Activity In Alzheimer's Disease Research Articles

Association of Sleep-Disordered Breathing With Alzheimer Disease Biomarkers in Community-Dwelling Older Adults

Increasing evidence suggests that sleep-disordered breathing (SDB) increases the risk of developing Alzheimer clinical syndrome. However, the brain mechanisms underlying the link between SDB and Alzheimer disease are still unclear. To determine which brain changes are associated with the presence of SDB in older individuals who are cognitively unimpaired, including changes in amyloid deposition, gray matter volume, perfusion, and glucose metabolism. This cross-sectional study was conducted using data from the Age-Well randomized clinical trial of the Medit-Ageing European project, acquired between 2016 and 2018 at Cyceron Center in Caen, France. Community-dwelling older adults were assessed for eligibility and were enrolled in the Age-Well clinical trial if they did not meet medical or cognitive exclusion criteria and were willing to participate. Participants who completed a detailed neuropsychological assessment, polysomnography, a magnetic resonance imaging, and florbetapir and fluorodeoxyglucose positron emission tomography scans were included in the analyses. Based on an apnea-hypopnea index cutoff of 15 events per hour, participants were classified as having SDB or not. Voxelwise between-group comparisons were performed for each neuroimaging modality, and secondary analyses aimed at identifying which SDB parameter (sleep fragmentation, hypoxia severity, or frequency of respiratory disturbances) best explained the observed brain changes and assessing whether SDB severity and/or SDB-associated brain changes are associated with cognitive and behavioral changes. Of 157 participants initially assessed, 137 were enrolled in the Age-Well clinical trial, and 127 were analyzed in this study. The mean (SD) age of the 127 participants was 69.1 (3.9) years, and 80 (63.0%) were women. Participants with SDB showed greater amyloid burden (t114 = 4.51; familywise error-corrected P = .04; Cohen d, 0.83), gray matter volume (t119 = 4.12; familywise error-corrected P = .04; Cohen d, 0.75), perfusion (t116 = 4.62; familywise error-corrected P = .001; Cohen d, 0.86), and metabolism (t79 = 4.63; familywise error-corrected P = .001; Cohen d, 1.04), overlapping mainly over the posterior cingulate cortex and precuneus. No association was found with cognition, self-reported cognitive and sleep difficulties, or excessive daytime sleepiness symptoms. The SDB-associated brain changes in older adults who are cognitively unimpaired include greater amyloid deposition and neuronal activity in Alzheimer disease-sensitive brain regions, notably the posterior cingulate cortex and precuneus. These results support the need to screen and treat for SDB, especially in asymptomatic older populations, to reduce Alzheimer disease risk. ClinicalTrials.gov Identifier: NCT02977819.

Characterization of the dynamic behavior of neural activity in Alzheimer’s disease: exploring the non-stationarity and recurrence structure of EEG resting-state activity

Objective. Mild cognitive impairment (MCI) and dementia due to Alzheimer’s disease (AD) have been shown to induce perturbations to normal neuronal behavior and disrupt neuronal networks. Recent work suggests that the dynamic properties of resting-state neuronal activity could be affected by MCI and AD-induced neurodegeneration. The aim of the study was to characterize these properties from different perspectives: (i) using the Kullback–Leibler divergence (KLD), a measure of non-stationarity derived from the continuous wavelet transform; and (ii) using the entropy of the recurrence point density () and the median of the recurrence point density (), two novel metrics based on recurrence quantification analysis. Approach. KLD, and were computed for 49 patients with dementia due to AD, 66 patients with MCI due to AD and 43 cognitively healthy controls from 60 s electroencephalographic (EEG) recordings with a 10 s sliding window with no overlap. Afterwards, we tested whether the measures reflected alterations to normal neuronal activity induced by MCI and AD. Main results. Our results showed that frequency-dependent alterations to normal dynamic behavior can be found in patients with MCI and AD, both in non-stationarity and recurrence structure. Patients with MCI showed signs of patterns of abnormal state recurrence in the theta (4–8 Hz) and beta (13–30 Hz) frequency bands that became more marked in AD. Moreover, abnormal non-stationarity patterns were found in MCI patients, but not in patients with AD in delta (1–4 Hz), alpha (8–13 Hz), and gamma (30–70 Hz). Significance. The alterations in normal levels of non-stationarity in patients with MCI suggest an initial increase in cortical activity during the development of AD. This increase could possibly be due to an impairment in neuronal inhibition that is not present during later stages. MCI and AD induce alterations to the recurrence structure of cortical activity, suggesting that normal state switching during rest may be affected by these pathologies.

