Abstract：
:PICALM is a highly validated genetic risk factor for Alzheimer's disease (AD). We found that reduced expression of PICALM in AD and murine brain endothelium correlated with amyloid-β (Aβ) pathology and cognitive impairment. Moreover, Picalm deficiency diminished Aβ clearance across the murine blood-brain barrier (BBB) and accelerated Aβ pathology in a manner that was reversible by endothelial PICALM re-expression. Using human brain endothelial monolayers, we found that PICALM regulated PICALM/clathrin-dependent internalization of Aβ bound to the low density lipoprotein receptor related protein-1, a key Aβ clearance receptor, and guided Aβ trafficking to Rab5 and Rab11, leading to Aβ endothelial transcytosis and clearance. PICALM levels and Aβ clearance were reduced in AD-derived endothelial monolayers, which was reversible by adenoviral-mediated PICALM transfer. Inducible pluripotent stem cell-derived human endothelial cells carrying the rs3851179 protective allele exhibited higher PICALM levels and enhanced Aβ clearance. Thus, PICALM regulates Aβ BBB transcytosis and clearance, which has implications for Aβ brain homeostasis and clearance therapy.
journal_name
Nat Neuroscijournal_title
Nature neuroscienceauthors
Zhao Z,Sagare AP,Ma Q,Halliday MR,Kong P,Kisler K,Winkler EA,Ramanathan A,Kanekiyo T,Bu G,Owens NC,Rege SV,Si G,Ahuja A,Zhu D,Miller CA,Schneider JA,Maeda M,Maeda T,Sugawara T,Ichida JK,Zlokovic BVdoi
10.1038/nn.4025subject
Has Abstractpub_date
2015-07-01 00:00:00pages
978-87issue
7eissn
1097-6256issn
1546-1726pii
nn.4025journal_volume
18pub_type
杂志文章abstract：:Despite the numerous examples of anticipatory cognitive processes at micro and macro levels in many animal species, the idea that anticipation of specific words plays an integral role in real-time language processing has been contentious. Here we exploited a phonological regularity of English indefinite articles ('an'...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn1504
更新日期：2005-08-01 00:00:00
abstract：:Ample evidence suggests that primary visual cortex is involved in the perception of form, and there is increasing evidence that it may also be important in the perception of surfaces. Perceptual qualities of surfaces, such as brightness, are based on extensive integration of information throughout the visual field. In...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/2849
更新日期：1998-11-01 00:00:00
abstract：:Leucine-rich repeat kinase 2 (LRRK2) is enriched in the striatal projection neurons (SPNs). We found that LRRK2 negatively regulates protein kinase A (PKA) activity in the SPNs during synaptogenesis and in response to dopamine receptor Drd1 activation. LRRK2 interacted with PKA regulatory subunit IIβ (PKARIIβ). A lack...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn.3636
更新日期：2014-03-01 00:00:00
abstract：:Mammalian hearing owes its remarkable sensitivity and frequency selectivity to a local mechanical feedback process within the cochlea. Cochlear outer hair cells (OHCs) function as the key elements in the feedback loop in which the fast somatic motility of OHCs is thought to be the source of cochlear amplification. An ...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn1509
更新日期：2005-08-01 00:00:00
abstract：:Most neurons receive thousands of synaptic inputs onto widely spread dendrites. Because of dendritic filtering, distant synapses should have less efficacy than proximal ones. To investigate this, we characterized the amplitude and kinetics of excitatory synaptic input across the apical dendrites of CA1 pyramidal neuro...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/78800
更新日期：2000-09-01 00:00:00
abstract：:We combined psychophysical and transcranial magnetic stimulation studies to investigate the dynamics of action anticipation and its underlying neural correlates in professional basketball players. Athletes predicted the success of free shots at a basket earlier and more accurately than did individuals with comparable ...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn.2182
更新日期：2008-09-01 00:00:00
abstract：:Brain tumor initiating cells (BTICs) co-opt the neuronal high affinity glucose transporter, GLUT3, to withstand metabolic stress. We investigated another mechanism critical to brain metabolism, mitochondrial morphology, in BTICs. BTIC mitochondria were fragmented relative to non-BTIC tumor cell mitochondria, suggestin...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn.3960
更新日期：2015-04-01 00:00:00
abstract：:We used cortex-specific deletion of the transcription factor gene COUP-TFI (also known as Nr2f1) in mice to demonstrate previously unknown fundamental roles for it in patterning mammalian neocortex into areas. The highest COUP-TFI expression is observed in the cortical progenitors and progeny in parietal and occipital...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn1958
更新日期：2007-10-01 00:00:00
abstract：:Humans, and animals, often encounter ambiguous situations that require a decision on whether to take an offense or a defense strategy. Behavioral studies suggest that a strategy decision is frequently made before concrete options are evaluated. It remains enigmatic, however, how a strategy is determined without explor...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn.3999
更新日期：2015-05-01 00:00:00
abstract：:Cell type-specific expression of optogenetic molecules allows temporally precise manipulation of targeted neuronal activity. Here we present a toolbox of four knock-in mouse lines engineered for strong, Cre-dependent expression of channelrhodopsins ChR2-tdTomato and ChR2-EYFP, halorhodopsin eNpHR3.0 and archaerhodopsi...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn.3078
更新日期：2012-03-25 00:00:00
abstract：:Adult neurogenesis occurs in the hippocampus and the olfactory bulb of the mammalian CNS. Recent studies have demonstrated that newborn granule cells of the adult hippocampus are postsynaptic targets of excitatory and inhibitory neurons, but evidence of synapse formation by the axons of these cells is still lacking. B...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn.2156
更新日期：2008-08-01 00:00:00
abstract：:Autophosphorylation of alpha calcium-calmodulin-dependent kinase II (alphaCaMKII) has been proposed to be the key event in memory storage. We tested this hypothesis with autophosphorylation-deficient mutant mice in hippocampus- and amygdala-dependent learning and memory tasks and found that the autophosphorylation of ...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn1431
更新日期：2005-04-01 00:00:00
abstract：:The brain is the central organ involved in perceiving and adapting to social and physical stressors via multiple interacting mediators, from the cell surface to the cytoskeleton to epigenetic regulation and nongenomic mechanisms. A key result of stress is structural remodeling of neural architecture, which may be a si...
