Tetrahydrocurcumin Has Similar Anti-Amyloid Properties as Curcumin: In Vitro Comparative Structure-Activity Studies

Despite its potent anti-amyloid properties, the utility of curcumin (Cur) for the treatment of Alzheimer’s disease (AD) is limited due to its low bioavailability. Tetrahydrocurcumin (THC), a more stable metabolite has been found in Cur-treated tissues. We compared the anti-amyloid and neuroprotective properties of curcumin, bisdemethoxycurcumin (BDMC), demethoxycurcumin (DMC) and THC using molecular docking/dynamics, in-silico and in vitro studies. We measured the binding affinity, H-bonding capabilities of these compounds with amyloid beta protein (Aβ). Dot blot assays, photo-induced cross linking of unmodified protein (PICUP) and transmission electron microscopy (TEM) were performed to monitor the Aβ aggregation inhibition using these compounds. Neuroprotective effects of these derivatives were evaluated in N2a, CHO and SH-SY5Y cells using Aβ42 (10 µM) as a toxin. Finally, Aβ-binding capabilities were compared in the brain tissue derived from the 5× FAD mouse model of AD. We observed that THC had similar binding capability and Aβ aggregation inhibition such as keto/enol Cur and it was greater than BDMC and DMC. All these derivatives showed a similar degree of neuroprotection in vitro and labeled Aβ-plaques ex vivo. Overall, ECur and THC showed greater anti-amyloid properties than other derivatives. Therefore, THC, a more stable and bioavailable metabolite may provide greater therapeutic efficacy in AD than other turmeric derivatives.

A Predictive and Preventive Model for Onset of Alzheimer's Disease

Alzheimer's Disease (AD) is a neurodegenerative irreversible brain disorder that gradually wipes out the memory, thinking skills and eventually the ability to carry out day-to-day tasks. The amount of AD patients is rapidly increasing due to several lifestyle changes that affect biological functions. Detection of AD at its early stages helps in the treatment of patients. In this paper, a predictive and preventive model that uses biomarkers such as the amyloid-beta protein is proposed to detect, predict, and prevent AD onset. A Convolution Neural Network (CNN) based model is developed to predict AD at its early stages. The results obtained proved that the proposed model outperforms the traditional Machine Learning (ML) algorithms such as Logistic Regression, Support Vector Machine, Decision Tree Classifier, and K Nearest Neighbor algorithms.

Testing Fmr1KO Phenotypes in Response to GSK3 Inhibitors: SB216763 versus AFC03127

Glycogen synthase kinase 3 (GSK3) is a proline-directed serine-threonine kinase that is associated with several neurological disorders, including Alzheimer’s disease and fragile X syndrome (FXS). We tested the efficacy of a novel GSK3 inhibitor AFC03127, which was developed by Angelini Pharma, in comparison to the metabotropic glutamate receptor 5 inhibitor 2-Methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP) and the GSK3 inhibitor SB216763 in in vivo and in vitro assays in Fmr1KO mice, a mouse model useful for the study of FXS. The in vivo assay tested susceptibility to audiogenic-induced seizures (AGS) whereas the in vitro assays assessed biomarker expression and dendritic spine length and density in cultured primary neurons as a function of drug dose. MPEP and SB216763 attenuated AGS in Fmr1KO mice, whereas AFC03127 did not. MPEP and AFC03127 significantly reduced dendritic expression of amyloid-beta protein precursor (APP). All drugs rescued spine length and the ratio of mature dendritic spines. Spine density was not statistically different between vehicle and GSK3 inhibitor-treated cells. The drugs were tested over a wide concentration range in the in vitro assays to determine dose responses. A bell-shaped dose response decrease in APP expression was observed in response to AFC03127, which was more effective than SB216763. These findings confirm previous studies demonstrating differential effects of various GSK3 inhibitors on AGS propensity in Fmr1KO mice and confirm APP as a downstream biomarker that is responsive to GSK3 activity.

