In vitro model of neurotoxicity of A? 1?42 and neuroprotection by a pentapeptide: irreversible events during the first hour

Datki, Zsolt; Papp, Rita; Zádori, Dénes; Soós, Katalin; Fülöp, Lívia; Juhász, Anna; Laskay, G.; Hetényi, Csaba; Mihalik, Erzsébet; Zarándi, Márta; Penke, Botond

doi:10.1016/j.nbd.2004.08.007

Cited by 67 publications

(58 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…SY5Y cells have been used extensively to study mechanisms of A␤ toxicity. A␤ binds to the neurites of differentiated SY5Y cells, promoting neurite degeneration and induction of tau hyperphosphorylation (Datki et al, 2004). Similar data are reported for rat and human cultured neurons (Gong et al, 2003;Lacor et al, 2004;Deshpande et al, 2006).…”

Section: Discussionsupporting

confidence: 73%

“…Differentiated SY5Y cells express BDNF and TrkB, the high-affinity BDNF receptor, and become dependent on BDNF for survival (Kaplan et al, 1993;Encinas et al, 2000;Feng et al, 2001). Furthermore, differentiated SY5Y cells develop a neuronal appearance, with long cell processes and expression of neuron-specific markers (Pahlman et al, 1984(Pahlman et al, , 1990Encinas et al, 2000) and, like human cortical neurons, are sensitive to A␤ (Lambert et al, 1994;Datki et al, 2004;Deshpande et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Oligomeric Amyloid Decreases Basal Levels of Brain-Derived Neurotrophic factor (BDNF) mRNA via Specific Downregulation of BDNF Transcripts IV and V in Differentiated Human Neuroblastoma Cells

Garzon¹,

Fahnestock²

2007

J. Neurosci.

165

127

View full text Add to dashboard Cite

Alzheimer's disease (AD) is a senile dementia characterized by amyloid plaques, neurofibrillary tangles, and synaptic and cell loss. The "amyloid cascade" hypothesis suggests that amyloid-␤ (A␤), the peptide deposited as amyloid plaques, is the primary insult in AD. However, debate continues over the mechanism of A␤ toxicity and whether fibrillar or oligomeric A␤ is the active species of the peptide that ultimately causes the synaptic loss and dementia associated with AD. Brain-derived neurotrophic factor (BDNF) is required for survival and function of cells compromised in AD. Decreased BDNF causes defects in long-term potentiation and memory and correlates with cognitive decline. We previously demonstrated that BDNF reduction occurs early in the course of AD, suggesting that decreased BDNF may promote neuronal dysfunction in AD. We also demonstrated that three of seven human BDNF transcripts are specifically downregulated in AD. What pathological feature(s) of AD leads to the decreased BDNF is unknown.In this study, we administered both fibrillar and oligomeric conformations of A␤ 1-42 to differentiated SH-SY5Y, a human neuroblastoma cell line, and measured both phosphorylated cAMP response element-binding protein (CREB), a regulator of BDNF transcription, and BDNF total mRNA. We found that oligomeric but not fibrillar preparations of A␤ 1-42 significantly decrease both phosphorylated CREB and total BDNF mRNA. Furthermore, oligomeric A␤ 1-42 decreases BDNF transcripts IV and V in these cells, demonstrating that A␤ 1-42 downregulates the major BDNF transcript decreased in vivo in the AD brain. Thus, oligomeric A␤ 1-42 could compromise neuronal function, causing memory loss and cognitive dysfunction by downregulation of BDNF in AD.

show abstract

Section: Discussionsupporting

confidence: 73%

Section: Introductionmentioning

confidence: 99%

Oligomeric Amyloid Decreases Basal Levels of Brain-Derived Neurotrophic factor (BDNF) mRNA via Specific Downregulation of BDNF Transcripts IV and V in Differentiated Human Neuroblastoma Cells

Garzon¹,

Fahnestock²

2007

J. Neurosci.

165

127

View full text Add to dashboard Cite

show abstract

“…The Congo Red content was measured photometrically at 490 nm (free Congo Red) and 550 nm (bound Congo Red) with an ELISA plate reader. Under these conditions, the optical density at 550 nm of the A␤ aggregate-Congo Red complex is a measure of the amount of aggregates adsorbed to the cell membrane [22]. Congo Red values are reported as percentage increases versus respective untreated fibroblasts (assumed as 100%).…”

