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Abnormal tau protein impairs mitochondrial function, including transport, dynamics, and bioenergetics. Mitochondria interact with the endoplasmic reticulum (ER) via mitochondria‐associated ER membranes (MAMs), which coordinate and modulate many cellular functions, including mitochondrial cholesterol metabolism. Here, we show that abnormal tau loosens the association between the ER and mitochondria in vivo and in vitro. Especially, ER‐mitochondria interactions via vesicle‐associated membrane protein‐associated protein (VAPB)—protein tyrosine phosphatase‐interacting protein 51 (PTPIP51) are decreased in the presence of abnormal tau. Disruption of MAMs in cells with abnormal tau alters the levels of mitochondrial cholesterol and pregnenolone, indicating that conversion of cholesterol into pregnenolone is impaired. Opposite effects are observed in the absence of tau. Besides, targeted metabolomics reveals overall alterations in cholesterol‐related metabolites by tau. The inhibition of GSK3β decreases abnormal tau hyperphosphorylation and increases VAPB–PTPIP51 interactions, restoring mitochondrial cholesterol and pregnenolone levels. This study is the first to highlight a link between tau‐induced impairments in the ER‐mitochondria interaction and cholesterol metabolism. Synopsis: Endoplasmic reticulum (ER)—mitochondria coupling regulates many cellular functions, including mitochondrial cholesterol metabolism. This study shows that abnormal tau protein disrupts ER—mitochondria contacts, impairing cholesterol metabolism and pregnenolone synthesis within mitochondria. Contact points between the endoplasmic reticulum (ER) and mitochondria are decreased in the presence of P301L mutant tau protein.P301Ltau disturbs cholesterol metabolism and its conversion to pregnenolone within mitochondria.P301Ltau expression and tau knockout show opposite effects on ER‐mitochondria association and cholesterol metabolism.The P301Ltau‐induced disruption of ER‐mitochondria contacts and cholesterol homeostasis is restored by GSK3β inhibition. [ABSTRACT FROM AUTHOR]

Musashi RNA-binding proteins (MSIs) retain a pivotal role in stem cell maintenance, tumorigenesis, and nervous system development. Recently, we showed in C. elegans that Musashi (MSI-1) actively promotes forgetting upon associative learning via a 3'UTR-dependent translational expression of the Arp2/3 actin branching complex. Here, we investigated the evolutionary conserved role of MSI proteins and the effect of their pharmacological inhibition on memory. Expression of human Musashi 1 (MSI1) and Musashi 2 (MSI2) under the endogenous Musashi promoter fully rescued the phenotype of msi-1(lf) worms. Furthermore, pharmacological inhibition of human MSI1 and MSI2 activity using (-)- gossypol resulted in improved memory retention, without causing locomotor, chemotactic, or learning deficits. No drug effect was observed in msi-1(lf) treated worms. Using Western blotting and confocal microscopy, we found no changes in MSI-1 protein abundance following (-)- gossypol treatment, suggesting that Musashi gene expression remains unaltered and that the compound exerts its inhibitory effect post-translationally. Additionally, (-)- gossypol suppressed the previously seen rescue of the msi-1(lf) phenotype in worms expressing human MSI1 specifically in the AVA neuron, indicating that (-)- gossypol can regulate the Musashi pathway in a memory-related neuronal circuit in worms. Finally, treating aged worms with (-)- gossypol reversed physiological age-dependent memory decline. Taken together, our findings indicate that pharmacological inhibition of Musashi might represent a promising approach for memory modulation. [ABSTRACT FROM AUTHOR]

Emotional information is better remembered than neutral information. Extensive evidence indicates that the amygdala and its interactions with other cerebral regions play an important role in the memory-enhancing effect of emotional arousal.While the cerebellum has been found to be involved in fear conditioning, its role in emotional enhancement of episodic memory is less clear. To address this issue, we used a wholebrain functional MRI approach in 1,418 healthy participants. First, we identified clusters significantly activated during enhanced memory encoding of negative and positive emotional pictures. In addition to the well-known emotional memory–related cerebral regions, we identified a cluster in the cerebellum. We then used dynamic causal modeling and identified several cerebellar connections with increased connection strength corresponding to enhanced emotional memory, including one to a cluster covering the amygdala and hippocampus, and bidirectional connections with a cluster covering the anterior cingulate cortex. The present findings indicate that the cerebellum is an integral part of a network involved in emotional enhancement of episodic memory. [ABSTRACT FROM AUTHOR]

Background: To assess the psychological consequences of changes during the coronavirus 2019 (COVID-19) pandemic in the Iranian population. Methods: We performed an anonymous online survey in the first 3 weeks of March 2020. Individuals older than 14 who could read Persian, and lived in Iran, were eligible for the study. The participants had to rate their stress levels and depressive symptoms (using a nine-item Patient Health Questionnaire PHQ-9) during the last 2 weeks and before the pandemic retrospectively. The changes in the psychological measurements and their association with the sociodemographic factors and burdens due to confinement were assessed. Results: Overall, among the 3,210 subjects who participated in our study, both the stress levels and average depression scores increased. However, about 23% of the subjects reported a decrease in their stress levels. The burden of childcare, restrictions in private life, and thoughts about the future were positively correlated with the changes in the stress levels and depression scores (|r| > 0.15). However, feeling relieved in the pandemic condition, and enjoying more family time were associated with less change in the stress and depression scores. Being religious (odds ratio [OR] [CI]: 1.5 [1.3-1-8]) and older age (OR [CI]: 2.9 [1.8-4.6] for >55 years old) were identified as the resilience factors, whereas being a student (OR [CI]: 2.1 [1.6;2.7]), seeking a job (OR [CI]: 2.6 [1.8;3.9]), and history of a psychiatric disorder (OR [CI]: 3.2 [2.6;4]) were identified as the risk factors for depression. Conclusions: The stress levels and depressive symptoms have increased during the COVID-19 pandemic and this increase is related to different social and personal burdens due to the confinement conditions. [ABSTRACT FROM AUTHOR]