Novel microRNA-455-3p mouse models to study Alzheimers disease pathogenesis

MicroRNA-455-3p is one of the highly conserved miRNAs involved in several human diseases but newly explored by our lab in Alzheimers disease (AD). Our past studies unveiled the biomarker and therapeutic potentials of miR-455-3p in AD. Our in vitro study exhibited the protective role of miR-455-3p against AD toxicities in reducing full-length APP and amyloid-beta protein levels, and also reducing defective mitochondrial biogenesis, impaired mitochondrial dynamics and synaptic deficiencies. Next, we sought to determine the essential roles of miR-455-3p in AD using mouse models. Therefore, for the first time we generated both transgenic (TG) and knockout (KO) mouse models of miR-455-3p. We determined the positive and negative effects of miR-455-3p on mice cognitive function, mitochondrial biogenesis, mitochondrial dynamics, mitochondrial number and length, dendritic spine density, synapse numbers and synaptic activity in 12-month-old miR-455-3p TG and KO mice. MiR-455-3p TG mice lived 5 months longer than wild-type (WT) mice, whereas KO mice lived 4 months shorter than their WT counterparts. Morris water maze test showed improved cognitive behavior, spatial learning and memory in miR-455-3p TG mice relative to age-matched WT mice and miR-455-3p KO mice. Further, mitochondrial biogenesis, dynamics and synaptic activities were enhanced in miR-455-3p TG mice, while these were reduced in KO mice. Overall, miR-455-3p TG mice displayed protective effects and miR-455-3p KO mice exhibited deleterious effects in relation to AD pathogenesis. Both mouse models could be ideal research tools to understand the molecular mechanism of miR-455-3p in AD and other human diseases.

Neuroinflammatory and neurometabolic consequences from inhaled 2020 California wildfire smoke-derived particulate matter at a remote location

Utilizing a mobile laboratory located >300 km away from wildfire smoke (WFS) sources, this study examined the systemic immune response profile, with a focus on neuroinflammatory and neurometabolic consequences, resulting from inhalation exposure to naturally occurring wildfires in California and Arizona in 2020. After a 20-day exposure period, WFS-derived particulate matter inhalation resulted in significant neuroinflammation while immune activity in the peripheral (lung, bone marrow) appeared to be resolved in C57BL/6 mice. Importantly, WFS exposure increased cerebrovascular endothelial cell activation and expression of adhesion molecules (VCAM-1 and ICAM-1) in addition to increased glial activation and peripheral immune cell infiltration into the brain. Flow cytometry analysis revealed proinflammatory phenotypes of microglia and peripheral immune subsets in the brain of WFS-exposed mice. Interestingly, endothelial cell neuroimmune activity was differentially associated with levels of PECAM-1 expression, suggesting that subsets of cerebrovascular endothelial cells were transitioning to resolution of inflammation following the 20-day exposure. Neurometabolites related to protection against aging, such as NAD+ and taurine, were decreased by WFS exposure. Additionally, increased pathological amyloid-beta protein accumulation, a hallmark of neurodegeneration, was observed. Neuroinflammation, together with decreased levels of key neurometabolites, have important implications in priming inflammaging and aging-related neurodegenerative phenotypes.

Successful electroconvulsive therapy for depression in a man with cerebral amyloid angiopathy

Cerebral amyloid angiopathy (CAA) is a condition characterised by accumulation of amyloid beta protein (Aβ) in the wall of cerebral blood vessels which increases the risk of intracranial haemorrhage and contributes to cognitive impairment. We describe the case of a man around the age of 70 with ‘probable’ CAA according to the modified Boston criteria and severe depression whose depression was treated successfully with electroconvulsive therapy (ECT). To the best of our knowledge, there are no earlier published reports of ECT in a patient with CAA. We briefly discuss possible safety measures for these patients, the impact of ECT on cognition in CAA and a possible influence of ECT on Aβ clearance.

2. What causes dementia?

‘What causes dementia?’ looks at the mechanisms underlying dementia. Dr Aloysius Alzheimer identified two key features in the brain. These were a build-up of plaques dominated by the amyloid-beta protein and tangled or misfolded tau proteins. How do we research the causes of dementia? Options include animal studies, human samples including stem cells and organoids, and improved neuroscience technologies such as brain scans and MRIs. Some scientists argue that smaller soluble oligomers are as dangerous as amyloid plaques, some continue to support the amyloid cascade theory, and others look elsewhere for advances and a possible cure. Theories beyond the amyloid hypothesis are receiving more funding, changing the focus of research.