journal_title：Nature neuroscience
pub_type： 杂志文章,评审
doi：10.1038/nn.4086
更新日期：2015-10-01 00:00:00
abstract：:Human neurodegenerative disorders are among the most difficult to study. In particular, the inability to readily obtain the faulty cell types most relevant to these diseases has impeded progress for decades. Recent advances in pluripotent stem cell technology now grant access to substantial quantities of disease-perti...
journal_title：Nature neuroscience
pub_type： 杂志文章,评审
doi：10.1038/nn.3425
更新日期：2013-07-01 00:00:00
abstract：:The accessory olfactory bulb (AOB) is a critical olfactory structure that has been implicated in mediating social behavior. It receives input from the vomeronasal organ and projects to targets in the amygdaloid complex. Its anterior and posterior components (aAOB and pAOB) display molecular, connectional and functiona...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn.3297
更新日期：2013-02-01 00:00:00
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journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn1805
更新日期：2006-12-01 00:00:00
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journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/13197
更新日期：1999-10-01 00:00:00
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journal_title：Nature neuroscience
pub_type： 评论,杂志文章
doi：10.1038/nn1206-1463
更新日期：2006-12-01 00:00:00
abstract：:The specification of area identities in the cerebral cortex is a complex process, primed by intrinsic cortical cues and refined after the arrival of afferent fibers from the thalamus. Little is known about the genetic control of the early steps of this process, but the distinctive expression pattern of the homeogene E...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/76630
更新日期：2000-07-01 00:00:00
abstract：:Cannabis is the most frequently used illicit psychoactive substance worldwide; around one in ten users become dependent. The risk for cannabis use disorder (CUD) has a strong genetic component, with twin heritability estimates ranging from 51 to 70%. Here we performed a genome-wide association study of CUD in 2,387 ca...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/s41593-019-0416-1
更新日期：2019-07-01 00:00:00
abstract：:Binocular competition is thought to drive eye-specific segregation in the developing visual system, potentially through Hebbian synaptic learning rules that are sensitive to correlations in afferent activity. Altering retinal activity can disrupt eye-specific segregation, but little is known about the temporal feature...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn.3007
更新日期：2011-11-18 00:00:00
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journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn.2307
更新日期：2009-05-01 00:00:00
abstract：:Dot patterns sliding transparently across one another are normally perceived as independently moving surfaces. Recordings from direction-selective neurons in area MT of the macaque suggested that this perceptual segregation did not depend on the presence of two peaks in the population activity. Rather, the visual syst...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/72985
更新日期：2000-03-01 00:00:00
abstract：:Neurobiological theories of knowledge processing are biased toward the language-dominant (usually the left) hemisphere. Does the right hemisphere critically contribute to knowledge processing? J.A. is a left-hemisphere language-dominant individual who suffered a lesion confined to the right mid- and anterior fusiform ...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn1721
更新日期：2006-07-01 00:00:00
abstract：:In the nose, odorants are detected on the cilia of olfactory sensory neurons (OSNs), where a cAMP-mediated signaling pathway transforms odor stimulation into electrical responses. Phosphodiesterase (PDE) activity in OSN cilia has long been thought to account for rapid response termination by degrading odor-induced cAM...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn.2289
更新日期：2009-04-01 00:00:00
abstract：:Leptin regulates energy balance. However, knowledge of the critical intracellular transducers of leptin signaling remains incomplete. We found that Rho-kinase 1 (ROCK1) regulates leptin action on body weight homeostasis by activating JAK2, an initial trigger of leptin receptor signaling. Leptin promoted the physical i...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn.3207
更新日期：2012-10-01 00:00:00
abstract：:Neuronal migration disorders such as lissencephaly and subcortical band heterotopia are associated with epilepsy and intellectual disability. DCX, PAFAH1B1 and TUBA1A are mutated in these disorders; however, corresponding mouse mutants do not show heterotopic neurons in the neocortex. In contrast, spontaneously arisen...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn.3729
更新日期：2014-07-01 00:00:00
abstract：:Synaptic cadherin adhesion complexes are known to be key regulators of synapse plasticity. However, the molecular mechanisms that coordinate activity-induced modifications in cadherin localization and adhesion and the subsequent changes in synapse morphology and efficacy remain unknown. We demonstrate that the intrace...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn.3657
更新日期：2014-04-01 00:00:00
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journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/393
更新日期：1998-06-01 00:00:00
abstract：:Previous work has shown that human adolescents may be hypersensitive to rewards, but it is not known which aspect of reward processing is responsible for this. We separated decision value and prediction error signals and found that neural prediction error signals in the striatum peaked in adolescence, whereas neural d...
journal_title：Nature neuroscience
pub_type： 杂志文章
doi：10.1038/nn.2558
更新日期：2010-06-01 00:00:00