RT-QuIC detection of tauopathies using full-length tau substrates

ABSTRACT Early detection and diagnosis of neurodegenerative diseases has been hampered by the lack of sensitive testing. Real-time quaking induced conversion (RT-QuIC) has been used for the early and sensitive detection of prion-induced neurologic disease, and has more recently been adapted to detect misfolded alpha-synuclein and tau as biomarkers for neurodegenerative disease. Here we use full-length recombinant tau substrates to detect tau seeding activity in Alzheimer’s disease and other human tauopathies.

Serum HDL Associated Antioxidant Activity in Alzheimer's Disease: Paraoxonase1 and Dysfunctional HDL.

Human serum paraoxonase1 (PON1) is a high-density lipoprotein (HDL) associated antioxidant enzymes. We aimed to research the PON1 activity in Alzheimer's disease (AD) not accompanied with any disorders and other conditions influencing the PON1 activity. We studied the PON1 activity and PON1 related lipid parameters in two groups, probable sporadic late onset AD (n:30) and those with healthy subjects (n:32). These groups were homogeneous, in which the subjects did not have any cardiovascular risk factors or other conditions affecting PON1 activity. We found increased high-density lipoprotein cholesterol (HDL-C) and significantly decreased PON1 activity in the AD patients. A patient with a PON1 activity value of ≤ 151 U/L had a 5.48-fold higher risk for AD, compared to those with a PON1 activity value of > 151 U/L. Decreased PON1 activity may play a role in the oxidative stress (OS) related pathogenesis of AD. An increased HDL-C with the decreased PON1 activity may bring the concept of dysfunctional HDL into question in the pathogenesis of AD. It may be emphasized in the pathogenesis of AD for further studies.

Paroxysmal slow cortical activity in Alzheimer's disease and epilepsy is associated with blood-brain barrier dysfunction.

A growing body of evidence shows that epileptic activity is frequent but often undiagnosed in patients with Alzheimer's disease (AD) and has major therapeutic implications. Here, we analyzed electroencephalogram (EEG) data from patients with AD and found an EEG signature of transient slowing of the cortical network that we termed paroxysmal slow wave events (PSWEs). The occurrence per minute of the PSWEs was correlated with level of cognitive impairment. Interictal (between seizures) PSWEs were also found in patients with epilepsy, localized to cortical regions displaying blood-brain barrier (BBB) dysfunction, and in three rodent models with BBB pathology: aged mice, young 5x familial AD model, and status epilepticus-induced epilepsy in young rats. To investigate the potential causative role of BBB dysfunction in network modifications underlying PSWEs, we infused the serum protein albumin directly into the cerebral ventricles of naïve young rats. Infusion of albumin, but not artificial cerebrospinal fluid control, resulted in high incidence of PSWEs. Our results identify PSWEs as an EEG manifestation of nonconvulsive seizures in patients with AD and suggest BBB pathology as an underlying mechanism and as a promising therapeutic target.

Novel Peptidomic Approach for Identification of Low and High Molecular Weight Tauopathy Peptides Following Calpain Digestion, and Primary Culture Neurotoxic Challenges.

Tauopathy is a class of a neurodegenerative disorder linked with tau hyperphosphorylation, proteolysis, and aggregation. Tau can be subjected to proteolysis upon calpain activation in Alzheimer disease (AD), and traumatic brain injury (TBI). We and others have extensively researched calpain-mediated tau breakdown products (Tau-BDP; 45K, 35K, and 17K). Tau proteolysis might also generate low molecular weight (LMW ≤10K) proteolytic peptides after neurodegenerative damage. In this study, we have subjected purified tau protein (phospho and non-phospho) and mouse brain lysate to calpain-1 digestion to characterize the LMW generated by nano-liquid chromatography coupled to electrospray ionization to tandem mass spectrometry (nano-LC-ESI-MS/MS). We have also challenged differentiated primary cerebrocortical neuronal cultures (CTX) with neurotoxic agents (calcium ionophore calcimycin (A23187), staurosporine (STS), N-methyl-D-aspartate (NMDA), and Maitotoxin (MTX)) that mimic neurodegeneration to investigate the peptidome released into the conditioned cell media. We used a simple workflow in which we fractionate LMW calpain-mediated tau peptides by ultrafiltration (molecular weight cut-off value (MWCO) of 10K) and subject filtrate fractions to nano-LC-MS/MS analysis. The high molecular weight (HMW) peptides and intact proteins retained on the filter were analyzed separately by western blotting using total and phospho-specific tau antibodies. We have identified several novel proteolytic tau peptides (phosphorylated and non-phosphorylated) that are only present in samples treated with calpain or cell-based calpain activation model (particularly N- and C-terminal peptides). Our findings can help in developing future research strategies emphasizing on the suppression of tau proteolysis as a target.

