Non-fibrillar soluble oligomeric forms of amyloid-β peptide (oAβ) and tau proteins are likely to play a major role in Alzheimer's disease (AD). The prevailing hypothesis on the disease ...etiopathogenesis is that oAβ initiates tau pathology that slowly spreads throughout the medial temporal cortex and neocortices independently of Aβ, eventually leading to memory loss. Here we show that a brief exposure to extracellular recombinant human tau oligomers (oTau), but not monomers, produces an impairment of long-term potentiation (LTP) and memory, independent of the presence of high oAβ levels. The impairment is immediate as it raises as soon as 20 min after exposure to the oligomers. These effects are reproduced either by oTau extracted from AD human specimens, or naturally produced in mice overexpressing human tau. Finally, we found that oTau could also act in combination with oAβ to produce these effects, as sub-toxic doses of the two peptides combined lead to LTP and memory impairment. These findings provide a novel view of the effects of tau and Aβ on memory loss, offering new therapeutic opportunities in the therapy of AD and other neurodegenerative diseases associated with Aβ and tau pathology.
Background
Although the benefits of a range of disability‐centric therapies have been well studied, little remains known about how they work, let alone how to monitor these benefits in a precise and ...reliable way.
Methods
Here, in two independent studies, we examine how sessions consisting of occupational or music therapy, both widely recognised for their effectiveness, modulate levels of salivary α‐amylase (sAA), a now time‐ and cost‐efficient marker of stress, in individuals with intellectual disability and autism spectrum disorder. Pre‐session and post‐session levels of sAA were compared in both groups in response to therapy and control sessions.
Results
In comparison to control sessions, occupational therapy significantly dampened rises in sAA levels while music therapy significantly decreased baseline sAA levels, highlighting the ability of both types of therapy to reduce stress and by proxy contribute to enhancing overall well‐being.
Conclusions
Not only do these results confirm the stress‐reducing nature of two types of multisensory therapy, but they support the use of sAA as a potential tool for evaluating stress levels in individuals with intellectual disability and autism spectrum disorder, providing an important physiological lens that may guide strategies in clinical and non‐clinical care for individuals with disabilities.
Background Although the benefits of a range of disability-centric therapies have been well studied, little remains known about how they work, let alone how to monitor these benefits in a precise and ...reliable way. Methods Here, in two independent studies, we examine how sessions consisting of occupational or music therapy, both widely recognised for their effectiveness, modulate levels of salivary alpha-amylase (sAA), a now time- and cost-efficient marker of stress, in individuals with intellectual disability and autism spectrum disorder. Pre-session and post-session levels of sAA were compared in both groups in response to therapy and control sessions. Results In comparison to control sessions, occupational therapy significantly dampened rises in sAA levels while music therapy significantly decreased baseline sAA levels, highlighting the ability of both types of therapy to reduce stress and by proxy contribute to enhancing overall well-being. Conclusions Not only do these results confirm the stress-reducing nature of two types of multisensory therapy, but they support the use of sAA as a potential tool for evaluating stress levels in individuals with intellectual disability and autism spectrum disorder, providing an important physiological lens that may guide strategies in clinical and non-clinical care for individuals with disabilities.
Giant colonic diverticulum, defined as a single diverticulum ≤ 4 cm, is rarely encountered. Due to the high incidence of complications related to the disease, obtaining the correct diagnosis early in ...the disease course is essential. Diagnosis is usually reached by conventional and cross-sectional abdominal radiography. Treatment decisions should be ideally made by a multidisciplinary discussion among surgeons, interventional radiologists, and the patient. The treatment of choice is the surgical management by open or laparoscopic approach.
Alzheimer’s disease is a devastating cureless neurodegenerative disorder affecting >35 million people worldwide. The disease is caused by toxic oligomers and aggregates of amyloid β protein and the ...microtubule-associated protein tau. Recently, the Lys-specific molecular tweezer CLR01 has been shown to inhibit aggregation and toxicity of multiple amyloidogenic proteins, including amyloid β protein and tau, by disrupting key interactions involved in the assembly process. Following up on these encouraging findings, here, we asked whether CLR01 could protect primary neurons from Alzheimer’s disease-associated synaptotoxicity and reduce Alzheimer’s disease–like pathology in vivo. Using cell culture and brain slices, we found that CLR01 effectively inhibited synaptotoxicity induced by the 42-residue isoform of amyloid β protein, including ∼80% inhibition of changes in dendritic spines density and long-term potentiation and complete inhibition of changes in basal synaptic activity. Using a radiolabelled version of the compound, we found that CLR01 crossed the mouse blood–brain barrier at ∼2% of blood levels. Treatment of 15-month-old triple-transgenic mice for 1 month with CLR01 resulted in a decrease in brain amyloid β protein aggregates, hyperphosphorylated tau and microglia load as observed by immunohistochemistry. Importantly, no signs of toxicity were observed in the treated mice, and CLR01 treatment did not affect the amyloidogenic processing of amyloid β protein precursor. Examining induction or inhibition of the cytochrome P450 metabolism system by CLR01 revealed minimal interaction. Together, these data suggest that CLR01 is safe for use at concentrations well above those showing efficacy in mice. The efficacy and toxicity results support a process-specific mechanism of action of molecular tweezers and suggest that these are promising compounds for developing disease-modifying therapy for Alzheimer’s disease and related disorders.
