Ofir Levi

ApoE4 impairs hippocampal plasticity isoform-specifically and blocks the environmental stimulation of synaptogenesis and memory

Alzheimers disease (AD) is associated with genetic risk factors, of which the allele E4 of apolipoprotein E (apoE4) is the most prevalent, and is affected by environmental factors that include education early in life and socioeconomic background. The extent to which environmental factors affect the phenotypic expression of the AD genetic risk factors is not known. Here we show that the neuronal and cognitive stimulations, which are elicited by environmental enrichment at a young age, are markedly affected by the apoE genotype. Accordingly, exposure to an enriched environment of young mice transgenic for human apoE3, which is the benign AD apoE allele, resulted in improved learning and memory, whereas mice transgenic for human apoE4 were unaffected by the enriched environment and their learning and memory were similar to those of the nonenriched apoE3 transgenic mice. These cognitive effects were associated with higher hippocampal levels of the presynaptic protein synaptophysin and of NGF in apoE3 but not apoE4 transgenic mice. In contrast, cortical synaptophysin and NGF levels of the apoE3 and apoE4 transgenic mice were similarly elevated by environmental enrichment. These findings show that apoE4 impairs hippocampal plasticity and isoform-specifically blocks the environmental stimulation of synaptogenesis and memory. This provides a novel mechanism by which environmental factors can modulate the function and phenotypic expression of the apoE genotype.

Environmental enrichment stimulates neurogenesis in apolipoprotein E3 and neuronal apoptosis in apolipoprotein E4 transgenic mice

Neurodegeneration in Alzheimers disease (AD) is associated with the activation of neurogenesis. The mechanisms underlying this crosstalk between neuronal death and birth and the extent to which it is affected by genetic risk factors of AD are not known. We employed transgenic mice expressing human apolipoprotein E4 (apoE4), the most prevalent genetic risk factor for AD, or expressing human apoE3 (an AD‐benign allele), in order to examine the hypothesis that apoE4 tilts the balance between neurogenesis and neuronal cell death in favor of the latter. The results showed an isoform‐specific increase in neurogenesis in the hippocampal dentate gyrus (DG) under standard conditions in apoE4‐transgenic mice. Environmental stimulation, which increases neurogenesis in the DG of apoE3‐transgenic and wild‐type mice, had the opposite effect on the apoE4 mice, where it triggered apoptosis while decreasing hippocampal neurogenesis. These effects were specific to the DG and were not observed in the subventricular zone, where neurogenesis was unaffected by either the apoE genotype or the environmental conditions. These in vivo findings demonstrate a linkage between neuronal apoptosis and the impaired neuronal plasticity and cognition of apoE4‐transgenic mice, and suggest that similar interactions between apoE4 and environmental factors might occur in AD.

Threat-Related Attention Bias Variability and Posttraumatic Stress

OBJECTIVE Threat monitoring facilitates survival by allowing one to efficiently and accurately detect potential threats. Traumatic events can disrupt healthy threat monitoring, inducing biased and unstable threat-related attention deployment. Recent research suggests that greater attention bias variability, that is, attention fluctuations alternating toward and away from threat, occurs in participants with PTSD relative to healthy comparison subjects who were either exposed or not exposed to traumatic events. The current study extends findings on attention bias variability in PTSD. METHOD Previous measurement of attention bias variability was refined by employing a moving average technique. Analyses were conducted across seven independent data sets; in each, data on attention bias variability were collected by using variants of the dot-probe task. Trauma-related and anxiety symptoms were evaluated across samples by using structured psychiatric interviews and widely used self-report questionnaires, as specified for each sample. RESULTS Analyses revealed consistent evidence of greater attention bias variability in patients with PTSD following various types of traumatic events than in healthy participants, participants with social anxiety disorder, and participants with acute stress disorder. Moreover, threat-related, and not positive, attention bias variability was correlated with PTSD severity. CONCLUSIONS These findings carry possibilities for using attention bias variability as a specific cognitive marker of PTSD and for tailoring protocols for attention bias modification for this disorder.