Section: Time-course Of Aβ Aggregate Binding To Cell Surface Membranementioning

confidence: 99%

Increased susceptibility to amyloid toxicity in familial Alzheimer's fibroblasts

Cecchi

Fiorillo

Baglioni

et al. 2007

Neurobiology of Aging

View full text Add to dashboard Cite

Much experimental evidence suggests that an imbalance in cellular redox status is a major factor in the pathogenesis of Alzheimer's disease (AD). Our previous data showed a marked increase in membrane lipoperoxidation in primary fibroblasts from familial AD (FAD) patients. In the present study, we demonstrate that when oligomeric structures of A␤ 1-40 and A␤ 1-42 are added to the culture media, they accumulate quicker near the plasma membrane, and are internalized faster and mostly in APPV717I fibroblasts than in age-matched healthy cells; this results in an earlier and sharper increase in the production of reactive oxygen species (ROS). Higher ROS production leads in turn to an increase in membrane oxidative-injury and significant impairment of cellular antioxidant capacity, giving rise to apoptotic cascade activation and finally to a necrotic outcome. In contrast, healthy fibroblasts appear more resistant to amyloid oxidative-attack, possibly as a result of their plasma membrane integrity and powerful antioxidant capacity. Our data are consistent with increasing evidence that prefibrillar aggregates, compared to mature fibrils, are likely the more toxic species of the peptides. These findings provide compelling evidence that cells bearing increased membrane lipoperoxidation are more susceptible to aggregate toxicity as a result of their reduced ability to counteract amyloid oligomeric attack.

show abstract

“…This strategy relies on three major properties of '-sheet breaker' peptides (i) to ensure specific binding -sheet breakers are usually derived from the amyloidogenic sequences of their intended protein targets, (ii) known -sheetinterrupting amino acid residues, such as proline, are incorporated [97] and (iii) charged residues are often added to either end of the peptide to improve solubility [98]. -sheet breaker peptides have been shown to be effective in disrupting amyloid formation by A [96,99,100], PrP [101], and the yeast prion protein Sup35 [102]. Although there is no precedent for this in the literature, any small molecule approach directed towards inhibiting extracellular protein aggregation and/or toxicity might conceivably also affect receptor-mediated clearance processes.…”

Section: Chaperonesmentioning

confidence: 99%

Therapeutic Targets in Extracellular Protein Deposition Diseases

Wyatt¹,

Yerbury²,

Poon³

et al. 2009

CMC

View full text Add to dashboard Cite

Many litres of fluids are found outside cells in the human body. These fluids are rich in dissolved proteins that each have a characteristic three dimensional shape, necessary for normal function, which has been attained by the correct folding of their polypeptide chain(s). The structure of these extracellular proteins can be damaged by a variety of environmental stresses (e. g. heat and oxidation) leading to their partial unfolding and aggregation. This in turn can produce toxic soluble aggregates and/or large insoluble protein deposits, either of which can disrupt normal body function (e. g. in Alzheimer's disease and the systemic amyloidoses). A small family of abundant human blood proteins with the ability to inhibit the aggregation and deposition of stressed (partially unfolded) proteins has been discovered. These extracellular chaperones (ECs) form stable, soluble complexes with stressed proteins. It has been proposed that once bound to stressed proteins, ECs guide them to specific cell surface receptors that direct the "cargo" into lysosomes for degradation. Thus ECs and their receptors may be critical parts of a quality control system to protect the body against the deleterious effects of inappropriately aggregating extracellular proteins. This review focuses on the role of extracellular protein aggregation and deposition in disease, what little is known about mechanisms that act to control these processes, and, lastly, potential new targets for drug development. Newly identified potential drug targets include direct inhibition of protein aggregation, and manipulation of the expression levels of ECs and their receptors.

show abstract

In vitro model of neurotoxicity of A? 1?42 and neuroprotection by a pentapeptide: irreversible events during the first hour

Cited by 67 publications

References 32 publications

Oligomeric Amyloid Decreases Basal Levels of Brain-Derived Neurotrophic factor (BDNF) mRNA via Specific Downregulation of BDNF Transcripts IV and V in Differentiated Human Neuroblastoma Cells

Oligomeric Amyloid Decreases Basal Levels of Brain-Derived Neurotrophic factor (BDNF) mRNA via Specific Downregulation of BDNF Transcripts IV and V in Differentiated Human Neuroblastoma Cells

Increased susceptibility to amyloid toxicity in familial Alzheimer's fibroblasts

Therapeutic Targets in Extracellular Protein Deposition Diseases

Contact Info

Product

Resources

About