Elevated concentrations of amyloid-ß oligomers and their proapoptotic effects on age-related cataract.

Recently, amyloid-ß oligomers (AßOs) have been studied as the primary pathogenic substances in Alzheimer's disease (AD). Our previous study revealed that the Aß expression level is closely related to ARC progression. Here, we demonstrated that the accumulation of AßOs in the lens epithelium of age-related cataract (ARC) patients increased during ARC progression and that this alteration was consistent with the changes in mitochondrial function, oxidative stress, and cellular apoptosis. In vitro, human lens epithelial cells (HLECs) treated with AßOs exhibited Ca2+ dyshomeostasis, impaired mitochondrial function, elevated oxidative stress levels, and increased apoptosis. Moreover, the proapoptotic effect of AßOs was alleviated after the uptake of mitochondrial Ca2+ was inhibited. These results establish that AßOs may promote HLEC apoptosis by inducing mitochondrial Ca2+ overload, thus preliminarily revealing the possible association between the accumulation of AßOs and other pathological processes in ARC.

Linking activation of synaptic NMDA receptors-induced CREB signaling to brief exposure of cortical neurons to oligomeric amyloid-beta peptide.

Amyloid-beta peptide oligomers (AßO) have been considered "primum movens" for a cascade of events that ultimately cause selective neuronal death in Alzheimer's disease (AD). However, initial events triggered by AßO have not been clearly defined. Synaptic (Syn) N-methyl-d-aspartate receptors (NMDAR) are known to activate cAMP response element-binding protein (CREB), a transcriptional factor involved in gene expression related to cell survival, memory formation and synaptic plasticity, whereas activation of extrasynaptic (ESyn) NMDARs was linked to excitotoxic events. In AD brain, CREB phosphorylation/activation was shown to be altered, along with dyshomeostasis of intracellular Ca2+ (Ca2+ i). Thus, in this work, we analyze acute/early and long-term AßO-mediated changes in CREB activation involving Syn or ESyn NMDARs in mature rat cortical neurons. Our findings show that acute AßO exposure produce early increase in phosphorylated CREB, reflecting CREB activity, in a process occurring through Syn NMDAR-mediated Ca2+ influx. Data also demonstrate that AßO long-term (24 h) exposure compromises synaptic function related to Ca2+-dependent CREB phosphorylation/activation and nuclear CREB levels and related target genes, namely Bdnf, Gadd45γ, and Btg2. Data suggest a dual effect of AßO following early or prolonged exposure in mature cortical neurons through the activation of the CREB signaling pathway, linked to the activation of Syn NMDARs.

Oligomerization and Conformational Change Turn Monomeric ß-Amyloid and Tau Proteins Toxic: Their Role in Alzheimer's Pathogenesis.

The structural polymorphism and the physiological and pathophysiological roles of two important proteins, ß-amyloid (Aß) and tau, that play a key role in Alzheimer's disease (AD) are reviewed. Recent results demonstrate that monomeric Aß has important physiological functions. Toxic oligomeric Aß assemblies (AßOs) may play a decisive role in AD pathogenesis. The polymorph fibrillar Aß (fAß) form has a very ordered cross-ß structure and is assumed to be non-toxic. Tau monomers also have several important physiological actions; however, their oligomerization leads to toxic oligomers (TauOs). Further polymerization results in probably non-toxic fibrillar structures, among others neurofibrillary tangles (NFTs). Their structure was determined by cryo-electron microscopy at atomic level. Both AßOs and TauOs may initiate neurodegenerative processes, and their interactions and crosstalk determine the pathophysiological changes in AD. TauOs (perhaps also AßO) have prionoid character, and they may be responsible for cell-to-cell spreading of the disease. Both extra- and intracellular AßOs and TauOs (and not the previously hypothesized amyloid plaques and NFTs) may represent the novel targets of AD drug research.

Cellular Receptors of Amyloid ß Oligomers (AßOs) in Alzheimer's Disease.