WWC1 is a scaffolding protein in the evolutionarily conserved Hippo signaling network and is genetically linked to human memory and synaptic plasticity. In the archives of Science Signaling, Stepan et al. demonstrate the translational potential of modulating WWC1 through pharmacological inhibition of Hippo-pathway kinases to enhance cognition. [ABSTRACT FROM AUTHOR]

Smartphone-based virtual reality (VR) applications (apps) might help to counter low utilization rates of available treatments for fear of heights. Demonstration of effectiveness in real-life situations of such apps is crucial, but lacking so far. Objective of this study was to develop a stand-alone, smartphone-based VR exposure app—Easy Heights—and to test its effectiveness in a real-life situation. We performed a single-blind, parallel group, randomized controlled trial. We recruited 70 participants with fear of heights, aged 18–60 years. Primary outcome was performance in a real-life Behavioral Avoidance Test (BAT) on a lookout tower after a single 1-h app use (phase 1) and after additional repeated (6 × 30 min) app use at home (phase 2). After phase 2, but not phase 1, participants in the Easy Heights condition showed significantly higher BAT scores compared to participants in the control condition (Cohen's d = 1.3, p = 0.0001). Repeated use of our stand-alone, smartphone-based VR exposure app reduces avoidance behavior and fear, providing a low-threshold treatment for fear of heights. [ABSTRACT FROM AUTHOR]

Extensive pharmacologic, genetic, and epigenetic research has linked the glucocorticoid receptor (GR) to memory processes, and to risk and symptoms of posttraumatic stress disorder (PTSD). In the present study we investigated the epigenetic pattern of 12 genes involved in the regulation of GR signaling in two African populations of heavily traumatized individuals: Survivors of the rebel war in northern Uganda (n = 463) and survivors of the Rwandan genocide (n = 350). The strongest link between regional methylation and PTSD risk and symptoms was observed for NTRK2, which encodes the transmembrane receptor tropomyosin-related kinase B, binds the brain-derived neurotrophic factor, and has been shown to play an important role in memory formation. NTRK2 methylation was not related to trauma load, suggesting that methylation differences preexisted the trauma. Because NTRK2 methylation differences were predominantly associated with memory-related PTSD symptoms, and because they seem to precede traumatic events, we next investigated the relationship between NTRK2 methylation and memory in a sample of nontraumatized individuals (n = 568). We found that NTRK2 methylation was negatively associated with recognition memory performance. Furthermore, fMRI analyses revealed NTRK2 methylation-dependent differences in brain network activity related to recognition memory. The present study demonstrates that NTRK2 is epigenetically linked to memory functions in nontraumatized subjects and to PTSD risk and symptoms in traumatized populations. [ABSTRACT FROM AUTHOR]

The amygdala is critically involved in emotional processing, including fear responses, and shows hyperactivity in anxiety disorders. Previous research in healthy participants has indicated that amygdala activity is down-regulated by cognitively demanding tasks that engage the PFC. It is unknown, however, if such an acute down-regulation of amygdala activity might correlate with reduced fear in anxious participants. In an fMRI study of 43 participants (11 men) with fear of snakes, we found reduced amygdala activity when visual stimuli were processed under high cognitive load, irrespective of whether the stimuli were of neutral or phobic content. Furthermore, dynamic causal modeling revealed that this general reduction in amygdala activity was partially mediated by a load-dependent increase in dorsolateral PFC activity. Importantly, high cognitive load also resulted in an acute decrease in perceived phobic fear while viewing the fearful stimuli. In conclusion, our data indicate that a cognitively demanding task results in a top–down regulation of amygdala activity and an acute reduction of fear in phobic participants. These findings may inspire the development of novel psychological intervention approaches aimed at reducing fear in anxiety disorders. [ABSTRACT FROM AUTHOR]

Only a small proportion of what we see can later be recalled. Up to date it is unknown how far differences in visual exploration during encoding affect the strength of episodic memories. Here, we identified individual gaze characteristics by analyzing eye tracking data in a picture encoding task performed by 967 healthy subjects during fMRI. We found a positive correlation between fixation frequency during visual exploration and subsequent free recall performance. Brain imaging results showed a positive correlation of fixation frequency with activations in regions related to vision and memory, including the medial temporal lobe. To investigate if higher fixation frequency is causally linked to better memory, we experimentally manipulated visual exploration patterns in an independent population of 64 subjects. Doubling the number of fixations within a given exploration time increased subsequent free recall performance by 19%. Our findings provide evidence for a causal relationship between fixation frequency and episodic memory for visual information. [ABSTRACT FROM AUTHOR]