Effect of Temperature and pH on the Secondary Structure and Denaturation Process of Jumbo Squid Hepatopancreas Cathepsin D.

Cathepsin D is a lysosomal enzyme that is found in all organisms acting in protein turnover, in humans it is present in some types of carcinomas, and it has a high activity in Parkinson's disease and a low activity in Alzheimer disease. In marine organisms, most of the research has been limited to corroborate the presence of this enzyme. It is known that cathepsin D of some marine organisms has a low thermostability and that it has the ability to have activity at very acidic pH. Cathepsin D of the Jumbo squid (Dosidicus gigas) hepatopancreas was purified and partially characterized. The secondary structure of these enzymes is highly conserved so the role of temperature and pH in the secondary structure and in protein denaturation is of great importance in the study of enzymes. The secondary structure of cathepsin D from jumbo squid hepatopancreas was determined by means of circular dichroism spectroscopy. In this article, our purpose was to determine the secondary structure of the enzyme and how it is affected by subjecting it to different temperature and pH conditions. Circular dichroism technique was used to measure the modifications of the secondary structure of cathepsin D when subjected to different treatments. The methodology consisted in dissecting the hepatopancreas of squid and freeze drying it. Then a crude extract was prepared by mixing 1: 1 hepatopancreas with assay buffer, the purification was in two steps; the first step consisted of using an ultrafiltration membrane with a molecular cut of 50 kDa, and the second step, a pepstatin agarose resin was used to purification the enzyme. Once the enzyme was purified, the purity was corroborated with SDS PAGE electrophoresis, isoelectric point and zymogram. Circular dichroism is carried out by placing the sample with a concentration of 0.125 mg / mL in a 3 mL quartz cell. The results were obtained in mdeg (millidegrees) and transformed to mean ellipticity per residue, using 111 g/mol molecular weight/residue as average. Secondary-structure estimation from the far-UV CD spectra was calculated using K2D Dichroweb software. It was found that α helix decreases at temperatures above 50 °C and above pH 4. Heating the enzyme above 70°C maintains a low percentage of α helix and increases β sheet. Far-UV CD measurements of cathepsin D showed irreversible thermal denaturation. The process was strongly dependent on the heating rate, accompanied by a process of oligomerization of the protein that appears when the sample is heated, and maintained a certain time at this temperature. An amount typically between 3 and 4% α helix of their secondary structure remains unchanged. It is consistent with an unfolding process kinetically controlled due to the presence of an irreversible reaction. The secondary structure depends on pH, and a pH above 4 causes α helix structures to be modified. In conclusion, cathepsin D from jumbo squid hepatopancreas showed retaining up to 4% α helix at 80°C. The thermal denaturation of cathepsin D at pH 3.5 is under kinetic control and follows an irreversible model.

Cell Type Specific Expression of Toll-Like Receptors in Human Brains and Implications in Alzheimer's Disease.

Toll-like receptors mediate important cellular immune responses upon activation via various pathogenic stimuli such as bacterial or viral components. The activation and subsequent secretion of cytokines and proinflammatory factors occurs in the whole body including the brain. The subsequent inflammatory response is crucial for the immune system to clear the pathogen(s) from the body via the innate and adaptive immune response. Within the brain, astrocytes, neurons, microglia, and oligodendrocytes all bear unique compositions of Toll-like receptors. Besides pathogens, cellular damage and abnormally folded protein aggregates, such as tau and Amyloid beta peptides, have been shown to activate Toll-like receptors in neurodegenerative diseases such as Alzheimer's disease. This review provides an overview of the different cell type-specific Toll-like receptors of the human brain, their activation mode, and subsequent cellular response, as well as their activation in Alzheimer's disease. Finally, we critically evaluate the therapeutic potential of targeting Toll-like receptors for treatment of Alzheimer's disease as well as discussing the limitation of mouse models in understanding Toll-like receptor function in general and in Alzheimer's disease.