It is estimated that Alzheimer's disease (AD) affects tens of millions of people, comprising not only suffering patients, but also their relatives and caregivers. AD is one of age-related neurodegenerative diseases (NDs) characterized by progressive synaptic damage and neuronal loss, which result in gradual cognitive impairment leading to dementia. The cause of AD remains still unresolved, despite being studied for more than a century. The hallmark pathological features of this disease are senile plaques within patients' brain composed of amyloid beta (Aß) and neurofibrillary tangles (NFTs) of Tau protein. However, the roles of Aß and Tau in AD pathology are being questioned and other causes of AD are postulated. One of the most interesting theories proposed is the causative role of amyloid β oligomers (AßOs) aggregation in the pathogenesis of AD. Moreover, binding of AßOs to cell membranes is probably mediated by certain proteins on the neuronal cell surface acting as AßO receptors. The aim of our paper is to describe alternative hypotheses of AD etiology, including genetic alterations and the role of misfolded proteins, especially Aß oligomers, in Alzheimer’s disease. Furthermore, in this review we present various putative cellular AßO receptors related to toxic activity of oligomers.

Microglial derived tumor necrosis factor-α drives Alzheimer's disease-related neuronal cell cycle events.

Massive neuronal loss is a key pathological hallmark of Alzheimer's disease (AD). However, the mechanisms are still unclear. Here we demonstrate that neuroinflammation, cell autonomous to microglia, is capable of inducing neuronal cell cycle events (CCEs), which are toxic for terminally differentiated neurons. First, oligomeric amyloid-beta peptide (AßO)-mediated microglial activation induced neuronal CCEs via the tumor-necrosis factor-α (TNFα) and the c-Jun Kinase (JNK) signaling pathway. Second, adoptive transfer of CD11b+ microglia from AD transgenic mice (R1.40) induced neuronal cyclin D1 expression via TNFα signaling pathway. Third, genetic deficiency of TNFα in R1.40 mice (R1.40-Tnfα(-/-)) failed to induce neuronal CCEs. Finally, the mitotically active neurons spatially co-exist with F4/80+ activated microglia in the human AD brain and that a portion of these neurons are apoptotic. Together our data suggest a cell-autonomous role of microglia, and identify TNFα as the responsible cytokine, in promoting neuronal CCEs in the pathogenesis of AD.

Injection of exogenous amyloid-ß oligomers aggravated cognitive deficits, and activated necroptosis, in APP23 transgenic mice.

Alzheimer's disease (AD) is a neurodegenerative disease that is characterized by the loss of synapses and neurons in the brain, and the accumulation of amyloid plaques. Aß oligomers (AßO) play a critical role in the pathogenesis of AD. Although there is increasing evidence to support the involvement of necroptosis in the pathogenesis of AD, the exact mechanism remains elusive. In the present study, we explored the effect of exogenous AßO injection on cell necroptosis and cognitive deficits in APP23 transgenic mice. We found that intrahippocampal injection of AßO accelerated the development of AD pathology and caused cognitive impairment in APP23 mice. Specifically, AßO injection significantly accelerated the accumulation of AßO and increased the expression level of phosphorylated-tau, and also induced necroptosis. Behavioral tests showed that AßO injection was associated with cognitive impairment. Furthermore, necroptosis induced by AßO injection occurred predominantly in microglia of the AD brain. We speculate that AßO increased necroptosis by activating microglia, resulting in cognitive deficits. Our results may aid in an understanding of the role played by AßO in AD from an alternative perspective and provide new ideas and evidence for necroptosis as a potential intervention and therapeutic target for AD.

ACU193: An Immunotherapeutic Poised to Test the Amyloid ß Oligomer Hypothesis of Alzheimer's Disease.

Alzheimer's disease (AD) is an age-related neurodegenerative disease that affects 50 million people worldwide, with 10 million new cases occurring each year. The emotional and economic impacts of AD on patients and families are devastating. Approved treatments confer modest improvement in symptoms, and recently one treatment obtained accelerated approval from the United States Food and Drug Administration (FDA) and may have modest disease modifying benefit. Research over the past three decades has established a clear causal linkage between AD and elevated brain levels of amyloid ß (Aß) peptide, and substantial evidence now implicates soluble, non-fibrillar Aß oligomers (AßOs) as the molecular assemblies directly responsible for AD-associated memory and cognitive failure and accompanying progressive neurodegeneration. The widely recognized linkage of elevated Aß and AD spawned a comprehensive 20-year therapeutic campaign that focused primarily on two strategies - inhibition of the secretase enzymes responsible for Aß production and clearance of Aß peptide or amyloid plaques with Aß-directed immunotherapeutics. Unfortunately, all clinical trials of secretase inhibitors were unsuccessful. Of the completed phase 3 immunotherapy programs, bapineuzumab (targeting amyloid plaque) and solanezumab (targeting Aß monomers) were negative, and the crenezumab program (targeting Aß monomers and to a small extent oligomers) was stopped for futility. Aducanumab (targeting amyloid plaques), which recently received FDA accelerated approval, had one positive and one negative phase 3 trial. More than 25 negative randomized clinical trials (RCTs) have evaluated Aß-targeting therapeutics, yet none has directly evaluated whether selective blockage of disease-relevant AßOs can stop or reverse AD-associated cognitive decline. Here, we briefly summarize studies that establish the AD therapeutic rationale to target AßOs selectively, and we describe ACU193, the first AßO-selective immunotherapeutic to enter human clinical trials and the first positioned to test the AßO hypothesis of AD.