Emotional enhancement of memory by noradrenergic mechanisms is well-described, but the long-term consequences of such enhancement are poorly understood. Over time, memory traces are thought to undergo a neural reorganization, that is, a systems consolidation, during which they are, at least partly, transferred from the hippocampus to neocortical networks. This transfer is accompanied by a decrease in episodic detailedness. Here we investigated whether norepinephrine (NE) administration into the basolateral amygdala after training on an inhibitory avoidance discrimination task, comprising two distinct training contexts, alters systems consolidation dynamics to maintain episodic-like accuracy and hippocampus dependency of remote memory. At a 2-d retention test, both saline- and NE-treated rats accurately discriminated the training context in which they had received footshock. Hippocampal inactivation with muscimol before retention testing disrupted discrimination of the shock context in both treatment groups. At 28 d, saline-treated rats showed hippocampus-independent retrieval and lack of discrimination. In contrast, NE-treated rats continued to display accurate memory of the shock–context association. Hippocampal inactivation at this remote retention test blocked episodic-like accuracy and induced a general memory impairment. These findings suggest that the NE treatment altered systems consolidation dynamics by maintaining hippocampal involvement in the memory. This shift in systems consolidation was paralleled by time-regulated DNA methylation and transcriptional changes of memory-related genes, namely Reln and Pkmζ, in the hippocampus and neocortex. The findings provide evidence suggesting that consolidation of emotional memories by noradrenergic mechanisms alters systems consolidation dynamics and, as a consequence, influences the maintenance of long-term episodic-like accuracy of memory. [ABSTRACT FROM AUTHOR]

The identification of genes related to encoding, storage, and retrieval of memories is a major interest in neuroscience. In the current study, we analyzed the temporal gene expression changes in a neuronal mRNA pool during an olfactory long-term associative memory (LTAM) in Caenorhabditis elegans hermaphrodites. Here, we identified a core set of 712 (538 upregulated and 174 downregulated) genes that follows three distinct temporal peaks demonstrating multiple gene regulation waves in LTAM. Compared with the previously published positive LTAM gene set (Lakhina et al., 2015), 50% of the identified upregulated genes here overlap with the previous dataset, possibly representing stimulus-independent memory-related genes. On the other hand, the remaining genes were not previously identified in positive associative memory and may specifically regulate aversive LTAM. Our results suggest a multistep gene activation process during the formation and retrieval of long-term memory and define general memory-implicated genes as well as conditioning-type-dependent gene sets. [ABSTRACT FROM AUTHOR]

Child abuse is associated with a number of emotional and behavioral problems. Nevertheless, it has been argued that these adverse consequences may not hold for societies in which many of the specific acts of abuse are culturally normed. Epigenetic modifications in the genes of the hypothalamus–pituitary–adrenal axis may provide a potential mechanism translating abuse into altered gene expression, which subsequently results in behavioral changes. Our investigation took place in Tanzania, a society in which many forms of abuse are commonly employed as disciplinary methods. We included 35 children with high exposure and compared them to 25 children with low exposure. Extreme group comparisons revealed that children with high exposure reported more mental health problems. Child abuse was associated with differential methylation in the proopiomelanocortin gene (POMC), measured both in saliva and in blood. Hierarchical clustering based on the methylation of the POMC gene found two distinct clusters. These corresponded with children's self-reported abuse, with two-thirds of the children allocated into their respective group. Our results emphasize the consequences of child abuse based on both molecular and behavioral grounds, providing further evidence that acts of abuse affect children, even when culturally acceptable. Furthermore, on a molecular level, our findings strengthen the credibility of children's self-reports. [ABSTRACT FROM PUBLISHER]

Episodic memory performance is the result of distinct mental processes, such as learning, memory maintenance, and emotional modulation of memory strength. Such processes can be effectively dissociated using computational models. Here we performed gene set enrichment analyses of model parameters estimated from the episodic memory performance of 1,765 healthy young adults. We report robust and replicated associations of the amine compound SLC (solute-carrier) transporters gene set with the learning rate, of the collagen formation and transmembrane receptor protein tyrosine kinase activity gene sets with the modulation of memory strength by negative emotional arousal, and of the L1 cell adhesion molecule (L1CAM) interactions gene set with the repetition- based memory improvement. Furthermore, in a large functional MRI sample of 795 subjects we found that the association between L1CAM interactions and memory maintenance revealed large clusters of differences in brain activity in frontal cortical areas. Our findings provide converging evidence that distinct genetic profiles underlie specific mental processes of human episodic memory. They also provide empirical support to previous theoretical and neurobiological studies linking specific neuromodulators to the learning rate and linking neural cell adhesion molecules to memory maintenance. Furthermore, our study suggests additional memory-related genetic pathways, which may contribute to a better understanding of the neurobiology of human memory. [ABSTRACT FROM AUTHOR]

The dorsolateral prefrontal cortex (DLPFC) plays a key role in working memory. Evidence indicates that transcranial magnetic stimulation (TMS) over the DLPFC can interfere with working memory performance. Here we investigated for how long continuous theta-burst stimulation (cTBS) over the DLPFC decreases working memory performance and whether the effect of cTBS on performance depends on working memory load. Forty healthy young subjects received either cTBS over the left DLPFC or sham stimulation before performing a 2-, and 3-back working memory letter task. An additional 0-back condition served as a non-memory-related control, measuring general attention. cTBS over the left DLPFC significantly impaired 2-back working memory performance for about 15 min, whereas 3-back and 0-back performances were not significantly affected. Our results indicate that the effect of left DLPFC cTBS on working memory performance lasts for roughly 15 min and depends on working memory load. [ABSTRACT FROM AUTHOR]