Regulation of hippocampal cholesterol metabolism by apoE and environmental stimulation

Alzheimers disease is associated with genetic risk factors, of which the allele E4 of apolipoprotein E (apoE4) is the most prevalent, and it is also affected by environmental factors such as early life education. We have recently shown, utilizing apoE‐deficient and apoE transgenic mice, that synaptogenesis in the hippocampus following environmental stimulation is affected by apoE. In view of the pivotal role of cholesterol in synaptic plasticity, and of its suggested role in synaptogenesis, we presently examined the effects of apoE and environmental stimulation on brain cholesterol homeostasis. The hippocampal levels of cholesterol and its precursors and metabolites in control mice were not affected by exposure to environmental stimulation. In contrast, the hippocampal levels of cholesterol and its precursors lathosterol and desmosterol and metabolite 24S‐hydroxycholesterol were lower in apoE‐deficient mice that were maintained in a regular environmental than those of corresponding control mice, whereas they were markedly elevated following environmental stimulation. Histological and immunohistochemical experiments revealed that the combined stimulatory effects of apoE deficiency and environmental stimulation on cholesterol metabolism were associated with marked activation of hippocampal astrocytes and with the abnormal accumulation of cholesterol in neurons and astrocytes. These effects were rescued similarly in apoE3 and apoE4 transgenic mice. These findings suggest that apoE plays an important role in the translocation of cholesterol from astrocytes to neurons in vivo and in the regulation and homeostasis of this process.

Intraneuronal amyloid‐β plays a role in mediating the synergistic pathological effects of apoE4 and environmental stimulation

The allele E4 of apolipoprotein E4 (apoE4), which is the most prevalent genetic risk factor of Alzheimer’s disease (AD), inhibits synaptogenesis and neurogenesis and stimulates apoptosis in brains of apoE4 transgenic mice that have been exposed to an enriched environment. In the present study, we investigated the hypothesis that the brain activity‐dependent impairments in neuronal plasticity, induced by apoE4, are mediated via the amyloid cascade. Importantly, we found that exposure of mice transgenic for either apoE4, or the Alzheimer’s disease benign allele apoE3, to an enriched environment elevates similarly the hippocampal levels of amyloid‐β peptide (Aβ) and apoE of these mice, but that the degree of aggregation and spatial distribution of Aβ in these mice are markedly affected by the apoE genotype. Accordingly, environmental stimulation triggered the formation of extracellular plaque‐like Aβ deposits and the accumulation of intra‐neuronal oligomerized Aβ specifically in brains of apoE4 mice. Further experiments revealed that hippocampal dentate gyrus neurons are particularly susceptible to apoE4 and environmental stimulation and that these neurons are specifically enriched in both oligomerized Aβ and apoE. These findings show that the impairments in neuroplasticity which are induced by apoE4 following environmental stimulation are associated with the accumulation of intraneuronal Aβ and suggest that oligomerized Aβ mediates the synergistic pathological effects of apoE4 and environmental stimulation.

Brain area- and isoform-specific inhibition of synaptic plasticity by apoE4

The allele E4 of apolipoprotein E4 (apoE4), the most prevalent genetic risk factor of Alzheimers disease (AD), inhibits the improvements in learning and memory which result from exposure of apoE transgenic mice to environmental stimulation (ES). In the present study, we investigated the extent to which these cognitive deficits are associated with distinct presynaptic, postsynaptic and axonal impairments and whether these effects are brain area-specific. Exposure to an enriched environment of young mice transgenic for human apoE3, which is the AD benign apoE allele, increased the levels of the presynaptic protein synaptophysin and of the dendritic marker MAP-2 in the hippocampus and entorhinal cortex, whereas the corresponding levels of these proteins in the apoE4 transgenic mice were unaffected by the enriched environment. In contrast, the levels of synaptophysin and MAP-2 in the motor cortex were elevated by environmental stimulation in both the apoE3 and the apoE4 transgenic mice. These findings show that apoE4 inhibits synaptic plasticity following environmental stimulation and that this effect is both isoform- and brain area-specific.

