Effects Of Beta-amyloid Research Articles

Ginkgolide B: mechanisms of neurobiological effects, prospects for use in the therapy of Alzheimer's disease

The review presents an analysis of experimental data on the study of neurobiological effects of ginkgolide B, which may find application in the therapy of Alzheimer's disease (AD). Ginkgolide B is a diterpene trilactone isolated from the leaves of the relict woody plant Ginkgo biloba L., which has been used for thousands of years in traditional Chinese medicine as a neuroprotective agent. In recent years, this compound has attracted attention because of its wide range of neurobiological effects. The neuroprotective effect of ginkgolide B on brain neurons when exposed to various neurotoxins has been established. This compound has also been shown to effectively protect neurons from the effects of beta-amyloid. Studies have revealed the ability of ginkgolide B to reduce microglia activity and regulate neurotransmitter release. In vivo experiments have shown that this substance significantly increases the expression of brain-derived neurotrophic factor (BDNF) and improves cognitive functions, including memory and learning. It is concluded that ginkgolide B, apparently, may find application in the future as a multi-targeted agent of complex therapy of AD.

Impact of Lactate on Mitochondrial Activity in Endothelial Cells Exposed in vitro to the Acute Toxic Effect of beta-Amyloid

Impact of Lactate on Mitochondrial Activity in Endothelial Cells Exposed in vitro to the Acute Toxic Effect of beta-Amyloid

Reduced Levels of ABCA1 Transporter Are Responsible for the Cholesterol Efflux Impairment in β-Amyloid-Induced Reactive Astrocytes: Potential Rescue from Biomimetic HDLs.

The cerebral synthesis of cholesterol is mainly handled by astrocytes, which are also responsible for apoproteins’ synthesis and lipoproteins’ assembly required for the cholesterol transport in the brain parenchyma. In Alzheimer disease (AD), these processes are impaired, likely because of the astrogliosis, a process characterized by morphological and functional changes in astrocytes. Several ATP-binding cassette transporters expressed by brain cells are involved in the formation of nascent discoidal lipoproteins, but the effect of beta-amyloid (Aβ) assemblies on this process is not fully understood. In this study, we investigated how of Aβ1-42-induced astrogliosis affects the metabolism of cholesterol in vitro. We detected an impairment in the cholesterol efflux of reactive astrocytes attributable to reduced levels of ABCA1 transporters that could explain the decreased lipoproteins’ levels detected in AD patients. To approach this issue, we designed biomimetic HDLs and evaluated their performance as cholesterol acceptors. The results demonstrated the ability of apoA-I nanodiscs to cross the blood–brain barrier in vitro and to promote the cholesterol efflux from astrocytes, making them suitable as a potential supportive treatment for AD to compensate the depletion of cerebral HDLs.

The effect of beta-amyloid and tau protein aggregations on magnetic susceptibility of anterior hippocampal laminae in Alzheimer's diseases

Previous studies have reported the changes of magnetic susceptibility induced by iron deposition in hippocampus of Alzheimer's disease (AD) brains. It is well-known that hippocampus is divided into well-defined laminar architecture, which, however, is difficult to be resolved with in-vivo MRI due to the limited imaging resolution. The present study aims to investigate layer-specific magnetic susceptibility in the hippocampus of AD patients using high-resolution ex-vivo MRI, and elucidate its relationship with beta amyloid (Aβ) and tau protein histology. We performed quantitative susceptibility mapping (QSM) and T2* mapping on postmortem anterior hippocampus samples from four AD, four Primary Age-Related Tauopathy (PART), and three control brains. We manually segmented each sample into seven layers, including four layers in the cornu ammonis1 (CA1) and three layers in the dentate gyrus (DG), and then evaluated AD-related alterations of susceptibility and T2* values and their correlations with Aβ and tau in each hippocampal layer. Specifically, we found (1) layer-specific variations of susceptibility and T2* measurements in all samples; (2) the heterogeneity of susceptibility were higher in all layers of AD patients compared with the age- and gender-matched PART cases while the heterogeneity of T2* values were lower in four layers of CA1; and (3) voxel-wise MRI-histological correlation revealed both susceptibility and T2* values in the stratum molecular (SM) and stratum lacunosum (SL) layers were correlated with the Aβ content in AD, while the T2* values in the stratum radiatum (SR) layer were correlated with the tau content in the PART but not AD. These findings suggest a selective effect of the Aβ- and tau-pathology on the susceptibility and T2* values in the different layers of anterior hippocampus. Particularly, the alterations of magnetic susceptibility in the SM and SL layers may be associated with Aβ aggregation, while those in the SR layermay reflect the age-related tau protein aggregation.