Extensive evidence indicates that women outperform men in episodic memory tasks. Furthermore, women are known to evaluate emotional stimuli as more arousing than men. Because emotional arousal typically increases episodic memory formation, the females' memory advantage might be more pronounced for emotionally arousing information than for neutral information. Here, we report behavioral data from 3398 subjects, who performed picture rating and memory tasks, and corresponding fMRI data from up to 696 subjects. We were interested in the interaction between sex and valence category on emotional appraisal, memory performances, and fMRI activity. The behavioral results showed that females evaluate in particular negative (p < 10-16)andpositive(p = 2 X 10-4), but not neutral pictures, as emotionally more arousing (Pinteraction < 10-16) than males. However, in the free recall females outperformed males not only in positive (p < 10-16) and negative (p < 5 X 10-5), but also in neutral picture recall (p < 3.4 X 10-8), with a particular advantage for positive pictures (Pinteraction < 4.4 X 10 10). Importantly, females' memory advantage during free recall was absent in a recognition setting. We identified activation differences in fMRI, which corresponded to the females' stronger appraisal of especially negative pictures, but no activation differences that reflected the interaction effect in the free recall memory task. In conclusion, females' valence-category-specific memory advantage is only observed in a free recall, but not a recognition setting and does not depend on females' higher emotional appraisal. [ABSTRACT FROM AUTHOR]

Positive and negative emotional events are better remembered than neutral events. Studies in animals suggest that this phenomenon depends on the influence of the amygdala upon the hippocampus. In humans, however, it is largely unknown how these two brain structures functionally interact and whether these interactions are similar between positive and negative information. Using dynamic causal modeling of fMRI data in 586 healthy subjects, we show that the strength of the connection from the amygdala to the hippocampus was rapidly and robustly increased during the encoding of both positive and negative pictures in relation to neutral pictures. We also observed an increase in connection strength from the hippocampus to the amygdala, albeit at a smaller scale. These findings indicate that, during encoding, emotionally arousing information leads to a robust increase in effective connectivity from the amygdala to the hip-pocampus, regardless of its valence. [ABSTRACT FROM AUTHOR]

Recent evidence suggests that altered expression and epigenetic modification of the glucocorticoid receptor gene (NR3C1) are related to the risk of post-traumatic stress disorder (PTSD). The underlying mechanisms, however, remain unknown. Because glucocorticoid receptor signaling isknownto regulate emotionalmemoryprocesses, particularly in men, epigenetic modifications ofNR3C1might affect the strength of traumatic memories. Here, we found that increasedDNAmethylation at the NGFI-A (nerve growth factor-induced protein A) binding site of the NR3C1 promoter was associated with less intrusive memory of the traumatic event and reduced PTSD risk in male, but not female survivors of the Rwandan genocide. NR3C1 methylation was not significantly related to hyperarousal or avoidance symptoms. We further investigated the relationship between NR3C1 methylation and memory functions in a neuroimaging study in healthy subjects. Increased NR3C1 methylation-which was associated with lower NR3C1 expression-was related to reduced picture recognition in male, but not female subjects. Furthermore, we found methylation-dependent differences in recognition memory-related brain activity in men. Together, these findings indicate that an epigenetic modification of the glucocorticoid receptor gene promoter is linked to interindividual and gender-specific differences in memory functions and PTSD risk. [ABSTRACT FROM AUTHOR]

Memory performance is the result of many distinct mental processes, such as memory encoding, forgetting, and modulation of memory strength by emotional arousal. These processes, which are subserved by partly distinct molecular profiles, are not always amenable to direct observation. Therefore, computational models can be used to make inferences about specific mental processes and to study their genetic underpinnings. Here we combined a computational model-based analysis of memory-related processes with high density genetic information derived from a genome-wide study in healthy young adults. After identifying the best-fitting model for a verbal memory task and estimating the best-fitting individual cognitive parameters, we found a common variant in the gene encoding the brain-specific angiogenesis inhibitor 1-associated protein 2 (BAIAP2) that was related to the model parameter reflecting modulation of verbal memory strength by negative valence. We also observed an association between the same genetic variant and a similar emotional modulation phenotype in a different population performing a picture memory task. Furthermore, using functional neuroimaging we found robust genotype-dependent differences in activity of the parahippocampal cortex that were specifically related to successful memory encoding of negative versus neutral information. Finally, we analyzed cortical gene expression data of 193 deceased subjects and detected significant BAIAP2 genotype-dependent differences in BAIAP2 mRNA levels. Our findings suggest that model-based dissociation of specific cognitive parameters can improve the understanding of genetic underpinnings of human learning and memory. [ABSTRACT FROM AUTHOR]

Cortisol is known to affect memory processes. On the one hand, stress-induced or pharmacologically induced elevations of cortisol levels enhance memory consolidation. On the other hand, such experimentally induced elevations of cortisol levels have been shown to impair memory retrieval. However, the effects of individual differences in basal cortisol levels on memory processes remain largely unknown. Here we tested whether individual differences in cortisol levels predict picture learning and recall in a large sample. A total of 1225 healthy young women and men viewed two different sets of emotional and neutral pictures on two consecutive days. Both sets were recalled after a short delay (10 min). On Day 2, the pictures seen on Day 1 were additionally recalled, resulting in a long-delay (20 hr) recall condition. Cortisol levels were measured three times on Days 1 and 2 via saliva samples before encoding, between encoding and recall as well as after recall testing. We show that stronger decreases in cortisol levels during retrieval testing were associated with better recall performance of pictures, regardless of emotional valence of the pictures or length of the retention interval (i.e., 10 min vs. 20 hr). In contrast, average cortisol levels during retrieval were not related to picture recall. Remarkably during encoding, individual differences in average cortisol levels as well as changes in cortisol did not predict memory recall. Our results support previous findings indicating that higher cortisol levels during retrieval testing hinders recall of episodic memories and extend this view onto interindividual changes in basal cortisol levels. [ABSTRACT FROM AUTHOR]