Acute delivery of attention bias modification training (ABMT) moderates the association between combat exposure and posttraumatic symptoms: a feasibility study

Combat deployment enhances risk for posttraumatic stress symptoms. We assessed whether attention bias modification training (ABMT), delivered immediately prior to combat, attenuates the association between combat exposure and stress-related symptoms. 99 male soldiers preparing for combat were randomized to receive either an ABMT condition designed to enhance vigilance toward threat or an attention control training (ACT) designed to balance attention deployment between neutral and threat words. Frequency of combat events, and symptoms of PTSD and depression were measured prior to deployment and at a two-month follow-up. Regression analysis revealed that combat exposure uniquely accounted for 4.6% of the variance in stress-related symptoms change from baseline to follow-up and that the interaction between ABMT and combat exposure accounted for additional 5.4% of the variance. Follow-up analyses demonstrate that ABMT moderated the association between combat exposure and symptoms. ABMT appear to have potential as a preventative intervention to reduce risk for stress-related symptoms associated with combat exposure.

Cognitive–Behavioural Therapy and Psychodynamic Psychotherapy in the Treatment of Combat-Related Post-Traumatic Stress Disorder: A Comparative Effectiveness Study

UNLABELLED This study compared the effectiveness of two psychotherapy approaches for treating combat veterans with chronic post-traumatic stress disorder (PTSD): cognitive-behavioural therapy (CBT) and psychodynamic psychotherapy (PDT). These treatments are routinely used by the Unit for Treatment of Combat-Related PTSD of the Israel Defense Forces (IDF). IDF veterans with chronic PTSD were assigned to either CBT (n = 148) or PDT (n = 95) based on the nature of their complaint and symptoms. Psychiatric status was assessed at baseline, post-treatment and 8-12 months follow-up using the Clinician-Administered PTSD Scale, the PTSD Questionnaire, the Montgomery and Asberg Depression Rating Scale and the Psychotherapy Outcome Assessment and Monitoring System-Trauma Version assessment questionnaire. Both treatment types resulted in significant reduction in symptoms and with improved functioning from pre-treatment to post-treatment, which were maintained at follow-up. No differences between the two treatments were found in any the effectiveness measures. At post-treatment, 35% of the CBT patients and 45% of the PDT patients remitted, with no difference between the groups. At follow-up, remission rates were 33% and 36% for the CBT and PDT groups, respectively. The study recommends further randomized controlled trials to determine treatment efficacy. Copyright

Individual Therapy via the Phenomenon of Hope for Treating Chronic and Complex PTSD

Evidence-based treatment (EBT) supports different types of cognitive-behavioral therapy (CBT) for treating post-traumatic stress disorder (PTSD). Yet, a growing body of evidence shows a high therapy dropout rate and non-response rate among PTSD patients, especially patients with complex PTSD. A different, short-term therapeutic approach is therefore needed which combines CBT and psychodynamic therapy (PDT) because it is better for patients with chronic and/or complex PTSD to work with clarified stages and an end of treatment in mind. The patients mental structure is conceptualized as a continuum, and functional problems are regarded as stemming from cognitive structures and unresolved developmental conflict. The five phases of the phenomenon of hope model proposed in an earlier article—a connection phase; an agency and pathway phase (developing a goal-oriented decision-making pattern and learning to plan toward goal achievement); a reconstruction phase; a phase of processing the conflict characteristic of PTSD by utilizing the natural power of hope; and a summary and separation phase—advance a short-term therapy that combines CBT and PDT techniques. This integrated therapy is based on notes that were kept relating to the case study of a chronic PTSD patient.

Binary phenomenon of Hope: Perceptions of Traumatized Veterans

This is the second article in a phenomenological study of hope among 10 Israeli reserve soldiers with chronic posttraumatic stress disorder. The aim of the second analysis was to learn about the veterans’ conceptualization of hope. The picture of hope that emerges from the analysis of their interviews is of a binary phenomenon in which hope develops but may also be arrested, is conscious but also unconscious, and strengthens the individual but may also weaken one. These findings show the binary phenomenon of hope and how it contributes to coping with traumatic events and therefore can assist professional workers who treat individuals suffering from posttraumatic stress disorder.