Impact of Amyloid Burden on Regional Functional Synchronization in the Cognitively Normal Older Adults

Previous studies have shown aberrant functional connectivity in preclinical Alzheimer’s disease (AD). However, the effects of beta-amyloid (Aβ) retention on regional functional synchronization in cognitively normal older adults still remain unclear. The aim of this study was to explore the distinctive association pattern between Aβ retention and regional functional synchronization in cognitively normal older adults. Sixty-one older adults with normal cognition underwent functional magnetic resonance imaging and regional functional synchronizations were quantified using regional homogeneity (ReHo). Subjects were dichotomized using 18F-Florbetaben positron emission tomography imaging into subjects with (Aβ+; n = 30) and without (Aβ-; n = 31) Aβ burden. The Aβ+ group exhibited significantly higher ReHo in the fusiform gyrus and lower ReHo in the precuneus compared with the Aβ- group. We found significant negative correlations between global Aβ retention and ReHo in the precuneus and medial prefrontal cortex and positive correlations between global Aβ retention and ReHo in the bilateral lingual gyrus, left fusiform gyrus, and right middle temporal gyrus in the Aβ+ group. Our findings suggest that regional functional synchronization might have distinctive association patterns with Aβ retention in the cognitively normal older adults. These findings can enrich the functional characterization of early stages of disease progression in AD.

P27 Minimising the toxic effects of beta-Amyloid 42 on oxidative stress

It is becoming increasingly apparent that the highly amyloidogenic beta-Amyloid 42 peptide is involved in various mechanisms which are instrumental to Alzheimer’s disease (AD) pathogenesis. Recent reports have shown that such a mechanism is the induction of oxidative stress early on in the disease process. It is believed that beta-Amyloid becomes a source of free radicals itself and this contributes to the initiation of lipid peroxidation, which modifies membrane fluidity and leads to disruption of mitochondrial metabolism, respiration and reactive oxygen species levels. Oxidative stress could be minimised using dietary or supplemented antioxidant therapies. Here we will discuss our findings regarding 12-oxo phytodienoic acid, jasmonic acid, and methyl jasmonate as antioxidant agents that can protect and E18 rat primary hippocampal neurons against beta-Amyloid 42 induced oxidative stress and toxicity. We report that all three compounds act as antioxidants and are able to reduce beta-Amyloid 42 induced increases in mitochondrial and nuclear ROS levels, however at varying potencies. The Jasmonates antioxidant capacities suggests that there is potential for use as an AD treatment however further research is currently underway to investigate other potential effects and to elucidate their specificity at reducing beta-Amyloid 42 induced toxicity.

Investigating the effects of beta-amyloid on hippocampal signalling in Alzheimer's disease