Protective and anti-oxidative effects of curcumin and resveratrol on Aß-oligomer-induced damage in the SH-SY5Y cell line.

Alzheimer's disease (AD) is a degenerative disorder characterized by the loss of synapses and neurons in the brain, and results in the accumulation of amyloid-based neurotic plaques. Amyloid-ß oligomers (AßO) are widely accepted as the main neurotoxin that induces oxidative stress and neuronal loss in AD. In this study, an oxidative stress model of the neuroblastoma SH-SY5Y cell line exposed to AßO was established to simulate an AD cell model. Exposure to AßO significantly reduced the viability of cultured SH-SY5Y cells (p < 0.05) and significantly increased intracellular reactive oxygen species (ROS) (p < 0.01). AßO exposure also induced oxidative stress in SH-SY5Y cells. Furthermore, AßO significantly increased the level of hyperphosphorylation of tau at sites T181 and T205 in SH-SY5Y cells (p < 0.01). Using edaravone, a free radical scavenger with neuroprotective properties, as the control, the possible protective and anti-oxidative effects of curcumin (40 µM) and resveratrol (20 µM) were evaluated. The results suggest that curcumin and resveratrol decreased ROS generation, attenuated oxidative stress, inhibited tau hyperphosphorylation, and protected SH-SY5Y cells from AßO damage. Both curcumin and resveratrol are promising supplements or medicine as therapeutic agents for the treatment of AD.

Prions and Neurodegenerative Diseases: A Focus on Alzheimer's Disease.

Specific protein misfolding and aggregation are mechanisms underlying various neurodegenerative diseases such as prion disease and Alzheimer's disease (AD). The misfolded proteins are involved in prions, amyloid-ß (Aß), tau, and α-synuclein disorders; they share common structural, biological, and biochemical characteristics, as well as similar mechanisms of aggregation and self-propagation. Pathological features of AD include the appearance of plaques consisting of deposition of protein Aß and neurofibrillary tangles formed by the hyperphosphorylated tau protein. Although it is not clear how protein aggregation leads to AD, we are learning that the cellular prion protein (PrPC) plays an important role in the pathogenesis of AD. Herein, we first examined the pathogenesis of prion and AD with a focus on the contribution of PrPC to the development of AD. We analyzed the mechanisms that lead to the formation of a high affinity bond between Aß oligomers (AßOs) and PrPC. Also, we studied the role of PrPC as an AßO receptor that initiates an AßO-induced signal cascade involving mGluR5, Fyn, Pyk2, and eEF2K linking Aß and tau pathologies, resulting in the death of neurons in the central nervous system. Finally, we have described how the PrPC-AßOs interaction can be used as a new potential therapeutic target for the treatment of PrPC-dependent AD.

Statistical Approach and Neutron Activation Analysis for Determining Essential and Toxic Elements in Two Kinds of Algerian Artemisia Plant.

In this study, two kinds of Artemisia plant, Artemisia campestris L. and Artemisia herba-alba Asso., collected from different locations in Djelfa province, Algeria, were subjected to an instrumental neutron activation analysis (INAA) in order to determine their essential and toxic elements for the first time. The obtained results for both types revealed the existence of twenty-one elements, namely, As, Ba, Br, Ca, Ce, Co, Cr, Cs, Eu, Fe, Hf, K, La, Na, Rb, Sb, Sc, Sm, Sr, Yb, and Zn, where, the elements K, Ca, Fe, and Na respectively showed a significant concentration. On the other hand, the tolerable daily intake (TDI) of the studied plants for an adult person per day was within the tolerance limits imposed by the World Health Organization (WHO). Hence, these findings might therefore be used to offer scientific basis for an optimum usage of the studied plants and so enriches the database of medicinal herbs.

Early-Occurring Dendritic Spines Alterations in Mouse Models of Alzheimer's Disease Inform on Primary Causes of Neurodegeneration.

