Aβ-induced Neurodegeneration Research Articles

Small Molecule, Non-Peptide p75NTR Ligands Inhibit Aβ-Induced Neurodegeneration and Synaptic Impairment

The p75 neurotrophin receptor (p75NTR) is expressed by neurons particularly vulnerable in Alzheimer's disease (AD). We tested the hypothesis that non-peptide, small molecule p75NTR ligands found to promote survival signaling might prevent Aβ-induced degeneration and synaptic dysfunction. These ligands inhibited Aβ-induced neuritic dystrophy, death of cultured neurons and Aβ-induced death of pyramidal neurons in hippocampal slice cultures. Moreover, ligands inhibited Aβ-induced activation of molecules involved in AD pathology including calpain/cdk5, GSK3β and c-Jun, and tau phosphorylation, and prevented Aβ-induced inactivation of AKT and CREB. Finally, a p75NTR ligand blocked Aβ-induced hippocampal LTP impairment. These studies support an extensive intersection between p75NTR signaling and Aβ pathogenic mechanisms, and introduce a class of specific small molecule ligands with the unique ability to block multiple fundamental AD-related signaling pathways, reverse synaptic impairment and inhibit Aβ-induced neuronal dystrophy and death.

S.07.03 Transforming growth factor-β1 (TGF-β1) signaling as a new pharmacological target against Aβ-induced neurodegeneration

S.07.03 Transforming growth factor-β1 (TGF-β1) signaling as a new pharmacological target against Aβ-induced neurodegeneration

P.4.02 Transforming growth factor-β1 (TGF-β1) signaling as a new pharmacological target against Aβ-induced neurodegeneration

P.4.02 Transforming growth factor-β1 (TGF-β1) signaling as a new pharmacological target against Aβ-induced neurodegeneration

Aβ1-42 stimulates actin polymerization in hippocampal neurons through Rac1 and Cdc42 Rho GTPases

A number of psychiatric and neurodegenerative disorders, such as Alzheimer's disease, are characterized by abnormalities in the neuronal cytoskeleton. Here, we find that the enhancement in actin polymerization induced by fibrillar amyloid-beta peptide (Abeta) is associated with increased activity of Rac1/Cdc42 Rho GTPases. Rac1 upregulation involves the participation of Tiam1, a Rac guanine-nucleotide exchange factor, where Abeta exposure leads to Tiam1 activation by a Ca(2+)-dependent mechanism. These results point to Rho GTPases as one of the targets in Abeta-induced neurodegeneration in Alzheimer's disease pathology, with a role in mediating changes in the actin cytoskeletal dynamics.

Neuroprotective effect of TNFα against the β-amyloid neurotoxicity mediated by CDK5 kinase

The tumor necrosis factor alpha (TNFα) plays a dual role in producing either neurodegeneration or neuroprotection in the central nervous system. Despite that TNFα was initially described as a cell death inductor, neuroprotective effects against cell death induced by several neurotoxic insults have been reported. Tau hyperphosphorylation and neuronal death found in Alzheimer disease is mediated by deregulation of the cdk5/p35 complex induced by Aβ treatments. Since TNFα affects cdk5 activity, we investigated its possible protective role against the Aβ-induced neurodegeneration, as mediated by cdk5. TNFα pretreatments significantly reduced the hippocampal neuronal cell death induced by the effects of Aβ 42 peptide. In addition, this pretreatment reduced the increase in the activity of cdk5 induced by Aβ 42 in primary neurons. Next, we investigated the Alzheimer type phosphorylation of tau protein induced by Aβ 42. We observed that the pretreatment of neurons with TNFα reduces tau hyperphosphorylation. Taken together, these results define a novel neuroprotective effect of TNFα in preventing neuronal cell death and cdk5-dependent tau hyperphosphorylation. This phenomenon, taken together with other previous findings, suggests that the inflammatory response due to Aβ peptide plays a key role in the development of Alzheimer etiopathogenesis.