Characterization of EEG Resting-state Activity in Alzheimer's Disease by Means of Recurrence Plot Analyses.

The main objective of this study was to characterize EEG resting-state activity in 55 Alzheimer's disease (AD) patients and 29 healthy controls by means of TREND, a measure based on recurrence quantification analysis. TREND was computed from 60-second recordings of consecutive EEG activity, divided into non-overlapping windows of length 1, 2, 3, 5, 10, 15, 20 and 60 seconds. This measure was computed in the conventional EEG frequency bands (delta, theta, alpha, beta-1, beta-2 and gamma). The parameters delay (τ) and embedding dimension (m) were first optimized for every window size and frequency band under study. These embedding parameters proved to be frequency-dependent. Furthermore, 10 s epochs were set as the minimum length required to avoid spurious results. Statistically significant differences between both groups were found (p <; 0.05, Mann-Whitney U-test). The groups showed differences in TREND in the theta (4-8 Hz), beta1 (13-19 Hz) and beta-2 (19-30 Hz) frequency bands. Our results using TREND suggest that AD disrupts resting-state neural dynamics. Furthermore, these findings indicate that AD induces a frequency-dependent pattern of alterations in the non-stationarity levels of resting-state neural activity.

Polycomb repressive 2 complex-Molecular mechanisms of function.

Numerous molecular processes conduct epigenetic regulation of protein transcription to maintain cell specification. In this review, we discuss molecular mechanisms of the Polycomb group of proteins and its enzymatic role in epigenetics. More specifically, we focus on the Polycomb repressive complex 2 (PRC2) and the effects of its repressive marker. We have compiled information regarding the biological structure and how that impacts the stability of the complex. In addition, we examined functions of the individual core proteins of PRC2 in relation to the accessory proteins that interact with the complex. Lastly, we discuss the implications of unregulated and downregulated PRC2 activity in Alzheimer's disease and cancer and possible methods of treatment related to PRC2 regulation.

Aerobic Exercise Differential Alters Intrinsic Neuronal Properties In The 3xtg Mouse Model Of Alzheimer's Disease

PURPOSE: Alterations in network activities in Alzheimer’s disease (AD) are accompanied by an early imbalance of excitation and inhibition that related to cognitive function. Although that aerobic exercise could enhance synaptic plasticity from various AD mouse models have been found, the properties of neurons firing in specific conditions remain poorly understood. This study was to investigate the neurophysiological signals underlying the effects of aerobic exercise on the brains of APP/PS1/Tau transgenic (3χTg) mice and 129 mice as wild type (Wt) control at 9 months of age. METHODS: 3χTg mice (6 months old) were randomly divided into exercise groups and sedentary groups (AS, AE), and Wt mice as cohort control. The exercise groups would run on the treadmill for 12 weeks. Multichannel recording technology was used to record population spikes in cortical and hippocampal region at 9 months of age in vivo during awake or sleep state. Spike sorting was performed using offline sorter software. Pyramidal cells (PNs) were distinguished from putative interneurons (INs) on the basis of average firing rate, bursting properties, and spike width. RESULTS: Recordings took place across 5-7 consecutive days while mice were awake exploring or asleep, and the number of spikes was calculated every 10 sec as a session. During awake, in three AS, AE and Wt mice, we recorded 15 PNs, 48 PNs and 10 PNs, while 9, 23 and 11 INs in cortex (with a total of 192 place fields); 36 PNs, 77 PNs and 35 PNs, while 10, 37 and 15 INs in hippocampus (with a total of 330 place fields). During sleep state, with a total of 138 place fields, we recorded 22 PNs, 19 PNs and 13 PNs, while 7, 15 and 14 INs in cortex; 29 PNs, 58 PNs and 21 PNs, while 9, 24 and 11 INs in hippocampus (with a total of 270 place fields). In both awake and sleep state, IN firing rates were differential changed in AS compared to the control, and the ratio of IN/PN was lower in both cortex (0.6±0.02, 0.31±0.00) and hippocampus (0.28±0.00, 0.31±0.01) of AS compared to Wt mice (1.1±0.02, 0.43±0.01/ 1.08±0.02, 0.52±0.01, P<0.01). Exercise attenuated the phenomena (0.48±0.01, 0.48±0.01/0.79±0.02, 0.41±0.02, p<0.01). CONCLUSIONS: Aerobic exercise could regulate aberrant cellular neurophysiology related to cognitive impairments dependent network function.