Alzheimer's disease (AD) is the leading form of dementia and is characterised clinically by cognitive decline and impairments to memory function. The protein amyloid-β (Aβ) is thought to be a key mediator of this neurodegeneration [1]. Mounting evidence suggests that soluble Aβ1-42 oligomers (oAβ1-42) cause the impairments observed in early AD, which includes synapse loss and synaptic dysfunction. For example, oAβ1-42 inhibits hippocampal long-term potentiation (LTP) [2], an important synaptic plasticity thought to underlie memory formation in the brain [3]. We have recently found that postsynaptic infusion of oAβ into hippocampal neurons causes an increase in synaptic conductance attributed to changes in the excitatory glutamate receptor profile at the synapse. The relevance of this to synaptic dysregulation and consequence on hippocampal signalling is yet to be determined. Here we take a computational approach to investigate how oAβ1-42 dysregulates signalling within the hippocampus. We first develop a biophysical model of synaptic potentiation in a CA1 neuron, based on a simple kinetic synapse model and Hodgkin-Huxley formalism [4], which successfully reproduces the conductance increase observed in single-cell patch clamp experiments following oAβ application. We then extend this to investigate how this affects signalling across a small network of CA1 neurons, analysing the importance of connectivity strength and number of affected neurons to the overall dynamics of the system. Recent studies have suggested that there are two distinct types of CA1 neurons with different electrophysiological properties [5]. Therefore we also consider the impact a heterogeneous population would have on signalling across the network.

Effects of Beta-Amyloid on Resting State Functional Connectivity Within and Between Networks Reflect Known Patterns of Regional Vulnerability.

Beta-amyloid (Aβ) deposition is one of the hallmarks of Alzheimer's disease (AD). However, it is also present in some cognitively normal elderly adults and may represent a preclinical disease state. While AD patients exhibit disrupted functional connectivity (FC) both within and between resting-state networks, studies of preclinical cases have focused primarily on the default mode network (DMN). The extent to which Aβ-related effects occur outside of the DMN and between networks remains unclear. In the present study, we examine how within- and between-network FC are related to both global and regional Aβ deposition as measured by [(11)C]PIB-PET in 92 cognitively normal older people. We found that within-network FC changes occurred in multiple networks, including the DMN. Changes of between-network FC were also apparent, suggesting that regions maintaining connections to multiple networks may be particularly susceptible to Aβ-induced alterations. Cortical regions showing altered FC clustered in parietal and temporal cortex, areas known to be susceptible to AD pathology. These results likely represent a mix of local network disruption, compensatory reorganization, and impaired control network function. They indicate the presence of Aβ-related dysfunction of neural systems in cognitively normal people well before these areas become hypometabolic with the onset of cognitive decline.

Dangerous Liaisons between Beta-Amyloid and Cholinergic Neurotransmission

The review examines the multifaceted interactions between cholinergic transmission and beta-amyloid suggesting a continuum in the action of the peptide that at low concentrations (picomolar-low nanomolar) may directly stimulate nicotinic cholinergic receptor while desensitizing them at increasing concentrations (high nanomolar-low micromolar). In addition high beta-amyloid concentrations may reduce the synaptic release of several neurotransmitters, including glutamate, aspartate, GABA, glycine and dopamine, when the release is elicited through cholinergic stimulation but not following depolarization. The effect of beta-amyloid has been observed both in vitro and in vivo in at least three different brain areas (nucleus accumbens, striatum, hippocampus) suggesting that the peptide may exert some general effects even if not all the brain areas have been evaluated. In turn the activation of cholinergic receptors may affect the amyloid precursor protein processing diverting the metabolism toward non-amyloidogenic products. These actions, dissociated from those described in the case of high beta-amyloid concentrations leading to neurotoxic oligomers, may participate to cause dysfunctions in the neurotransmitter activity, in turn leading, at least from a theoretical point of view, to early neuropsychiatric disturbances in the disease. Complexively these observations underscore novel relationships between two main players in Alzheimer's disease pathogenesis that are beta-amyloid and cholinergic transmission. Also emerges the inherent difficulty of targeting beta-amyloid in a context in which the peptide exerts several actions beyond neurotoxicity.