Peroxisome proliferator-activated receptor γ is expressed in hippocampal neurons and its activation prevents β-amyloid neurodegeneration: role of Wnt signaling

The molecular pathogenesis of Alzheimer's disease (AD) involves the participation of the amyloid-β-peptide (Aβ), which plays a critical role in the neurodegeneration that triggers the disease. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors, which are members of the nuclear receptor family. We report here that (1) PPARγ is present in rat hippocampal neurons in culture. (2) Activation of PPARγ by troglitazone and rosiglitazone protects rat hippocampal neurons against Aβ-induced neurodegeneration, as shown by the 3-[4,5 -2yl]-2,5-diphenyltetrazolium bromide (MTT) reduction assay, immunofluorescence using an anti-heavy neurofilament antibody, and quantitative electron microscopy. (3) Hippocampal neurons treated with several PPARγ agonists, including troglitazone, rosiglitazone, and ciglitazone, prevent the excitotoxic Aβ-induced rise in bulk-free Ca 2+. (4) PPARγ activation results in the modulation of Wnt signaling components, including the inhibition of glycogen synthase kinase-3β (GSK-3β) and an increase of the cytoplasmic and nuclear β-catenin levels. We conclude that the activation of PPARγ prevents Aβ-induced neurodegeneration by a mechanism that may involve a cross talk between neuronal PPARγ and the Wnt signaling pathway. More important, the fact that the activation of PPARγ attenuated Aβ-dependent neurodegeneration opens the possibility to fight AD from a new therapeutic perspective.

Deposition of amyloid fibrils promotes cell-surface accumulation of amyloid β precursor protein

Amyloid β protein (Aβ) deposition and neuronal degeneration are characteristic pathological features of Alzheimer's disease (AD). In vitro, Aβ fibrils (fAβ) induce neuronal degeneration reminiscent to AD, but the mechanism of neurotoxicity is unknown. Here we show that amyloid fibrils increase the level of cell-surface full-length amyloid β precursor protein (h-AβPP) and secreted AβPP (s-AβPP). Pulse-chase analysis indicated that fAβ selectively inhibited the turnover of cell-surface AβPP, without altering its intracellular levels. FAβ-induced AβPP accumulation was not abrogated by cycloheximide, suggesting that increased protein synthesis is not critically required. Aβ fibrils sequester s-AβPP from the culture medium and promote its accumulation at the cell surface, indicating that binding of Aβ fibrils mediates AβPP accumulation. A time course analysis of Aβ treatment showed that AβPP level is elevated before significant cell death can be detected, while other toxic insults do not augment AβPP level, suggesting that AβPP may be specifically involved in early stages of Aβ-induced neurodegeneration. Finally, Aβ fibrils promote clustering of h-AβPP in abnormal focal adhesion-like (FA-like) structures that mediate neuronal dystrophy, increasing its association with the cytoskeleton. These results indicate that the interaction of Aβ fibrils with AβPP is an early event in the mechanism of Aβ-induced neurodegeneration that may play a significant role in AD pathogenesis.

Age-dependent neurodegeneration and Alzheimer-amyloid plaque formation in transgenic Drosophila.

Beta-amyloid peptides that are cleaved from the amyloid precursor protein (APP) play a critical role in Alzheimer's disease (AD) pathophysiology. Here, we show that in Drosophila, the targeted expression of the key genes of AD, APP, the beta-site APP-cleaving enzyme BACE, and the presenilins led to the generation of beta-amyloid plaques and age-dependent neurodegeneration as well as to semilethality, a shortened life span, and defects in wing vein development. Genetic manipulations or pharmacological treatments with secretase inhibitors influenced the activity of the APP-processing proteases and modulated the severity of the phenotypes. This invertebrate model of amyloid plaque pathology demonstrates Abeta-induced neurodegeneration as a basic biological principle and may allow additional genetic analyses of the underlying molecular pathways.

Amyloid β peptide induces tau phosphorylation and loss of cholinergic neurons in rat primary septal cultures

The neuropathological features associated with Alzheimer’s disease (AD) brain include the presence of extracellular neuritic plaques composed of amyloid β protein (Aβ), intracellular neurofibrillary tangles containing phosphorylated tau protein and the loss of basal forebrain cholinergic neurons which innervate regions such as the hippocampus and the cortex. Studies of the pathological changes that characterize AD and several other lines of evidence indicate that Aβ accumulation in vivo may initiate phosphorylation of tau protein, which by disrupting neuronal network may trigger the process of neurodegeneration observed in AD brains. However, the underlying cause of degeneration of the basal forebrain cholinergic neurons and their association, if any, to Aβ peptides or phosphorylated tau remains mostly unknown. In the present study, using rat primary septal cultures, we have shown that aggregated Aβ peptides, in a time (18–96 h)- and concentration (0.7–60 μM)-dependent manner, induce toxicity and decrease choline acetyltransferase enzyme activity in cultured neurons. Using immunocytochemistry and immunoblotting, we have also demonstrated that Aβ treatment can significantly increase the phosphorylation of tau protein in septal cultures. At the cellular level, hyperphosphorylated tau is mostly apparent in the somatodendritic compartment of the neurons. Aβ peptide (10 μM), in addition to tau phosphorylation, also activates mitogen-activated protein kinase and glycogen synthase kinase-3β, the two kinases which are known to be involved in the formation of hyperphosphorylated tau in the AD brain. Exposure to specific inhibitors of the mitogen-activated protein kinase (i.e. PD98059) or glycogen synthase kinase-3β (i.e. LiCl) attenuated the hyperphosphorylation of the tau protein in cultured neurons. Given the evidence that tau phosphorylation can induce cell loss by disrupting neuronal cytoskeleton, it is likely that aggregated Aβ peptide triggers degeneration of septal neurons, including those expressing the cholinergic phenotype, by phosphorylation of the tau protein activated by mitogen-activated protein kinase and glycogen synthase kinase-3β. These results, taken together, suggest that cultured septal cholinergic neurons are vulnerable to Aβ-mediated toxicity and tau phosphorylation may play an important role in Aβ-induced neurodegeneration.