ASAF: altered spontaneous activity fingerprinting in Alzheimer’s disease based on multisite fMRI

Several monocentric studies have noted alterations in spontaneous brain activity in Alzheimer’s disease (AD), although there is no consensus on the altered amplitude of low-frequency fluctuations in AD patients. The main aim of the present study was to identify a reliable and reproducible abnormal brain activity pattern in AD. The amplitude of local brain activity (AM), which can provide fast mapping of spontaneous brain activity across the whole brain, was evaluated based on multisite rs-fMRI data for 688 subjects (215 normal controls (NCs), 221 amnestic mild cognitive impairment (aMCI) 252 AD). Two-sample t-tests were used to detect group differences between AD patients and NCs from the same site. Differences in the AM maps were statistically analyzed via the Stouffer’s meta-analysis. Consistent regions of lower spontaneous brain activity in the default mode network and increased activity in the bilateral hippocampus/parahippocampus, thalamus, caudate nucleus, orbital part of the middle frontal gyrus and left fusiform were observed in the AD patients compared with those in NCs. Significant correlations (P < 0.05, Bonferroni corrected) between the normalized amplitude index and Mini-Mental State Examination scores were found in the identified brain regions, which indicates that the altered brain activity was associated with cognitive decline in the patients. Multivariate analysis and leave-one-site-out cross-validation led to a 78.49% prediction accuracy for single-patient classification. The altered activity patterns of the identified brain regions were largely correlated with the FDG-PET results from another independent study. These results emphasized the impaired brain activity to provide a robust and reproducible imaging signature of AD.

Iso-α-Acids, Bitter Components in Beer, Suppress Inflammatory Responses and Attenuate Neural Hyperactivation in the Hippocampus.

Due to the growth in aging populations worldwide, prevention and therapy for age-related cognitive decline and dementia are in great demand. We previously demonstrated that long-term intake of iso-α-acids, which are hop-derived bitter compounds found in beer, prevent Alzheimer’s pathology in a rodent model. On the other hand, the effects of iso-α-acids on neural activity in Alzheimer’s disease model mice have not been investigated. Here, we demonstrated that short-term intake of iso-α-acids suppresses inflammation in the hippocampus and improves memory impairment even after disease onset. Importantly, we demonstrated that short-term administration of iso-α-acids attenuated the neural hyperactivation in hippocampus. In 6-month-old 5 × FAD mice exhibiting hippocampus inflammation and memory impairment, oral administration of iso-α-acids for 7 days reduced inflammatory cytokines, including MIP-1α and soluble Aβ and improved object memory in the novel object recognition test. In 12-month-old J20 mice, intake of iso-α-acids for 7 days also suppressed inflammatory cytokines and soluble Aβ in the brain. Manganese-enhanced magnetic resonance imaging (MEMRI) of hippocampi of J20 mice showed increased manganese compared with wild type mice, but iso-α-acids canceled this increased MEMRI signal in J20 mice, particularly in the hippocampus CA1 and CA3 region. Taken together, these findings suggest that short-term intake of iso-α-acids can suppress hippocampus inflammation even after disease onset and improve hyper neural activity in Alzheimer’s disease model mice.

Eugenol Attenuates Scopolamine-Induced Hippocampal Cholinergic, Glutamatergic, and Mitochondrial Toxicity in Experimental Rats.

