Mher Alaverdyan

Curcumin Suppresses Soluble Tau Dimers and Corrects Molecular Chaperone, Synaptic, and Behavioral Deficits in Aged Human Tau Transgenic Mice

Background: Various types of Tau aggregates in AD brains may differentially impact neurodegeneration. Results: Curcumin selectively suppresses soluble Tau dimers and corrects molecular chaperone, synaptic, and behavioral deficits. Conclusion: A drug increasing HSPs involved in Tau clearance reduced Tau dimers and improved cognition. Significance: Curcumin that reduced Tau dimers and increased molecular chaperones was efficacious without altering insoluble Tau. The mechanisms underlying Tau-related synaptic and cognitive deficits and the interrelationships between Tau species, their clearance pathways, and synaptic impairments remain poorly understood. To gain insight into these mechanisms, we examined these interrelationships in aged non-mutant genomic human Tau mice, with established Tau pathology and neuron loss. We also examined how these interrelationships changed with an intervention by feeding mice either a control diet or one containing the brain permeable beta-amyloid and Tau aggregate binding molecule curcumin. Transgene-dependent elevations in soluble and insoluble phospho-Tau monomer and soluble Tau dimers accompanied deficits in behavior, hippocampal excitatory synaptic markers, and molecular chaperones (heat shock proteins (HSPs)) involved in Tau degradation and microtubule stability. In human Tau mice but not control mice, HSP70, HSP70/HSP72, and HSP90 were reduced in membrane-enriched fractions but not in cytosolic fractions. The synaptic proteins PSD95 and NR2B were reduced in dendritic fields and redistributed into perikarya, corresponding to changes observed by immunoblot. Curcumin selectively suppressed levels of soluble Tau dimers, but not of insoluble and monomeric phospho-Tau, while correcting behavioral, synaptic, and HSP deficits. Treatment increased PSD95 co-immunoprecipitating with NR2B and, independent of transgene, increased HSPs implicated in Tau clearance. It elevated HSP90 and HSC70 without increasing HSP mRNAs; that is, without induction of the heat shock response. Instead curcumin differentially impacted HSP90 client kinases, reducing Fyn without reducing Akt. In summary, curcumin reduced soluble Tau and elevated HSPs involved in Tau clearance, showing that even after tangles have formed, Tau-dependent behavioral and synaptic deficits can be corrected.

Loss of MAP Function Leads to Hippocampal Synapse Loss and Deficits in the Morris Water Maze with Aging

Hyperphosphorylation and accumulation of tau aggregates are prominent features in tauopathies, including Alzheimers disease, but the impact of loss of tau function on synaptic and cognitive deficits remains poorly understood. We report that old (19–20 months; OKO) but not middle-aged (8–9 months; MKO) tau knock-out mice develop Morris Water Maze (MWM) deficits and loss of hippocampal acetylated α-tubulin and excitatory synaptic proteins. Mild motor deficits and reduction in tyrosine hydroxylase (TH) in the substantia nigra were present by middle age, but did not affect MWM performance, whereas OKO mice showed MWM deficits paralleling hippocampal deficits. Deletion of tau, a microtubule-associated protein (MAP), resulted in increased levels of MAP1A, MAP1B, and MAP2 in MKO, followed by loss of MAP2 and MAP1B in OKO. Hippocampal synaptic deficits in OKO mice were partially corrected with dietary supplementation with docosahexaenoic acid (DHA) and both MWM and synaptic deficits were fully corrected by combining DHA with α-lipoic acid (ALA), which also prevented TH loss. DHA or DHA/ALA restored phosphorylated and total GSK3β and attenuated hyperactivation of the tau C-Jun N-terminal kinases (JNKs) while increasing MAP1B, dephosphorylated (active) MAP2, and acetylated α-tubulin, suggesting improved microtubule stability and maintenance of active compensatory MAPs. Our results implicate the loss of MAP function in age-associated hippocampal deficits and identify a safe dietary intervention, rescuing both MAP function and TH in OKO mice. Therefore, in addition to microtubule-stabilizing therapeutic drugs, preserving or restoring compensatory MAP function may be a useful new prevention strategy.

Multivariate morphological brain signatures predict patients with chronic abdominal pain from healthy control subjects.

Abstract Irritable bowel syndrome (IBS) is the most common chronic visceral pain disorder. The pathophysiology of IBS is incompletely understood; however, evidence strongly suggests dysregulation of the brain–gut axis. The aim of this study was to apply multivariate pattern analysis to identify an IBS-related morphometric brain signature that could serve as a central biological marker and provide new mechanistic insights into the pathophysiology of IBS. Parcellation of 165 cortical and subcortical regions was performed using FreeSurfer and the Destrieux and Harvard-Oxford atlases. Volume, mean curvature, surface area, and cortical thickness were calculated for each region. Sparse partial least squares discriminant analysis was applied to develop a diagnostic model using a training set of 160 females (80 healthy controls and 80 patients with IBS). Predictive accuracy was assessed in an age-matched holdout test set of 52 females (26 healthy controls and 26 patients with IBS). A 2-component classification algorithm comprising the morphometry of (1) primary somatosensory and motor regions and (2) multimodal network regions explained 36% of the variance. Overall predictive accuracy of the classification algorithm was 70%. Small effect size associations were observed between the somatosensory and motor signature and nongastrointestinal somatic symptoms. The findings demonstrate that the predictive accuracy of a classification algorithm based solely on regional brain morphometry is not sufficient, but they do provide support for the utility of multivariate pattern analysis for identifying meaningful neurobiological markers in IBS.