Antibodies to synthetic fragment 95–123 of the prion protein protect neurons and astrocytes from beta-amyloid toxicity

Toxic effect of beta-amyloid on brain cells during Alzheimer's disease pathology is known to be associated with oxidative stress, intracellular Ca2+ increase in neurons and astrocytes and activation of reactive oxygen species production. Prion protein is involved in beta-amyloid toxicity. Here we investigated an effect of affinity purified antibodies to synthetic fragment 95-123 of the prion protein on beta-amyloid induced cell death, Ca(2+)-signal, reactive oxygen species production and caspase 3 activation. We have shown that antibodies to fragment 95-123 are able to protect neurons and astrocytes from beta-amyloid induced cell death with no effect on the intracellular Ca2+ concentration altered by beta-amyloid treatment. However, the antibodies significantly reduced Abeta induced reactive oxygen species production in astrocytes and decreased caspase 3 activation in neurons and astrocytes. Thus, induction of antibodies to synthetic fragment 95-123 of the prion protein provides a new approach to anti-AD vaccine design.

Effects of beta-amyloid on electrical synapses and electrical networks in the neocortex

Effects of beta-amyloid on electrical synapses and electrical networks in the neocortex

Effects of beta-amyloid on behavioral and amino acids spectrum in rats’ brain and their modulation by embryonic proteins

One of the crucial events in the pathogenesis of neurodegenerative disorders linked with dementia-like Alzheimer’s Disease (AD) is the disturbance in neurotransmission based on progressive deficit of neuromediators that is manifested by marked decrease in cognitive behavior, loss of memory and inability to learn as a result of impairment in synaptic plasticity of neurons. In this study we have used a new complex of proteoglycans of embryonic genesis (PEG) created by Prof. L. Mkrtchyan, as a possible therapeutic approach that can rescue neurons from further degeneration caused by beta-amyloid (Aβ). We attempt to reveal the biochemical (determination of neuroactive amino acids such as glutamate, GABA, taurine, glycine and aspartate) changes and behavior on Y-maze and avoidance/exploratory activity on elevated plus-maze task in rats’ brain after modeling Alzheimer’s disease by i.c.v. injection of Aβ25–35. Furthermore, in this study we analyzed the neuroprotective properties of PEG. Under the influence of PEG the concentration of all investigated amino acids both in cerebral cortex and hippocampus (except striatum changes) increased. In the present study we demonstrated that bilateral i.c.v. injection of aggregated Aβ25–35 in dosage 30 nmol/rat resulted in impairment in spatial alternation behavior. Both preliminary (single) and double injection of PEG showed constant improvement of spatial memory after the first trial up to 90 days after i.c.v. injection of aggregated Aβ25–35. Our findings suggest that proteoglycans of embryonic genesis in neurodegenerative state show an expressed regulatory–protective effect.

A role for p53 in the β-amyloid-mediated regulation of the lysosomal system

Beta-amyloid accumulates around neurons in Alzheimer's disease and is thought to contribute to the neurodegenerative process. This study examined the role of the tumour suppressor protein, p53, in the neurodegenerative pathway, with focus on the interaction of p53 with the lysosomal system. beta-Amyloid increased expression of p53 and its transcription target, Bax, in cultured cortical neurons. In addition, A beta increased the association of phospho-p53(ser15) with the lysosomal compartment and this correlated with destabilization of the lysosomal membrane and a concomitant increase in cytosolic cathepsin-L activity. These effects of beta-amyloid were abolished by the p53 inhibitor, pifithrin-alpha, and siRNA-mediated knockdown of p53, demonstrating that p53 is a critical regulator of lysosomal integrity and the induction of cathepsin-L protease activity. In addition, activation of the apoptotic cascade was abolished by pifithrin-alpha. We conclude that p53 associates with the lysosome to regulate a lysosomal branch of the apoptotic cascade which contributes to beta-amyloid-mediated neurodegeneration.

