Different Conformations of Amyloid β Induce Neurotoxicity by Distinct Mechanisms in Human Cortical Neurons

Deshpande, Atul; Mina, Erene; Glabe, Charles G.; Busciglio, Jorge

doi:10.1523/jneurosci.1189-06.2006

Cited by 464 publications

(369 citation statements)

References 75 publications

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“…Studies using animal models of AD or using cultured neurons suggest that prefibrillar Aβ aggregates, including LMW oligomers and protofibrils, exert their toxic effects by several potentially interrelated mechanisms, including pore formation 45 , channel-like activity 46 , permeabilization of lipid bilayers 47 , inhibition of K + currents in cortical cultures 40 , disruption of neuronal glutamate uptake 48 , activation of apoptosis 49 , oxidative damage 50 and degradation of postsynaptic density marker PSD- 95 (ref. 51).…”

Section: Introductionmentioning

confidence: 99%

Preparation and characterization of toxic Aβ aggregates for structural and functional studies in Alzheimer's disease research

2010

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Section: Introductionmentioning

confidence: 99%

Preparation and characterization of toxic Aβ aggregates for structural and functional studies in Alzheimer's disease research

2010

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“…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%

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.

170

127

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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.

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“…Furthermore, it is proposed that such deficits, particularly early in the disease, stem not from cell death per se, but rather from damage to synapses (Selkoe, 2006;Tanzi, 2005). Indeed, soluble oligomeric Aβ colocalizes with synapses within one hour in neuronal cultures (Deshpande, et al, 2006;Lacor, et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Rapid, concurrent alterations in pre- and postsynaptic structure induced by naturally-secreted amyloid-β protein

Calabrese

Shaked

Tabarean

et al. 2007

Molecular and Cellular Neuroscience

120

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In Alzheimer's disease increasing evidence attributes synaptic and cognitive deficits to soluble oligomers of amyloid β protein (Aβ), even prior to the accumulation of amyloid plaques, neurofibrillary tangles, and neuronal cell death. Here we show that within 1-2 hours picomolar concentrations of cell-derived, soluble Aβ induce specific alterations in pre-and postsynaptic morphology and connectivity in cultured hippocampal neurons. Clusters of presynaptic vesicle markers decreased in size and number at glutamatergic but not GABAergic terminals. Dendritic spines also decreased in number and became dysmorphic, as spine heads collapsed and/or extended long protrusions. Simultaneous time-lapse imaging of axon-dendrite pairs revealed that shrinking spines sometimes became disconnected from their presynaptic varicosity. Concomitantly, miniature synaptic potentials decreased in amplitude and frequency. Spine changes were prevented by blockers of nAChRs and NMDARs. Washout of Aβ within the first day reversed these spine changes. Further, spine changes reversed spontaneously by two days, because neurons acutely developed resistance to continuous Aβ exposure. Thus, rapid Aβ-induced synapse destabilization may underlie transient behavioral impairments in animal models, and early cognitive deficits in Alzheimer's patients.

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Different Conformations of Amyloid β Induce Neurotoxicity by Distinct Mechanisms in Human Cortical Neurons

Cited by 464 publications

References 75 publications

Preparation and characterization of toxic Aβ aggregates for structural and functional studies in Alzheimer's disease research

Preparation and characterization of toxic Aβ aggregates for structural and functional studies in Alzheimer's disease research

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

Rapid, concurrent alterations in pre- and postsynaptic structure induced by naturally-secreted amyloid-β protein

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