β/A4‐evoked degeneration of differentiated SH‐SY5Y human neuroblastoma cells

Lambert, Mary P.; Stevens, Gerin R.; Sabo, Shasta L.; Barber, Kirsten; Wang, G.; Wade, Warren S.; Krafft, Grant A.; Snyder, Seth W.; Holzman, Thomas F.; Klein, William L.

doi:10.1002/jnr.490390404

Cited by 77 publications

(53 citation statements)

References 34 publications

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“…Here, we demonstrate that oligomeric but not fibrillar A␤ 1-42 significantly decreases BDNF mRNA levels in differentiated SY5Y cells. Furthermore, undifferentiated, amyloid-treated SY5Y cells do not downregulate BDNF, consistent with previous reports that undifferentiated SY5Y cells are not responsive to A␤ (Lambert et al, 1994).…”

Section: Discussionsupporting

confidence: 92%

“…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%

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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

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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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Section: Discussionsupporting

confidence: 92%

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

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“…These findings support the contention that cholinergic neurons are particularly vulnerable in AD brain (15) and are consistent with the importance of AcCho in memory and learning processes (16,17). Peptides derived from the human AP sequence have been shown to cause toxic effects in cell lines and primary cultures of neuronal origin (18)(19)(20)(21)(22)(23) as well as in vivo (24,25). Moreover, injections of A13 1-40 or A,B 1-42 into the nucleus basalis magnocellularis or the medial septum of the rat brain cause neurodegeneration and reductions in the levels of cholinergic markers (26)(27)(28).…”

supporting

confidence: 81%

Amyloid beta-protein reduces acetylcholine synthesis in a cell line derived from cholinergic neurons of the basal forebrain.

Pedersen

Kłoczewiak

Blusztajn

1996

Proc. Natl. Acad. Sci. U.S.A.

122

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The characteristic features of a brain with Alzheimer disease (AD) include the presence of neuritic plaques composed of amyloid 3-protein (A,B) and reductions in the levels of cholinergic markers. Neurotoxic responses to A,B have been reported in vivo and in vitro, suggesting that the cholinergic deficit in AD brain may be secondary to the degeneration of cholinergic neurons caused by Aj8. However, it remains to be determined if A,B contributes to the cholinergic deficit in AD brain by nontoxic effects. We examined the effects of synthetic A,B peptides on the cholinergic properties of a mouse cell line, SN56, derived from basal forebrain cholinergic neurons. Aj8 1-42 and Aj3 1-28 reduced the acetylcholine (AcCho) content of the cells in a concentrationdependent fashion, whereas Af3 1-16 was inactive. Maximal reductions of 43% and 33% were observed after a 48-h treatment with 100 nM of A18 1-42 and 50 pM of A18 1-28, respectively. Neither A,B 1-28 nor A,B 1-42 at a concentration of 100 nM and a treatment period of 2 weeks was toxic to the cells. Treatment of the cells with A,B 25-28 (48 h; 100 nM) significantly decreased AcCho levels, suggesting that the sequence GSNK (aa 25-28) is responsible for the AcChoreducing effect of Af3. The reductions in AcCho levels caused by A,B 1-42 and Af3 1-28 were accompanied by proportional decreases in choline acetyltransferase activity. In contrast, acetylcholinesterase activity was unaltered, indicating that A18 specifically reduces the synthesis of AcCho in SN56 cells. The reductions in AcCho content caused by AfJ 1-42 could be prevented by a cotreatment with all-trans-retinoic acid (10 nM), a compound previously shown to increase choline acetyltransferase mRNA expression in SN56 cells. These results demonstrate a nontoxic, suppressive effect of A,B on AcCho synthesis, an action that may contribute to the cholinergic deficit in AD brain.An invariant pathological feature of a brain with Alzheimer disease (AD) is the formation of the neuritic plaque, a compacted extracellular deposit of amyloid filaments surrounded by dystrophic neurites (1). This amyloid is composed of the --4-kDa amyloid 13-protein (A13), which is proteolytically derived from a 110-130 kDa transmembrane glycoprotein known as the ,B-amyloid precursor protein (,BAPP) (1). Heterogeneous processing of 1APP results in the formation of A,B peptides ranging from 39 to 43 amino acids in length (1). Several missense mutations in the j3APP gene have been linked to familial AD (2-4), and some of these have been shown to result either in excess generation of AP3 (5-7) or in a shift to the production of longer, more amyloidogenic forms (8).Overexpression of the PAPP gene, which is located on the long arm of chromosome 21, occurs in Down syndrome (trisomy 21) patients, essentially all of whom exhibit AD brain pathology by the age of 40 (9). Furthermore, transgenic mice overexpressing a mutated human ,BAPP gene display many of the pathological features of AD brain, including the neuritic plaque (10). These observati...

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“…5). In accord with these results, phosphorylation of neuronal proteins including tau [30] and focal adhesion kinase (FAK) [56] has been shown to be induced by fibrillar Aβ and blocked by PP1 and LY294002 [55]. Phosphorylation of FAK is believed to be central in a number of important signaling pathways involving Src family kinases, PI3K and Akt.…”

Section: Discussionmentioning

confidence: 87%

“…Neurofibrillary degeneration also has been observed in transgenic mice expressing both human amyloid precursor protein (APP) and mutant tau [36] and of mice harboring APP, presenilin and mutant tau transgenes [46]. Additionally, several studies have shown that Aβ fibrils induce tau hyperphosphorylation in vitro [e.g., 8,30,42] and that Aβ fibrils do not cause degeneration of hippocampal neurons from tau knock-out mice [47], suggesting that tau is one of the major downstream targets of toxic Aβ.…”

Section: Introductionmentioning

confidence: 99%

Alzheimer's disease-type neuronal tau hyperphosphorylation induced by Aβ oligomers

Felice

Lambert

et al. 2008

Neurobiology of Aging

388

315

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Alzheimer's disease (AD) is characterized by presence of extracellular fibrillar Aβ in amyloid plaques, intraneuronal neurofibrillary tangles consisting of aggregated hyperphosphorylated tau and elevated brain levels of soluble Aβ oligomers (ADDLs). A major question is how these disparate facets of AD pathology are mechanistically related. Here we show that, independent of the presence of fibrils, ADDLs stimulate tau phosphorylation in mature cultures of hippocampal neurons and in neuroblastoma cells at epitopes characteristically hyperphosphorylated in AD. A monoclonal antibody that targets ADDLs blocked their attachment to synaptic binding sites and prevented tau hyperphosphorylation. Tau phosphorylation was blocked by the Src family tyrosine kinase inhibitor, 4-amino-5-(4-chlorophenyl)-7(t-butyl)pyrazol(3,4-D)pyramide (PP1), and by the phosphatidylinositol-3-kinase inhibitor LY294002. Significantly, tau hyperphosphorylation was also induced by a soluble aqueous extract containing Aβ oligomers from AD brains, but not by an extract from non-AD brains. Aβ oligomers have been increasingly implicated as the main neurotoxins in AD, and the current results provide a unifying mechanism in which oligomer activity is directly linked to tau hyperphosphorylation in AD pathology.

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β/A4‐evoked degeneration of differentiated SH‐SY5Y human neuroblastoma cells

Cited by 77 publications

References 34 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

Amyloid beta-protein reduces acetylcholine synthesis in a cell line derived from cholinergic neurons of the basal forebrain.

Alzheimer's disease-type neuronal tau hyperphosphorylation induced by Aβ oligomers

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