Selective Vulnerability of Neurons in Primary Cultures and in Neurodegenerative Diseases

Primary neuronal cultures are commonly used to dissect the molecular and cellular mechanisms that underlie human brain diseases. Neurons dissociated from an embryonic brain and grown in culture dishes are almost by definition different from those residing inside a living brain. Not only are the individual cells stripped of their normal chemical and physical contacts, but the cellular composition of the cultures (the ratio of cell types) can be affected by many intrinsic and extrinsic factors, including brain region, neuronal birthday, gender, genetic background and in vitro age. Changes in any of these factors may have a strong impact on the outcome of the experiment. In a recent study, Romito-DiGiacomo et al. /54/ demonstrated that when neurons were harvested from murine embryonic cortex, the typical protocol favored cells that were just finishing cell division at the time of harvest. By taking advantage of the fact that the date of the final cell division (birthday) of a neuron correlates with its final position in the cortical plate they were able to assay deeper layer neurons (layers V-VI) separately from the more superficial layers (layers II-III). They reported that while the superficial cells were sensitive to the toxic effect of beta-amyloid, the deeper layer neurons were virtually resistant to death in its presence. The findings recapitulate selective vulnerability in the neocortex of Alzheimer's disease. This is a beautiful example of how to turn the apparent weakness of primary cultures into strength through experimental design and data interpretation. Selective vulnerability is a common feature of neurodegenerative disease, thus it is critical to use the right primary culture. Do you know what is in your culture?

Beta-amyloid blocks high frequency stimulation induced LTP but not nicotine enhanced LTP

Nicotine has been postulated to be a possible neuroprotective agent in Alzheimer's Disease (AD). In the present studies, the effect of beta-amyloid (Aβ) was investigated on the nicotine enhancement of high-frequency-induced LTP. Perfusion of nicotine substantially enhanced HFS-induced LTP in both rat and mouse dentate gyrus. The enhancing action of nicotine was mediated via α7 nAChRs as it was absent in mice null for α7 nAChR. Aβ strongly inhibited the induction of LTP in control animals, with LTP being completely inhibited at 1 h post-HFS. Although Aβ also inhibited LTP in the presence of nicotine, the extent of the inhibition of LTP in nicotine perfused slices was similar to that in control, resulting in substantial LTP remaining in the presence of Aβ in the nicotine perfused slices. The nicotine enhanced LTP and the LTP remaining in the presence of Aβ and nicotine, although not the control LTP was dependent on activation of PKA. Chronic nicotine treatment also enhanced HFS-LTP recorded in acute slices taken from the nicotine-treated animals, and such LTP was only partially inhibited by Aβ. We postulate that nicotine-enhanced LTP has certain different mechanisms to that of control LTP which results in a resistance to inhibition by Aβ.

Beta-amyloid causes downregulation of calcineurin in neurons through induction of oxidative stress

Calcineurin is an abundant cytosolic protein that is implicated in the modulation of glutamate release. Here we show that the expression level of this enzyme is reduced in primary neuronal cultures treated with beta-amyloid. Parallel experiments in ETNA cell lines expressing SOD1 suggested that the effect of beta-amyloid on calcineurin expression is mediated by oxidative stress. The relevance of the in vitro experiments was assessed by analysis of tissue from patients with Alzheimer's disease (AD) and tissue from two strains of transgenic mice that mimic aspects of AD. The tissue from the AD brains displayed a pronounced downregulation of calcineurin immunoreactivity in profiles that were negative for glial fibrillary acidic protein (GFAP). In the hippocampus of the transgenic animals (which were analyzed in an early stage of the disease) the downregulation of calcineurin was restricted to mossy fiber terminals. A downregulation of the presynaptic pool of calcineurin may contribute to the dysregulation of glutamate release that is considered a hallmark of AD.

Acute effect of β amyloid on synchronized spontaneous Ca2+ oscillations in cultured hippocampal networks

The effects of beta amyloid (Abeta) on cytoplasmic Ca(2+) ([Ca(2+)](c)) have been studied extensively, but the current literature on this aspect is confusing. We reported that 20 microM Abeta(25-35) significantly inhibited the synchronized spontaneous cytoplasmic Ca(2+) transients immediately after application, whereas it had little effect on the baseline [Ca(2+)](c) concentration in neurons. Abeta(1-42) had a similar effect on the Ca(2+) transients as Abeta(25-35), while it increased baseline [Ca(2+)](c) concentration gradually. However, Abeta(1-40) had little effect on either Ca(2+) transients or baseline [Ca(2+)](c). Such differential effects of Abeta on Ca(2+) signals might explain, at least partially, the confusing observations from the previous studies and provide important therapeutic implications for preventing or reversing early neuron damage in Alzheimer's disease.