Sex differences in the influence of body mass index on anatomical architecture of brain networks

Background/Objectives:The brain has a central role in regulating ingestive behavior in obesity. Analogous to addiction behaviors, an imbalance in the processing of rewarding and salient stimuli results in maladaptive eating behaviors that override homeostatic needs. We performed network analysis based on graph theory to examine the association between body mass index (BMI) and network measures of integrity, information flow and global communication (centrality) in reward, salience and sensorimotor regions and to identify sex-related differences in these parameters.Subjects/Methods:Structural and diffusion tensor imaging were obtained in a sample of 124 individuals (61 males and 63 females). Graph theory was applied to calculate anatomical network properties (centrality) for regions of the reward, salience and sensorimotor networks. General linear models with linear contrasts were performed to test for BMI and sex-related differences in measures of centrality, while controlling for age.Results:In both males and females, individuals with high BMI (obese and overweight) had greater anatomical centrality (greater connectivity) of reward (putamen) and salience (anterior insula) network regions. Sex differences were observed both in individuals with normal and elevated BMI. In individuals with high BMI, females compared to males showed greater centrality in reward (amygdala, hippocampus and nucleus accumbens) and salience (anterior mid-cingulate cortex) regions, while males compared to females had greater centrality in reward (putamen) and sensorimotor (posterior insula) regions.Conclusions:In individuals with increased BMI, reward, salience and sensorimotor network regions are susceptible to topological restructuring in a sex-related manner. These findings highlight the influence of these regions on integrative processing of food-related stimuli and increased ingestive behavior in obesity, or in the influence of hedonic ingestion on brain topological restructuring. The observed sex differences emphasize the importance of considering sex differences in obesity pathophysiology.

Early intervention with docosahexanoic Acid (DHA) protects APOE4 acceleration of cognitive decline and plasma biomarkers in APOE4/5xFAD mice

healthy elderly (age > 65) in WHICAP, a community-based and ethnically diverse cohort in New York. The associations between plasma As40 and As42 levels and calorie-adjusted dietary intake of 10 nutrients [saturated fatty acid (SFA), mono-unsaturated fatty acid (MUFA), u-3 poly-unsaturated fatty acid (PUFA), u-6 PUFA, vitamin E, vitamin C, s-carotene, vitamin B12, folate, and vitamin D], selected due to their potential association with dementia risk, were examined using linear regression models, first unadjusted and then adjusted for age, gender, ethnicity, education, and s-amyloid assessment wave. Results: In an unadjusted model that simultaneously included all 10 nutrients, higher intake of u-3 PUFA was significantly associated with lower As40 (s 1⁄4 -25.9, p1⁄40.001) and lower As42 (s1⁄4 -11.9, p1⁄40.001) levels; higher intake of MUFAwas significantly associated with lower As40 (s 1⁄4 -1.6, p1⁄40.046) and As42 (s 1⁄4 -0.8, p1⁄40.023) levels. In an adjusted model, u-3 retained a strong association with lower plasma levels of As42 (s 1⁄4-13.6, p1⁄40.045) and As40 (s 1⁄4 -7.2, p1⁄40.021), while MUFAwas no longer associated with As. Other nutrients did not seem to be significantly associated with plasma levels of either As40 or As42. Conclusions: In cognitively healthy elders, higher dietary intake of u-3 PUFA is associated with lower plasma levels of both As40 and As42 (which are markers of slower cognitive decline and lower dementia risk inour cohort). Thus, plasma s-amyloid may be related to dietary habits.

Loss of Tau Function Causes Synaptic and Cognitive Deficits Resembling AD: Correction With Late Intervention Treatment

within 15 minutes of contact. Finally, these three biomarkers showed different adsorption ability and may cause difficulty to choose a unique tube with low adsorption for all biomarkers. Composition analysis of PP tubes revealed that only 3 tubes were pure PP, all others presenting copolymers with at least polyethylene. Surprisingly, pure PP tubes did not give the best results. This first comparative analysis of «PP» tubes strongly suggests the importance of tube types used in the observed between-center effects. Conclusions: Optimization of tube quality by surface pre-treatment or use of common tubes is needed for biomarker standardization, eventually leading to consensus medical decision points used in clinical routine or drug trials.

Protection of excitatory synapses by DHA through preserving function of NMDA-Tiam1-PAK signal pathway in Alzheimer models

Background: Epigenetic mechanisms such as post-translational histone modifications are increasingly recognized for their contribution to gene activation and silencing in the brain. Histone acetylation in particular has been shown to be important both in hippocampal long-term potentiation (LTP) and memory formation in mice. The involvement of the epigenetic modulation of memory formation has also been proposed in neuropathological models, although up to now no clear-cut connection has been demonstrated between histone modifications and Alzheimer’s disease (AD) etiology. Thus, we have undertaken preclinical studies in the APP/PS1 mouse model of AD to determine whether there are differences in histone acetylation levels during associative memory formation. Methods: Westen blot, LTP and contextual fear conditioning Results: After fear conditioning training, levels of hippocampal acetylated histone 4 (H4) in APP/PS1 mice were about 50% lower than in wild-type littermates. Interestingly, acute treatment with a histone deacetylase inhibitor, Trichostatin A (TSA), rescued the defect in CA3-CA1 LTP in slices from APP/PS1 mice. Moreover, TSA administration prior to training rescued both the defect in acetylated H4 levels and contextual freezing to wildtype values. This effect was likley due to amyloid-beta elevation as TSA rescued also the amyloid-beta induced defect in contextual fear memory. Conclusions: Based on this evidence, we propose the hypothesis that epigenetic mechanisms are involved in the altered synaptic function and memory associated with AD. In this respect, histone deacetylase inhibitors represent a new therapeutic target to effectively counteract disease progression.