The consensus that synaptic failure is the earliest cause of cognitive deterioration in Alzheimer's disease (AD) has initially led to investigate structural (dendritic spines) and physiological (LTP) synaptic dysfunctions in mouse models of AD with established cognitive alterations. The challenge is now to track down ultra-early alterations in spines to uncover causes rather than disease's symptoms. This review article pinpoints dysregulations of the postsynaptic density (PSD) protein network which alter the morphology and function of spines in pre- and early- symptomatic hAPP mouse models of AD, and, hence, inform on primary causes of neurodegeneration.

Uterine Adenosarcoma with Sarcomatous Overgrowth: A Case Report of Aggressive Disease in a 16-Year-Old Girl and a Literature Review.

BACKGROUND: Uterine adenosarcoma with sarcomatous overgrowth (ASSO) is a rare and aggressive disease. A case of a 16-year-old girl with uterine ASSO is reported herein. The patient received surgical resection and chemotherapy and remained alive without disease 11 months after the surgery. CASE: A 16-year-old girl was diagnosed with uterine ASSO, International Federation of Gynecology and Obstetrics (2009) stage I c. She underwent total abdominal hysterectomy, bilateral salpingectomy, and chemotherapy. She remains alive and there was no evidence of tumor recurrence on follow-up physical, laboratory, and ultrasound scan examinations. SUMMARY AND CONCLUSION: Surgery is the primary treatment for uterine ASSO, total abdominal or laparoscopic-assisted vaginal hysterectomy with or without bilateral salpingo-oophorectomy are recommended. Early surgical resection might increase survival of uterine adenosarcoma. Long-term follow-up of the patients is recommended because of the high chance of recurrence.

Modeling the neuron as a nanocommunication system to identify spatiotemporal molecular events in neurodegenerative disease.

AIM: In tauopathies such as Alzheimer's disease (AD), molecular changes spanning multiple subcellular compartments of the neuron contribute to neurodegeneration and altered axonal signaling. Computational modeling of end-to-end linked events benefit mechanistic analysis and can be informative to understand disease progression and accelerate development of effective therapies. In the calcium-amyloid beta model of AD, calcium ions that are an important regulator of neuronal function undergo dysregulated homeostasis that disrupts cargo loading for neurotrophic signaling along axonal microtubules (MTs). The aim of the present study was to develop a computational model of the neuron using a layered architecture simulation that enables us to evaluate the functionalities of several interlinked components in the calcium-amyloid beta model. METHODS: The elevation of intracellular calcium levels is modeled upon binding of amyloid beta oligomers (AßOs) to calcium channels or as a result of membrane insertion of oligomeric Aß1-42 to form pores/channels. The resulting subsequent Ca2+ disruption of dense core vesicle (DCV)-kinesin cargo loading and transport of brain-derived neurotrophic factor (BDNF) on axonal MTs are then evaluated. Our model applies published experimental data on calcium channel manipulation of DCV-BDNF and incorporates organizational complexity of the axon as bundled polar and discontinuous MTs. The interoperability simulation is based on the Institute of Electrical and Electronics Engineers standard association P1906.1 framework for nanoscale and molecular communication. RESULTS: Our analysis provides new spatiotemporal insights into the end-to-end signaling events linking calcium dysregulation and BDNF transport and by simulation compares the relative impact of dysregulation of calcium levels by AßO-channel interactions, oligomeric Aß1-42 pores/channel formation, and release of calcium by internal stores. The flexible platform of our model allows continued expansion of molecular details including mechanistic and morphological parameters of axonal cytoskeleton networks as they become available to test disease and treatment predictions. CONCLUSION: The present model will benefit future drug studies on calcium homeostasis and dysregulation linked to measurable neural functional outcomes. The algorithms used can also link to other multiscale multi-cellular modeling platforms to fill in molecular gaps that we believe will assist in broadening and refining multiscale computational maps of neurodegeneration.

Dopamine agonists rescue Aß-induced LTP impairment by Src-family tyrosine kinases.

