cerebral cortex
How aging affects the brain active milieu remains unknown. Here, the authors reveal atrophy and mitochondrial malfunction of astrocytes but not neurons in older human neocortex.
- Alexander Popov
- , Nadezda Brazhe
- & Alexey Semyanov
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| Open Access
GDF11 slows excitatory neuronal senescence and brain ageing by repressing p21
How excitatory neurons (EN) acquire senescence is unclear. Here, the authors show that GDF11 in ENs slows EN senescence, brain ageing, cognitive decline and maintains lifespan, revealing a mechanism underlying EN senescence and brain ageing.
- Di-Xian Wang
- , Zhao-Jun Dong
- & Jing-Wei Zhao
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Article
| Open Access
A 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 Access
Altered ubiquitin signaling induces Alzheimer’s disease-like hallmarks in a three-dimensional human neural cell culture model
Using a 3-D neural platform, the authors show that a ubiquitin variant is sufficient to induce Alzheimer’s disease-like pathology in human neurons. Suppressing expression of this variant improved pathology in neurons carrying familial mutations.
- Inbal Maniv
- , Mahasen Sarji
- & Michael H. Glickman
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| Open Access
Prevalence and mechanisms of somatic deletions in single human neurons during normal aging and in DNA repair disorders
DNA damage has been implicated in aging and neurodegeneration. Here, the authors develop a bioinformatic method to detect deletions in single neuron genome sequences and reveal an increased burden of somatic deletions during aging and in DNA repair disorders.
- Junho Kim
- , August Yue Huang
- & Eunjung Alice Lee
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Article
| Open Access
Pericyte 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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| Open Access
Rejuvenation of the aged brain immune cell landscape in mice through p16-positive senescent cell clearance
The authors discovered that proinflammatory senescent myeloid cells may recruit peripheral immune cells in the aged mouse brain. Their findings implicate senescent cell clearance as a strategy to counter aged brain inflammation and cognitive decline.
- Xu Zhang
- , Vesselina M. Pearsall
- & Marissa J. Schafer
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Article
| Open Access
Microglial 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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| Open Access
Clueless/CLUH regulates mitochondrial fission by promoting recruitment of Drp1 to mitochondria
Drp1 is the master regulator of mitochondrial fission, which has important impact on cellular functions. Here, Yang et al identified evolutionarily conserved proteins Clueless and its homolog CLUH as key regulators of Drp1 that function via translation of Drp1 receptors MiD49 and Mff.
- Huan Yang
- , Caroline Sibilla
- & Ming Guo
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| Open Access
A metabolome atlas of the aging mouse brain
Metabolites play an important role in physiology, yet the complexity of the metabolome and its interaction with disease and aging is poorly understood. Here the authors present a comprehensive atlas of the mouse brain metabolome and how it changes during aging.
- Jun Ding
- , Jian Ji
- & Oliver Fiehn
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| Open Access
Accelerated 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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| Open Access
Acetylated tau inhibits chaperone-mediated autophagy and promotes tau pathology propagation in mice
The tau protein has been implicated in neurodegenerative disorders and can propagate from cell to cell. Here, the authors show that tau acetylation reduces its degradation by chaperone-mediated autophagy, causing re-routing to other autophagic pathways and increasing extracellular tau release.
- Benjamin Caballero
- , Mathieu Bourdenx
- & Ana Maria Cuervo
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| Open Access
Asymmetric 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 Access
Aging alters neural activity at event boundaries in the hippocampus and Posterior Medial network
Although our lives are continuous, we perceive and remember experiences as discrete events. Here, the authors show that neural responses at event boundaries in the hippocampus and Posterior Medial cortical network decline as we age, and predict memory for narrative events.
- Zachariah M. Reagh
- , Angelique I. Delarazan
- & Charan Ranganath
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| Open Access
CircGRIA1 shows an age-related increase in male macaque brain and regulates synaptic plasticity and synaptogenesis
Circular RNAs are expressed in the brain and show age-dependent expression patterns. Here the authors show the circGRIA1 is expressed in an age-dependent manner in the male macaque brain and serves a functional role in synaptic plasticity.
- Kaiyu Xu
- , Ying Zhang
- & Jiali Li
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| Open Access
Brain age prediction using deep learning uncovers associated sequence variants
Machine learning algorithms can be trained to estimate age from brain structural MRI. Here, the authors introduce a new deep-learning-based age prediction approach, and then carry out a GWAS of the difference between predicted and chronological age, revealing two associated variants.
- B. A. Jonsson
- , G. Bjornsdottir
- & M. O. Ulfarsson
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Perspective
| Open Access
Evolving perspectives on the sources of the frequency-following response
The auditory frequency-following response (FFR) indexes the quality of neural sound encoding in the brain. In this Perspective, the authors discuss the potential of the FFR to provide a better understanding of sound encoding in the auditory system and its relationship to behavior.
- Emily B. J. Coffey
- , Trent Nicol
- & Nina Kraus
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| Open Access
Disentangling molecular alterations from water-content changes in the aging human brain using quantitative MRI
MRI has been used for the non-invasive imaging of human brain aging but is sensitive to both tissue molecular composition and water content. Here the authors present a quantitative MRI method that discriminates these factors and describe region-specific changes in the molecular composition of the aging human brain.