Twin-studies suggest that a significant portion of individual differences in the propensity to take risks resides in people's genetic make-up and there is evidence that variability in dopaminergic systems relates to individual differences in risky choice. We examined the link between risk taking in a risk taking task (the Balloon Analogue Risk Task, BART) and a variable number tandem repeat (VNTR) polymorphism in the 3'UTR of the dopamine transporter gene (SLC6A3/DAT1). Behavior in BART is known to be associated with activity in striatal reward-processing regions, and DAT1 is assumed to modulate striatal dopamine levels. We find that carriers of DAT1 alleles, which presumably result in lower striatal dopamine availability, showed more risk taking, relative to carriers of the alleles associated with higher striatal dopamine availability. Our analyses suggest that the mechanism underlying this association is diminished sensitivity to rewards among those who take more risks. Overall, our results support the notion that a behavioral genetic approach can be helpful in uncovering the basis of individual differences in risk taking. [ABSTRACT FROM AUTHOR]

Identifying molecular mechanisms that underlie learning and memory is one of the major challenges in neuroscience. Taken the advantages of the nematode Caenorhabditis elegans, we investigated ?-adducin (add-1) in aversive olfactory associative learning and memory. Loss of add-1 function selectively impaired short- and long-term memory without causing acquisition, sensory, or motor deficits. We showed that ?-adducin is required for consolidation of synaptic plasticity, for sustained synaptic increase of AMPA-type glutamate receptor (GLR-1) content and altered GLR-1 turnover dynamics. ADD-1, in a splice-form- and tissue-specific manner, controlled the storage of memories presumably through actin-capping activity. In support of the C. elegans results, genetic variability of the human ADD1 gene was significantly associated with episodic memory performance in healthy young subjects. Finally, human ADD1 expression in nematodes restored loss of C. elegans add-1 gene function. Taken together, our findings support a role for ?-adducin in memory from nematodes to humans. Studying the molecular and genetic underpinnings of memory across distinct species may be helpful in the development of novel strategies to treat memory-related diseases. [ABSTRACT FROM AUTHOR]

Despite the current progress in high-throughput, dense genome scans, a major portion of complex traits' heritability still remains unexplained, a phenomenon commonly termed ''missing heritability.'' The negligence of analytical approaches accounting for gene-gene interaction effects, such as statistical epistasis, is probably central to this phenomenon. Here we performed a comprehensive two-way SNP interaction analysis of human episodic memory, which is a heritable complex trait, and focused on 120 genes known to show differential, memory-related expression patterns in rat hippocampus. Functional magnetic resonance imaging was also used to capture genotype-dependent differences in memory-related brain activity. A significant, episodic memory-related interaction between two markers located in potassium channel genes (KCNB2 and KCNH5) was observed (Pnominal combined = 0.000001). The epistatic interaction was robust, as it was significant in a screening (Pnominal = 0.0000012) and in a replication sample (Pnominal = 0.01). Finally, we found genotype-dependent activity differences in the parahippocampal gyrus (Pnominal = 0.001) supporting the behavioral genetics finding. Our results demonstrate the importance of analytical approaches that go beyond single marker statistics of complex traits. [ABSTRACT FROM AUTHOR]

The genetic basis of phenotypic variation can be partially explained by the presence of copy-number variations (CNVs). Currently available methods for CNV assessment include high-density single-nucleotide polymorphism (SNP) microarrays that have become an indispensable tool in genome-wide association studies (GWAS). However, insufficient concordance rates between different CNV assessment methods call for cautious interpretation of results from CNV-based genetic association studies. Here we provide a cross-population, microarray-based map of copy-number variant regions (CNVRs) to enable reliable interpretation of CNV association findings. We used the Affymetrix Genome-Wide Human SNP Array 6.0 to scan the genomes of 1167 individuals from two ethnically distinct populations (Europe, N = 717; Rwanda, N = 450). Three different CNV-finding algorithms were tested and compared for sensitivity, specificity, and feasibility. Two algorithms were subsequently used to construct CNVR maps, which were also validated by processing subsamples with additional microarray platforms (Illumina 1M-Duo BeadChip, Nimblegen 385K aCGH array) and by comparing our data with publicly available information. Both algorithms detected a total of 42669 CNVs, 74% of which clustered in 385 CNVRs of a crosspopulation map. These CNVRs overlap with 862 annotated genes and account for approximately 3.3% of the haploid human genome. We created comprehensive cross-populational CNVR-maps. They represent an extendable framework that can leverage the detection of common CNVs and additionally assist in interpreting CNV-based association studies. [ABSTRACT FROM AUTHOR]

Brain-derived neurotrophic factor (BDNF) plays an important role in hippocampal synaptic plasticity and long-term potentiation. A valine (Val) to methionine (Met) substitution in the BDNF gene (Val66Met) has been associated with episodic memory performance. This study aimed at fine-mapping the genomic region harbouring BDNF and the adjacent gene, BDNFOS, in order to identify other possible memoryrelated gene variants. Healthy young Swiss adults (n=333) underwent a verbal memory free-recall task which used words with both neutral and emotional content. Genetic variability of the BDNF and BDNFOS region was covered by analysing 55 single nucleotide polymorphisms (SNPs). Among all examined SNPs, the non-synonymous Val66Met SNP rs6265 showed the highest significant level of association with memory performance for words with emotional content. Recall performance for neutral words was unrelated to the analysed SNPs. Our results support a role for the Val66Met BDNF polymorphism in episodic memory and suggest a modulatory influence of emotional valence. [ABSTRACT FROM AUTHOR]