Journal Scan

Alzheimer's disease (AD) is one of the most common neurodegenerative disorders in recent world, characterized by increased production of amyloid beta in the nervous system with an ultimate effect of apoptotic neurodegeneration. This study was aimed to investigate the neuroprotective effect of black soybean anthocyanins in a neurodegenerative model of amyloid beta 1–42 (Aβ1–42). Aβ1–42 was treated to HT22 cell lines or adult male rats via intra-cerebro-ventricular injection to induce neurotoxicity in these experimental models. Anthocyanins were treated 0.2 mg/kg in case of cell lines or 4 mg/kg intragastrically to adult rats to protect against Aβ-induced neurodegeneration. Assay for cell viability, mitochondrial membrane potential (Ψm), intracellular free Ca2+ and apoptotic cells (fluoro-jade B and TUNEL) were performed in vitro while western blot analyses were performed to the hippocampal proteins of adult rats. Our results showed that Aβ1–42 treatment reduced cell viability, disturbed the Ψm and Ca2+ homeostasis in and out of the cell, and increased neuronal apoptosis. Treatment with anthocyanins for 12 hr retained the cell viability, normalized Ψm and Ca2+ level, and decreased the neuronal cell death. In accordance, anthocyanins reversed Aβ-induced effect on protein expression of mitochondrial apoptotic pathway (Bax, cytochrome C, caspase-9 and caspase-3) and major Alzheimer's markers i.e. Aβ, APP, P-tau and BACE-1. Overall, our results showed that anthocyanins are potential candidates to treat neurodegenerative disorders like AD.

Tau is essential to beta -amyloid-induced neurotoxicity.

Senile plaques and neurofibrillary tangles, the two hallmark lesions of Alzheimer's disease, are the results of the pathological deposition of proteins normally present throughout the brain. Senile plaques are extracellular deposits of fibrillar beta-amyloid peptide (Abeta); neurofibrillary tangles represent intracellular bundles of self-assembled hyperphosphorylated tau proteins. Although these two lesions are often present in the same brain areas, a mechanistic link between them has yet to be established. In the present study, we analyzed whether tau plays a key role in fibrillar Abeta-induced neurite degeneration in central neurons. Cultured hippocampal neurons obtained from wild-type, tau knockout, and human tau transgenic mice were treated with fibrillar Abeta. Morphological analysis indicated that neurons expressing either mouse or human tau proteins degenerated in the presence of Abeta. On the other hand, tau-depleted neurons showed no signs of degeneration in the presence of Abeta. These results provide direct evidence supporting a key role for tau in the mechanisms leading to Abeta-induced neurodegeneration in the central nervous system. In addition, the analysis of the composition of the cytoskeleton of tau-depleted neurons suggested that the formation of more dynamic microtubules might confer resistance to Abeta-mediated neurodegeneration.

CAMP delays beta-amyloid (25-35) induced cell death in rat cortical neurons.

Beta-amyloid (A beta) accumulation is believed to contribute to neuronal cell death in Alzheimer's disease. To understand the role of cAMP in the regulation of A beta induced cell death, we used 8-chlorophenylthio-cAMP (8-CPT-cAMP, a cAMP analog) to raise intracellular cAMP levels. Exposure of rat cortical neurons to A beta(25-35) resulted in a gradual increase in lactate dehydrogenase (LDH) over 48 h, which was preceded by a transient elevation in caspase-3-like activity. In the presence of 8CPT-cAMP, both caspase-3 activity and LDH release was significantly reduced. These data suggest that elevation of intracellular cAMP levels attenuate A beta-induced neurotoxicity and may delay or prevent the onset of A beta-induced neurodegeneration.