- Shir Filo
- , Oshrat Shtangel
- & Aviv A. Mezer
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| Open Access
Brain tyrosinase overexpression implicates age-dependent neuromelanin production in Parkinson’s disease pathogenesis
It is unclear if neuromelanin plays a role in Parkinson’s disease pathogenesis since common laboratory animals lack this pigment. Authors show here that overexpression of human tyrosinase in the substantia nigra of rats resulted in an age-dependent production of human-like neuromelanin within nigral dopaminergic neurons and is associated with a Parkinson’s disease phenotype when allowed to accumulate above a specific threshold.
- Iria Carballo-Carbajal
- , Ariadna Laguna
- & Miquel Vila
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| Open Access
Combining lifestyle risks to disentangle brain structure and functional connectivity differences in older adults
Lifestyle factors such as smoking and exercise contribute to the health of the brain during aging, but previous studies have focused on the effects of single lifestyle variables. Here, the authors examine the combined and individual effects of four lifestyle variables on brain structure and function.
- Nora Bittner
- , Christiane Jockwitz
- & Svenja Caspers
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| Open Access
MiR-34 inhibits polycomb repressive complex 2 to modulate chaperone expression and promote healthy brain aging
miR-34 is known to regulate age-related gene expression in the Drosophila brain, and miR-34 overexpression can attenuate neurodegeneration induced by polyQ-expanded proteins. Here, Kennerdell and colleagues show that miR-34 confers longevity and neuroprotection via an epigenetic regulator Polycomb Repressive Complex 2 and molecular chaperone expression.
- Jason R. Kennerdell
- , Nan Liu
- & Nancy M. Bonini
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Article
| Open Access
Multivalent cross-linking of actin filaments and microtubules through the microtubule-associated protein Tau
The microtubule associated protein Tau also interacts with filamentous actin. Here the authors combine biophysical experiments and NMR studies to characterize the structural changes that occur in Tau upon binding to filamentous actin and show that phosphorylation of serine 262 attenuates actin binding of Tau.
- Yunior Cabrales Fontela
- , Harindranath Kadavath
- & Markus Zweckstetter
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| Open Access
Age-related delay in visual and auditory evoked responses is mediated by white- and grey-matter differences
Neural processing speed slows with age, but the relationship between this slowing and brain atrophy is unknown. Here, authors show that age-related functional brain differences in auditory and visual processing are partly due to structural differences in the distinct brain regions underlying these processes.
- D. Price
- , L. K. Tyler
- & R. N. A. Henson
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| Open Access
Preserved cognitive functions with age are determined by domain-dependent shifts in network responsivity
Cognitive abilities change with age, but why some decline and some do not is not clear. Here, the authors use data from the Cam-CAN cohort to show that distributed, multi-component brain responsivity and default-mode deactivation supports and characterizes preserved cognition across the adult lifespan.
- Dávid Samu
- , Karen L. Campbell
- & Lorraine K. Tyler
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| Open Access
Neuroanatomy accounts for age-related changes in risk preferences
Tolerance for risk decreases with age, but it is not known whether this shift can be accounted for by a neurobiological marker. Here, authors show that the age-related decrease in risk tolerance is better accounted for by grey matter decreases in right posterior parietal cortex than by age per se.
- Michael A. Grubb
- , Agnieszka Tymula
- & Ifat Levy
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| Open Access
Defective mitochondrial DNA homeostasis in the substantia nigra in Parkinson disease
Accumulated damage to mitochondrial DNA (mtDNA) occurs during the ageing process and neurodegenerative disease. Here, the authors show that mtDNA copy number increases in an age-dependent manner in substantia nigra of healthy individuals, but not in individuals with Parkinson disease.
- Christian Dölle
- , Irene Flønes
- & Charalampos Tzoulis
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| Open Access
Ageing increases reliance on sensorimotor prediction through structural and functional differences in frontostriatal circuits
Decline in sensorimotor skills with age may be due to an overreliance on the prediction of the sensory consequences of one’s actions. Here the authors show that sensorimotor attenuation increases with age, and that this is associated with structural and functional changes in frontostriatal circuits.
- Noham Wolpe
- , James N. Ingram
- & James B. Rowe
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| Open Access
Delayed glial clearance of degenerating axons in aged Drosophila is due to reduced PI3K/Draper activity
Glial engulfment declines with age, but the mechanism is unclear. Here authors show that in the Drosophilaolfactory system, glial phagocytosis of injury-induced degenerating axons decreases with age due to reduced PI3K/Draper activity, and restoring Draper in aged glia rescues such defects.
- Maria D. Purice
- , Sean D. Speese
- & Mary A. Logan
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| Open Access
Identification of chemicals that mimic transcriptional changes associated with autism, brain aging and neurodegeneration
This study presents gene expression responses of cultured brain cells to hundreds of chemicals found in the environment and in food. The authors identified chemicals that induce transcriptomic profiles that overlap those seen in human brains affected with autism, aging, and neurodegeneration.
- Brandon L. Pearson
- , Jeremy M. Simon
- & Mark J. Zylka
Modelling human neuronal catecholaminergic pigmentation in rodents recapitulates age-related neurodegenerative deficits