The deposition of amyloid β-protein (Aβ) in the vessel wall, i.e., cerebral amyloid angiopathy (CAA), is associated with Alzheimer’s disease (AD). Two types of CAA can be differentiated by the presence or absence of capillary Aβ-deposits. In addition, as in Alzheimer’s disease, risk for capillary CAA is associated with the apolipoprotein E ( APOE) ε4-allele. Because these morphological and genetic differences between the two types of AD-related CAA exist, the question arises as to whether there exist further differences between AD cases with and without capillary CAA and, if so, whether capillary CAA can be employed to distinguish and define specific subtypes of AD. To address this question, we studied AD and control cases both with and without capillary CAA to identify the following: (1) distinguishing neuropathological features; (2) alterations in perivascular protein expression; and (3) genotype-specific associations. More widespread Aβ-plaque pathology was observed in AD cases with capillary CAA than in those without. Expression of perivascular excitatory amino acid transporter 2 (EAAT-2/GLT-1) was reduced in cortical astrocytes of AD cases with capillary CAA in contrast to those lacking capillary Aβ-deposition and controls. Genetically, AD cases with capillary CAA were strongly associated with the APOE ε4 allele compared to those lacking capillary CAA and to controls. To further validate the existence of distinct types of AD we analyzed polymorphisms in additional apoE- and cholesterol-related candidate genes. Our results revealed an association between AD cases without capillary CAA (i.e., AD cases with CAA but lacking capillary CAA and AD cases without CAA) and the T-allele of the α2macroglobulin receptor/low-density lipoprotein receptor-related protein-1 ( LRP- 1) C766T polymorphism as opposed to AD cases with capillary CAA and non-AD controls. Taken together, these results indicate that AD cases with capillary CAA differ significantly from other AD cases both genetically and morphologically, thereby pointing to a specific capillary CAA-related and APOE ε4-associated subtype of AD. [ABSTRACT FROM AUTHOR]

Bipedalism, speech, and intellect are the most prominent traits that emerged in the evolution of Homo sapiens. Here, we describe a novel genetic cause of an "involution" phenotype in four patients, who are characterized by quadrupedal locomotion, intellectual impairment, the absence of speech, small stature, and hirsutism, observed in a consanguineous Brazilian family. Using whole-genome sequencing analysis and homozygous genetic mapping, we identified genes bearing homozygous genetic variants and found a homozygous 36.2 kb deletion in the gene of glutamate receptor delta 2 (GRID2) in the patients, resulting in the lack of a coding region from the fifth to the seventh exons. The GRID2 gene is highly expressed in the cerebellum cortex from prenatal development to adulthood, specifically in Purkinje neurons. Deletion in this gene leads to the loss of the alpha chain in the extracellular amino-terminal protein domain (ATD), essential in protein folding and transport from the endoplasmic reticulum (ER) to the cell surface. Then, we studied the evolutionary trajectories of the GRID2 gene. There was no sign of strong selection of the highly conservative GRID2 gene in ancient hominids (Neanderthals and Denisovans) or modern humans; however, according to in silico tests using the Mfold tool, the GRID2 gene possibly gained human-specific mutations that increased the stability of GRID2 mRNA. [ABSTRACT FROM AUTHOR]

Background: Whole-genome association studies in humans have enabled the unbiased discovery of new genes associated with human memory performance. However, such studies do not allow for a functional or causal testing of newly identified candidate genes. Since polymorphisms in Calsyntenin 2 (CLSTN2) showed a significant association with episodic memory performance in humans, we tested the C. elegans CLSTN2 ortholog CASY-1 for possible functions in the associative behavior of C. elegans. Methodology/Principal Findings: Using three different associative learning paradigms and functional rescue experiments, we show that CASY-1 plays an important role during associative learning in C. elegans. Furthermore, neuronal expression of human CLSTN2 in C. elegans rescues the learning defects of casy-1 mutants. Finally, genetic interaction studies and neuronspecific expression experiments suggest that CASY-1 may regulate AMPA-like GLR-1 glutamate receptor signaling. Conclusion/Significance: Our experiments demonstrate a remarkable conservation of the molecular function of Calsyntenins between nematodes and humans and point at a role of C. elegans casy-1 in regulating a glutamate receptor signaling pathway. [ABSTRACT FROM AUTHOR]

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressively disabling impairments in memory, cognition, and non-cognitive behavioural symptoms. Sporadic AD is multifactorial and genetically complex. While several monogenic mutations cause early-onset AD and gene alleles have been suggested as AD susceptibility factors, the only extensively validated susceptibility gene for late-onset AD is the apolipoprotein E (APOE) ε4 allele. Alleles of the APOE gene do not account for all of the genetic load calculated to be responsible for AD predisposition. Recently, polymorphisms across the neuronal sortilin-related receptor (SORL1) gene were shown to be significantly associated with AD in several cohorts. Here we present the results of our large case-control whole-genome scan at over 500,000 polymorphisms which presents weak evidence for association and potentially narrows the association interval. [ABSTRACT FROM AUTHOR]