Abnormality of G-protein-coupled receptor kinases at prodromal and early stages of Alzheimer's disease: an association with early beta-amyloid accumulation.

Overwhelming evidence indicates that the effects of beta-amyloid (Abeta) are dose dependent both in vitro and in vivo, which implies that Abeta is not directly detrimental to brain cells until it reaches a threshold concentration. In an effort to understand early Alzheimer's disease (AD) pathogenesis, this study focused on the effects of subthreshold soluble Abeta and the underlying molecular mechanisms in murine microglial cells and an AD transgenic mouse model. We found that there were two phases of dose-dependent Abeta effects on microglial cells: at the threshold of 5 microm and above, Abeta directly induced tumor necrosis factor-alpha (TNF-alpha) release, and at subthreshold doses, Abeta indirectly potentiated TNF-alpha release induced by certain G-protein-coupled receptor (GPCR) activators. Mechanistic studies revealed that subthreshold Abeta pretreatment in vitro reduced membrane GPCR kinase-2/5 (GRK2/5), which led to retarded GPCR desensitization, prolonged GPCR signaling, and cellular hyperactivity to GPCR agonists. Temporal analysis in an early-onset AD transgenic model, CRND8 mice, revealed that the membrane (functional) GRK2/5 in brain cortices were significantly reduced. More importantly, such a GRK abnormality took place before cognitive decline and changed in a manner corresponding with the mild to moderate soluble Abeta accumulation in these transgenic mice. Together, this study not only discovered a novel link between subthreshold Abeta and GRK dysfunction, it also demonstrated that the GRK abnormality in vivo occurs at prodromal and early stages of AD.

Interactions between p75 and TrkA receptors in differentiation and vulnerability of SN56 cholinergic cells to beta-amyloid.

NGF modifies cholinergic neurons through its low-p75 and high affinity-TrkA receptors. Native p75(+)TrkA(-) and trkA-transfected p75(+)TrkA(+) SN56 hybrid cholinergic septal cells were used here to discriminate effects mediated by each receptor. In TrkA(-) cells, NGF (100 ng/ml) affected neither choline acetyltransferase nor morphology but depressed pyruvate dehydrogenase activity by about 30%. Aged 25-35 beta-amyloid (1 microM) caused no changes in choline acetyltransferase and pyruvate dehydrogenase activities in nondifferentiated and differentiated TrkA(-) cells. On the contrary, in nondiferentiated TrkA(+) NGF brought about a 2.5-fold increase of choline acetyltransferase. In differentiated TrkA(+) cells, beta-amyloid resulted in no change in PDH but 65% suppression of choline acetyltransferase activity and reduction of their extensions. Thus, activation of TrkA receptors may overcome p75 receptor-mediated inhibitory effects on pyruvate dehydrogenase expression in cholinergic cells. On the other hand, it would make expression of choline acetyltransferase and cell differentiation more susceptible to suppressory effects of beta-amyloid.

The effect of beta-amyloid on neurons and the influence of glucocorticoid and age on such effect.

To explore the relationship between beta-amyloid (A beta) and the pathogenesis of Alzheimer disease (AD), after injection of beta-amyloid into the rat brain, the apoptosis of nerve cells and acetylcholine (Ach) content in rat hippocampus were examined by employing TUNEL technique and base hydroxylamine colorimetry respectively. The influence of age and glucocorticoid on the neurotoxic effect of A beta was also analyzed. A beta peptide could strongly induce the apoptosis of neurons in hippocampus, cortex and striate body (P < 0.05 or P < 0.01). In addition, the senility and glucocorticoid pre-treatment could enhance the toxic effect of A beta (P < 0.05 or P < 0.01). It is concluded that A beta may play an important role in the pathogenesis of Alzheimer disease via its induction of apoptosis of neurons and by decreasing the content of the Ach.