Question Understanding the cellular and molecular mechanisms underlying tDCS action is critical for a rationale use of this technique in clinical settings. Here we investigated the effects of tDCS on ...hippocampal synaptic plasticity and memory focusing on epigenetic mechanisms affecting the expression of plasticity-related genes. Methods Electrophysiological, behavioral and molecular indices of hippocampal plasticity were investigated following 20-min anodal tDCS delivered to awake mice. Results Hippocampal slices from tDCS-mice showed greater long-term potentiation (LTP) at CA3-CA1 synapses compared to sham-stimulated controls. Enhanced LTP was associated with improved hippocampal-dependent learning and memory assessed by the Morris water maze and novel object recognition tests. Remarkably, all these effects persisted 1 week after tDCS. Real-time PCR, Western Blotting and chromatin immunoprecipitation experiments revealed that tDCS effects were due to an intracellular signaling cascade including: (i) increased phosphorylation of cAMP response element-binding protein (CREB); (ii) enhanced CREB binding to the Bdnf promoter I; and, (iii) recruitment of the histone acetyltransferase CBP (CREB-binding protein) leading to enhanced histone 3 acetylation on Bdnf promoter I. As a consequence, the expression of Bdnf exons I and IX mRNAs was increased in the hippocampi of tDCS mice along with Bdnf protein levels. Accordingly, molecular, electrophysiological and behavioral effects of tDCS were prevented by mice treatment with either the acetylation inhibitor, curcumin, or the Bdnf receptor TrkB antagonist, ANA-12. Remarkably, we found that tDCS enhanced glycogen synthase kinase-3 β (GSK-3 β ) phosphorylation at Ser9 that was prevented by ANA-12, thus suggesting that GSK-3 β inhibition plays a role in the tDCS-induced increase of hippocampal plasticity. Conclusion Our findings show that anodal tDCS increases hippocampal LTP and memory via chromatin remodeling of Bdnf regulatory sequences leading to increased expression of this gene. These results lend support to the use of tDCS for prevention and treatment of brain diseases associated with impaired neuroplasticity.
Background
The incidence of type 1 diabetes mellitus (T1DM) in Sardinia is among the highest in the world (44.8 cases/100,000 person‐years). Recommendations of the Immunology of Diabetes Society ...advise evaluating autoantibody positivity in first‐degree relatives (FDRs) of patients with T1DM, for their higher risk to develop the disease. The aim of this study was to determine the prevalence of beta‐cell autoimmunity in FDRs of T1DM patients in Sardinia.
Methods
A total of 188 Sardinian families were recruited in collaboration between diabetes and pediatric units of university and district hospitals in Sardinia. The recruitment involved 188 patients with diagnosed T1DM and all their available FDRs (n = 447). Autoantibodies (Aabs) against GAD, IA2, insulin, and ZnT8 were measured in all subjects. Human leukocyte antigen (HLA) risk genotypes (HLA‐DR and DQ loci) were analyzed in 43 Aabs‐positive FDR.
Results
The prevalence of Aabs (any type of autoantibody, single or multiple) in FDR was 11.9% (53/447). Of those with autoantibodies, 62.3% (33/53) were positive to only 1 autoantibody, 22.6% (12/53) had 2 autoantibodies, 7.55% (4/53) had 3 autoantibodies, and 7.55% (4/53) had all 4 autoantibodies. Typing of HLA‐DR and DQ loci showed that 89% of FDR carried moderate‐ to high‐risk genotypes, with only 5 FDR with low‐risk genotypes.
Conclusions
The prevalence of T1DM autoantibodies in FDRs of T1DM patients was very high (11.9%) in the Sardinian population, higher than in other populations from the United States and Europe, and similar to that observed in Finland. Autoantibody positivity strongly associated with HLA risk. This study provides evidence of the high risk of T1DM in FDR of T1DM patients in Sardinia and warrants longitudinal follow‐up to estimate the risk of progression to T1DM in high‐risk populations.
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