Cognitive decline (CD) and delirium (PD) are commonly observed complications after bypass heart surgery. In this study we aimed to investigate whether certain genetic factors (alleles of the SOAT-1 gene) play a role in their appearance. We examined 137 patients receiving coronary bypass surgery with a neuropsychiatric test battery consisting of the Mini Mental State Examination (MMSE), the Brief Psychiatric Rating Scale (BPRS), the Wechsler's Memory Scale-Revised (WMS-R) on admission and one month after surgery, and the Delirium Rating Scale postoperatively, when indicated, and genotyped them in relation to the SOAT–1 genotypes (AA positive group with augmented protection of the nerve cells against stress and the AA negative group – AC and CC subgroups – with diminished protection against stress). We noted a significant decline in test results postoperatively and a high frequency of delirium (29.92% of the patients). None of these complications could be associated to the SOAT-1 genotypes. Our study confirmed the expected cognitive decline and highly frequent delirium after bypass heart surgery and excluded the possible role of SOAT-1 genotype polymorphisms in their genesis. [ABSTRACT FROM AUTHOR]

Microarrays enable the observation of gene expression in experimental models of Alzheimer's disease (AD), with implications for the human pathology. Histopathologically, AD is characterized by Aβ-containing plaques and tau-containing neurofibrillary tangles. Here, we used a human SH-SY5Y neuroblastoma cell system to assess the role of P301L mutant human tau expression, and treatment with or without Aβ on gene regulation. We found that Aβ and P301L tau expression independently affect the regulation of genes controlling cell proliferation and synaptic elements. Moreover, Aβ and P301L tau act synergistically on cell cycle and DNA damage genes, yet influence specific genes within these categories. By using neuronally differentiated P301L tau cells, we can show that Aβ treatment induces an early upregulation of cell cycle control and synaptic genes. At the protein level, by using Kinetworks™ multi-immunoblotting and BrdU labelling, we found that although P301L tau and Aβ both affected levels of cell cycle proteins, their effects were distinct, in particular concerning DNA damage proteins. Moreover, DNA synthesis was observed only when SH-SY5Y cells overexpressed human wild-type or P301L tau and were incubated with Aβ. Thus, our study shows that Aβ treatment and human tau overexpression in an AD cell culture model act synergistically to promote aberrant cell cycle re-entry, supporting the mitosis failure hypothesis in AD. [ABSTRACT FROM AUTHOR]

Cognitive decline and delirium are common complications after heart bypass surgery. Based on the reported role of the APOE-a4 allele in neurodegenerative diseases, we studied its association with these complications. A neuropsychological test battery consisting of the Mini Mental State Examination, the Wechsler's Memory Scale Revised, the Brief Psychiatric Rating Scale, and the Delirium Rating Scale was applied to 137 APOE-genotyped patients on admission and 1 month after bypass surgery. We correlated the APOE (apolipoprotein E) polymorphism with the postoperative test outcome by taking into account all factors known to influence cognitive capacity after heart surgery. There was a significant decline in all test results 1 month after surgery and a high frequency of postoperative delirium. Neither this decline nor the frequency of delirium was associated with the APOE-ε4 allele. This study confirms the high incidence of cognitive decline and delirium after coronary surgery, but it does not support the role of the APOE-ε4 allele in the occurrence of these complications. [ABSTRACT FROM AUTHOR]

Genome-wide linkage studies have defined a broad susceptibility region for late-onset Alzheimer's disease on chromosome 12, which contains the Low-Density Lipoprotein Receptor-Related Protein 6 (LRP6) gene, a coreceptor for Wnt signaling. Here, we report the association between common LRP6 variants and late-onset Alzheimer's disease in a multicenter case-control series as well as in a large family-based series ascertained by the National Institute of Mental Health-National Institute on Aging Genetics Initiative. As shown in the genome-wide linkage studies, our association depends mainly on apolipoprotein E-ε4 (APOE-ε4) carrier status. Haplotype tagging single-nucleotide polymorphisms (SNPs) with a set of seven allelic variants of LRP6 identified a putative risk haplotype, which includes a highly conserved coding sequence SNP: Ile-1062 → Val. Functional analyses revealed that the associated allele Val-1062, an allele previously linked to low bone mass, has decreased β-catenin signaling in HEK293T cells. Our study unveils a genetic relationship between LRP6 and APOE and supports the hypothesis that altered Wnt/β-catenin signaling may be involved in this neurodegenerative disease. [ABSTRACT FROM AUTHOR]

In Switzerland by 2045, we expect 2.7 Mio citizens aged 65+ of whom 1.0 Mio. aged 80+. A priority and focus of personalized health research is therefore aging biology to extend healthy life expectancy. Novel molecular and imaging features will emerge as candidate targets for risk prediction and screening of chronic diseases. It is of utmost importance to test the clinical and public health utility of candidate biomarkers evolving from this research in citizen reference cohorts. We will build a Swiss Aging Citizen Reference (SACR), a testable and scalable reference cohort offering interoperable, searchable, and accessible data. 1000 participants from existing Swiss citizen cohorts will be combined and analyzed for DNA methylation and MRI brain imaging. SACR will serve as a testbed for clinical and public health utility of candidate biomarkers. As for a proof-of-concept study, we will conduct an agnostic search for structural and functional brain features associated with epigenetic aging acceleration to examine the potential of epigenetic age acceleration as the intermediate aging biomarker and to better understand the aging mechanism in brain. [ABSTRACT FROM AUTHOR]