Eugenol is one of the essential chemical constituents of several functional food plants including Eugenia caryophyllata Thunb. (Family: Myrtaceae). Eugenol exhibits neuroprotective and anti-stress activities through multimodal mechanisms of action. Further, eugenol exerts anti-amnesic activity in Alzheimer's disease (AD)-like animals perhaps through anti-oxidant mechanism to date. Hence, the present study was designed to elaborate the anti-amnesic activity of eugenol in scopolamine-challenged rodents. Scopolamine (3mg/kg/day, i.p.) and eugenol (12.5, 25.0, and 50.0mg/kg) were administered to male rats for 14 consecutive days of the experimental schedule at a time lag of 30min. Eugenol (25.0 and 50.0mg/kg) attenuated scopolamine-induced loss in learning ability in terms of increased escape latency at day-4 (D-4) and memory function in terms of decreased time spent in target quadrant at D-5 of Morris water maze test protocol. Moreover, eugenol attenuated scopolamine-induced loss in spatial memory in terms of decreased percentage of spontaneous alteration behavior in Y-maze test. Additionally, eugenol attenuated scopolamine-induced hippocampal cholinergic dysfunction (decrease in acetylcholine level, increase in acetylcholinesterase activity, and decrease in density and affinity of M1 and total muscarinic receptor), glutamate neurotoxicity (increase in levels of glutamate, calcium, calcium-dependent calpain-2, and brain-derived neurotropic factor), and mitochondrial dysfunction (decrease in formazan produced, membrane potential, and oxidative stress) in rats. Thus, it could be considered as an alternate candidate in the management of AD. Moreover, inclusion of functional foods containing eugenol could be a better option to manage memory formation in neurological disorders.

Neuropathological correlates and genetic architecture of microglial activation in elderly human brain

Microglia, the resident immune cells of the brain, have important roles in brain health. However, little is known about the regulation and consequences of microglial activation in the aging human brain. Here we report that the proportion of morphologically activated microglia (PAM) in postmortem cortical tissue is strongly associated with β-amyloid, tau-related neuropathology, and the rate of cognitive decline. Effect sizes for PAM measures are substantial, comparable to that of APOE ε4, the strongest genetic risk factor for Alzheimer’s disease, and mediation models support an upstream role for microglial activation in Alzheimer’s disease via accumulation of tau. Further, we identify a common variant (rs2997325) influencing PAM that also affects in vivo microglial activation measured by [11C]-PBR28 PET in an independent cohort. Thus, our analyses begin to uncover pathways regulating resident neuroinflammation and identify overlaps of PAM’s genetic architecture with those of Alzheimer’s disease and several other traits.

Preference for emotionally meaningful activity in Alzheimer’s disease

Objectives: Socioemotional selectivity theory (SST) contends that future time perspective is the central determinant of healthy older adults’ prioritization of emotional gratification. We have shown elsewhere that individuals with Alzheimer’s disease (AD) are disoriented to future time perspective. This study examined whether these same participants would prioritize emotional gratification despite having distorted time perspective.Method: Performance of individuals with Alzheimer’s disease (AD) was compared against young, young-old, and old-old adults on a social activity preference card-sort task. We examined whether activity preferences differentially related to subjective wellbeing.Results: Multidimensional scaling revealed common dimensions along which groups considered social activities. The importance of these dimensions varied across healthy participant groups in ways predicted by SST. Dimensions related to knowledge acquisition were more important in youth than older age; emotional dimensions were more important to the older age groups. Despite AD, these individuals also prioritzed emotional gratification, suggesting that cognitive impairment is not a barrier to socioemotional selectivity. Preference for emotionally meaningful activities was positively associated with subjective wellbeing.Conclusion: Persons with AD are motivated towards emotionally meaningful ends and retain high levels of wellbeing. These findings have implications in the caregiving context for shaping social programs to better match goals and preferences.

HMGB1 gene silencing inhibits neuroinflammation via down-regulation of NF-κB signaling in primary hippocampal neurons induced by Aβ25–35

High mobility group box 1 protein (HMGB1) is potentially triggered by Aβ oligomers and other sterile injuries, and is a non-histone DNA binding nuclear protein with roles in neural development and neurodegeneration, which contribute to memory impairment and chronic neuroinflammation in the brain. However, the exact molecular mechanisms of HMGB1 activation in Alzheimer's disease (AD) were previously unknown. The present study aimed to elucidate the effects of HMGB1 in Aβ25–35-induced neuroinflammation in hippocampal neuron cultures. RNA interference (RNAi) HMGB1 treatment significantly reduced Aβ25–35-induced HMGB1 expression by almost 70% in primary hippocampal neurons. Furthermore, quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, and enzyme-linked immunosorbent assay (ELISA) demonstrated that short hairpin RNA (shRNA) for HMGB1 ameliorated Aβ25–35-treated neuroinflammation, including activation of advanced glycosylation end product-specific receptor (RAGE), toll-like receptor 4 (TLR4), and nuclear factor-kappa B (NF-κB)-p65, as well as induced the release of inflammatory mediators such as tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β), IL-6, and HMGB1 in primary hippocampal neurons and the culture supernatant. In addition, pretreatment with HMGB1-shRNA dramatically reduced both the degree of nuclear-cytoplasmic HMGB1 translocation of HMGB1 and NF-κB DNA binding. Together, the data indicate that HMGB1 mediates the pathogenesis of AD by activating RAGE/TLR4 signaling and that shRNA targeting HMGB1 may be a promising therapeutic strategy for treating AD.