Soluble forms of oligomeric amyloid beta (AßO) are involved in the loss of synaptic plasticity and memory, especially in early phases of Alzheimer's disease. Stimulation of dopamine D1/D5 receptors (D1R/D5R) is known to increase surface expression of synaptic α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate subtype glutamate and N-methyl-D-aspartate subtype glutamate receptors and facilitates the induction of the late phase of long-term potentiation (LTP), probably via a related mechanism. In this study, we show that the D1/D5R agonist SKF38393 protects LTP of hippocampal CA1 synapses from the deleterious action of oligomeric amyloid beta. Unexpectedly, the D1R/D5R-mediated recovery of LTP is independent of protein kinase A or phospholipase C pathways. Instead, we found that the inhibition of Src-family tyrosine kinases completely abolished the protective effects of D1R/D5R stimulation in a cellular model of learning and memory.

Hippocampal Injections of Oligomeric Amyloid ß-peptide (1-42) Induce Selective Working Memory Deficits and Long-lasting Alterations of ERK Signaling Pathway.

Increasing evidence suggests that abnormal brain accumulation of soluble rather than aggregated amyloid-ß1-42 oligomers (Aßo(1-42)) plays a causal role in Alzheimer's disease (AD). However, as yet, animal's models of AD based on oligomeric amyloid-ß1-42 injections in the brain have not investigated their long-lasting impacts on molecular and cognitive functions. In addition, the injections have been most often performed in ventricles, but not in the hippocampus, in spite of the fact that the hippocampus is importantly involved in memory processes and is strongly and precociously affected during the early stages of AD. Thus, in the present study, we investigated the long-lasting impacts of intra-hippocampal injections of oligomeric forms of Aßo(1-42) on working and spatial memory and on the related activation of ERK1/2. Indeed, the extracellular signal-regulated kinase (ERK) which is involved in memory function had been found to be activated by amyloid peptides. We found that repeated bilateral injections (1injection/day over 4 successive days) of oligomeric forms of Aßo(1-42) into the dorsal hippocampus lead to long-lasting impairments in two working memory tasks, these deficits being observed 7 days after the last injection, while spatial memory remained unaffected. Moreover, the working memory deficits were correlated with sustained impairments of ERK1/2 activation in the medial prefrontal cortex (mPFC) and the septum, two brain areas tightly connected with the hippocampus and involved in working memory. Thus, our study is first to evidence that sub-chronic injections of oligomeric forms of Aßo(1-42) into the dorsal hippocampus produces the main sign of cognitive impairments corresponding to the early stages of AD, via long-lasting alterations of an ERK/MAPK pathway in an interconnected brain networks.

A systematic review to determine reliability and usefulness of the field-based test batteries for the assessment of physical fitness in adolescents - The ASSO Project.

The aim of the present review is to investigate the main field-based tests, used alone or included in sport or fitness batteries, for the assessment of health- and skill-related physical fitness components in adolescents. Different scientific databases were searched through using the selected key words related to physical fitness and its components for adolescence. The search focused on original articles and reviews/meta-analyses using valid, reproducible and feasible tests that fit within the school environment. A total of 100 scientific manuscripts were included in the qualitative synthesis. The present systematic review pointed out 5 fitness tests that well adapt to the evaluation of the components of physical fitness of adolescents within a school environment: the 20 m shuttle run test for cardio-respiratory endurance; the handgrip strength test for upper body maximal strength; the standing broad jump test for lower body maximal strength; the sit-up test to exhaustion for muscular endurance and the 4×10 m shuttle run test for speed, agility and coordination. These fitness tests have been finally selected and incorporated into the Adolescents and Surveillance System for the Obesity prevention - Fitness Test Battery (ASSO-FTB), and will be adopted within the ASSO Project for evaluation purposes. This instrument could be also provided to teachers and people working in schools in order to assess physical fitness of adolescents over time and prevent obesity and related diseases.

Relaxant Effect of Essential Oil of Artemisia herba-alba Asso. on Rodent Jejunum Contractions.

Artemisia herba-alba Asso. is a shrub commonly encountered in Morocco. It is used in traditional medicine for treating intestinal disorders. The essential oil extracted from the plant's aerial parts reversibly relaxed the spontaneous tonus of the rabbit jejunum in a reversible concentration dependent manner with an IC(50) value of 97.33 ± 2.59 ng/ml and reversed the tonic contraction of rat jejunum induced by 75 mM KCl and 10(-6) M carbachol with IC(50) values of 115.5 ± 3.05 and 119.4 ± 20.86 ng/ml, respectively. The pre-treatment of the latter isolated intestine with this essential oil produced a dose-dependent shift of the Ca(++) and CCh dose-response curve to the right, with suppression of the maximal effect, similar to the non-competitive antagonist effect on muscarinic receptors and calcium channel, respectively.