Background: Colony-stimulating factor 1 (CSF1) regulates the proliferation and differentiation of myelomonocytic cells. Microglial cells of CSF1-deficient mice are reduced in number and are functionally impaired. CSF1-deficient mice exhibit subtle neurodevelopmental defects, enhanced neuronal vulnerability. Moreover, it has been reported that these mice may have amyloid-plaque-like depositions in the brain at an early age. The human CSF1 gene maps to chromosome 1p21–p13, a region previously linked to Alzheimer’s disease (AD). Thus, CSF1 is a functional and positional candidate gene for AD. Objective: We assessed if genetic variability of CSF1 may influence the risk for AD. Methods: We conducted a population-based case-control association study with 3 single nucleotide polymorphisms (SNPs) across the CSF1 locus in a sample of n = 185 (rs3093054, rs756325) and n = 327 (rs1058885) individuals. Results: None of the 3 investigated SNPs was associated with the risk for AD in our sample. Conclusion: These data do not support the hypothesis that genetic variability of CSF1 influences the risk for AD. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The role of iron metabolism in Alzheimer's disease (AD) is well documented. Regulation of the proteins that maintain cellular iron metabolism is mediated by two cytoplasmic RNA-binding proteins, the Iron Regulatory Proteins (IRP1 and IRP2), that function through post-transcriptional interactions with RNA stem loop structures called iron-responsive elements. As the primary mediator of iron homeostasis in neuronal cells, IRP2 is a strong candidate for polymorphisms that could impact AD pathogenesis. Thus, we performed a pilot study to assess polymorphisms in the gene encoding IRP2 (IREB2) on clinically well-characterized, post-mortem samples (50 AD and 50 controls). DNA sequence analysis of the IREB2 gene region revealed 14 polymorphisms. Two (rs2656070 and rs13180) showed statistically significant skewing of allelic and genotypic distributions between AD patients and controls. In silico analyses revealed that rs2656070 lies within a probable promoter and disrupts the binding sites of at least two known transcription factors. Though silent and likely not functionally relevant, rs13180 is in complete LD with rs2656070 (D' > 0.999), creating an IREB2-haplotype that is significantly associated with AD. Confirmation of this association in a larger cohort of cases and controls would further support the role of iron regulation in the pathogenesis of this catastrophic and increasingly common neurodegenerative disorder. [ABSTRACT FROM AUTHOR]

The role of iron metabolism in Alzheimer's disease (AD) is well documented. Regulation of the proteins that maintain cellular iron metabolism is mediated by two cytoplasmic RNA-binding proteins, the Iron Regulatory Proteins (IRP1 and IRP2), that function through post-transcriptional interactions with RNA stem loop structures called iron-responsive elements. As the primary mediator of iron homeostasis in neuronal cells, IRP2 is a strong candidate for polymorphisms that could impact AD pathogenesis. Thus, we performed a pilot study to assess polymorphisms in the gene encoding IRP2 (IREB2) on clinically well-characterized, post-mortem samples (50 AD and 50 controls). DNA sequence analysis of the IREB2 gene region revealed 14 polymorphisms. Two (rs2656070 and rs13180) showed statistically significant skewing of allelic and genotypic distributions between AD patients and controls. In silico analyses revealed that rs2656070 lies within a probable promoter and disrupts the binding sites of at least two known transcription factors. Though silent and likely not functionally relevant, rs13180 is in complete LD with rs2656070 (D' > 0.999), creating an IREB2-haplotype that is significantly associated with AD. Confirmation of this association in a larger cohort of cases and controls would further support the role of iron regulation in the pathogenesis of this catastrophic and increasingly common neurodegenerative disorder. [ABSTRACT FROM AUTHOR]

Alzheimer’s disease (AD) is the most common cause of dementia. It is characterized by β-amyloid (Aβ) plaques, neurofibrillary tangles and the degeneration of specifically vulnerable brain neurons. We observed high expression of the cholesterol 25-hydroxylase (CH25H) gene in specifically vulnerable brain regions of AD patients. CH25H maps to a region within 10q23 that has been previously linked to sporadic AD. Sequencing of the 5′ region of CH25H revealed three common haplotypes, CH25Hχ2, CH25Hχ3 and CH25Hχ4; CSF levels of the cholesterol precursor lathosterol were higher in carriers of the CH25Hχ4 haplotype. In 1,282 patients with AD and 1,312 healthy control subjects from five independent populations, a common variation in the vicinity of CH25H was significantly associated with the risk for sporadic AD (p = 0.006). Quantitative neuropathology of brains from elderly non-demented subjects showed brain Aβ deposits in carriers of CH25Hχ4 and CH25Hχ3 haplotypes, whereas no Aβ deposits were present in CH25Hχ2 carriers. Together, these results are compatible with a role of CH25Hχ4 as a putative susceptibility factor for sporadic AD; they may explain part of the linkage of chromosome 10 markers with sporadic AD, and they suggest the possibility that CH25H polymorphisms are associated with different rates of brain Aβ deposition. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

We report two 71-year-old female monozygotic twins presenting with advanced hyperostosis frontalis interna, obesity, shortness and cognitive impairment. They both have suffered from generalized seizures since their early adulthood. Moreover, the patients showed some additional conditions only occurring in one individual or the other such as migraine, marked recurrent depressive disorder or polyarthrosis. The symptoms common to both twins appear to correspond to the Morgagni-Stewart-Morel syndrome and indicate a genetic basis of this disorder as these features occur in genetically identical patients. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]