Design, synthesis and evaluation of curcumin-based fluorescent probes to detect Aβ fibrils

Amyloid β fibrillation is an early event in Alzheimer’s disease, so its detection is important to understand its roles in Alzheimer’s disease. Curcumin, which has poor water solubility, has been reported to have many pharmacological activities including potent anti-amyloid β fibril activity in Alzheimer’s disease. In this study, we found that curcumin analogues with the fluorescence property instead of non-inhibition of amyloid β fibrils. The development of new curcumin analogue, Me-CUR (9), as fluorescent switchable probe to detect amyloid β fibrils is described. Me-CUR (9) shows excellent fluorescence, especially higher than ThT (4), in the presence of amyloid β fibrils. These results suggest that Me-CUR (9) can become a useful in vitro amyloid fluorescence sensor for diagnosis of Alzheimer’s disease.

Dynamic Complexity of Spontaneous BOLD Activity in Alzheimer's Disease and Mild Cognitive Impairment Using Multiscale Entropy Analysis.

Alzheimer’s disease (AD) is characterized by progressive deterioration of brain function among elderly people. Studies revealed aberrant correlations in spontaneous blood oxygen level-dependent (BOLD) signals in resting-state functional magnetic resonance imaging (rs-fMRI) over a wide range of temporal scales. However, the study of the temporal dynamics of BOLD signals in subjects with AD and mild cognitive impairment (MCI) remains largely unexplored. Multiscale entropy (MSE) analysis is a method for estimating the complexity of finite time series over multiple time scales. In this research, we applied MSE analysis to investigate the abnormal complexity of BOLD signals using the rs-fMRI data from the Alzheimer’s disease neuroimaging initiative (ADNI) database. There were 30 normal controls (NCs), 33 early MCI (EMCI), 32 late MCI (LMCI), and 29 AD patients. Following preprocessing of the BOLD signals, whole-brain MSE maps across six time scales were generated using the Complexity Toolbox. One-way analysis of variance (ANOVA) analysis on the MSE maps of four groups revealed significant differences in the thalamus, insula, lingual gyrus and inferior occipital gyrus, superior frontal gyrus and olfactory cortex, supramarginal gyrus, superior temporal gyrus, and middle temporal gyrus on multiple time scales. Compared with the NC group, MCI and AD patients had significant reductions in the complexity of BOLD signals and AD patients demonstrated lower complexity than that of the MCI subjects. Additionally, the complexity of BOLD signals from the regions of interest (ROIs) was found to be significantly associated with cognitive decline in patient groups on multiple time scales. Consequently, the complexity or MSE of BOLD signals may provide an imaging biomarker of cognitive impairments in MCI and AD.

Exosomes Isolated From Human Umbilical Cord Mesenchymal Stem Cells Alleviate Neuroinflammation and Reduce Amyloid-Beta Deposition by Modulating Microglial Activation in Alzheimer's Disease.

Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by excessive accumulation of the amyloid-β peptide (Aβ) in the brain, which has been considered to mediate the neuroinflammation process. Microglial activation is the main component of neuroimmunoregulation. In recent years, exosomes isolated from human umbilical cord mesenchymal stem cells (hucMSC-exosomes) have been demonstrated to mimic the therapeutic effects of hucMSCs in many inflammation-related diseases. In this study, exosomes from the supernatant of hucMSCs were injected into AD mouse models. We observed that hucMSC-exosomes injection could repair cognitive disfunctions and help to clear Aβ deposition in these mice. Moreover, we found that hucMSC-exosomes injection could modulate the activation of microglia in brains of the mice to alleviated neuroinflammation. The levels of pro-inflammatory cytokines in peripheral blood and brains of mice were increased and the levels of anti-inflammatory cytokines were decreased. We also treated BV2 cells with hucMSC-exosomes in culture medium. HucMSC-exosomes also had inflammatory regulating effects to alternatively activate microglia and modulate the levels of inflammatory cytokines in vitro.