Amyloid-Beta Peptide Is Toxic to Neurons In Vivo via Indirect Mechanisms

Walsh, Desmond T.; Montero, Rosa; Bresciani, Laura G.; Jen, Angela; Leclercq, Pascale D.; Saunders, Debbie; EL-Amir, Ahmed N.; Gbadamoshi, Lukemann; Gentleman, Stephen M.; Jen, L.S.

doi:10.1006/nbdi.2002.0485

Cited by 63 publications

(77 citation statements)

References 32 publications

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“…LandMark LD Cardiovascular Tissue arrays were purchased from Ambion. IHC was performed by standard techniques as described (13). Anti-FXR antibodies [sc-1204 goat anti-FXR (C-terminal), and its corresponding blocking peptide; and sc-13063, rabbit anti-FXR (N-terminal)] were purchased from Santa Cruz Biotechnology and used at a dilution of 1:50.…”

Section: Methodsmentioning

confidence: 99%

Expression and activation of the farnesoid X receptor in the vasculature

Bishop‐Bailey

Walsh

Warner

2004

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

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The farnesoid X receptor͞bile acid receptor (FXR) is a recently discovered member of the nuclear hormone superfamily. FXR ligands have been proposed as targets in cardiovascular disease, regulating cholesterol metabolism and bile acid transport and metabolism in the liver and gastrointestinal tract. When we used a human cardiovascular tissue array, we found that FXR is expressed in a variety of normal and pathological human tissue. Particularly high levels of FXR were found in the vasculature and in a number of different metastatic cancers, as well as the previously identified target tissues of the liver, small intestine, and kidney. In vitro, FXR is present in rat and human vascular smooth muscle cells. When treated with a range of FXR ligands, vascular smooth muscle cells undergo apoptosis in a manner that correlates with the ligands' ability to activate FXR. Furthermore, FXR activators induce mRNA for the FXR target genes, phospholipid transfer protein, and the small heterodimer partner. FXR therefore is a functional protein in the vasculature that may provide a direct target for the treatment of proliferative and dyslipidaemic diseases.

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Section: Methodsmentioning

confidence: 99%

Expression and activation of the farnesoid X receptor in the vasculature

Bishop‐Bailey

Walsh

Warner

2004

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

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212

163

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“…These include similar fibrillar morphology, a core of cross-␤-sheet structure, and birefringence under cross-polarization after staining with Congo red. Numerous studies have linked cellular toxicity to fibrils (1)(2)(3)(4)(5). However, more recently, increasing evidence suggests that cytotoxicity associated with amyloid deposits is likely to be mediated by multiple aggregated forms of the protein.…”

mentioning

confidence: 99%

Annular Oligomeric Amyloid Intermediates Observed by in Situ Atomic Force Microscopy

Zhu¹,

Han

Zhou

et al. 2004

Journal of Biological Chemistry

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Amyloidoses and related protein deposition diseases involve the transformation of normally soluble proteins into insoluble deposits, usually fibrillar in nature. Although it was originally assumed that the fibrils were the toxic species, this assumption has recently been called into question. Accumulating evidence in several systems suggests that oligomeric intermediates on the aggregation pathway may be toxic. In the present study we used in situ atomic force microscopy to monitor aggregation in aqueous solution in real time. The sample used was an amyloidogenic immunoglobulin light chain, involved in AL or light chain amyloidosis. The nature of the observed oligomeric intermediates was dependent on the conditions of incubation, especially pH and ionic strength. Several different aggregation intermediates with a variety of morphologies, including annular or torus-shaped species, were observed. The data indicate that protein aggregation can be very complex, involving a variety of different oligomeric intermediates whose population will be determined by the kinetic and thermodynamic competition between them.

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“…This response was less specific to Aβ , with significant loss of PV-IR seen among the Aβ 42-1 reverse peptide group, consistent with previous findings from this laboratory. 22 Injection of sAβ appeared to have a more rapid impact on PV than either of the preaggregated treatments, producing a marked reduction in average PV-IR cell diameters at 48 hours; an effect that was only observed for preaggregated Aβ after 1-month survival. The reduction in PV cell diameters suggests that larger neurons (predominantly in the GCL) are more susceptible to ionic imbalance following Aβ than are smaller PV-IR interneurons, consistent with the pattern of Aβ-induced PGP 9.5 disruption.…”

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confidence: 89%

“…The former to act as a direct comparison with our previous studies. 6,22,25 It was noted that preaggregated Aβ peptides became highly viscous following incubation and exhibited both particulate and larger precipitates under the light microscope. We have previously confirmed that this change in viscosity correlates with positive staining for Congo Red, 23 indicative of the presence of Aβ fibrils and aggregates.…”

Section: Animals and Experimental Proceduresmentioning

confidence: 99%

“…Our investigations to date have suggested that a single intravitreal injection of preaggregated Aβ can precipitate degenerative changes in multiple interacting cellular systems including neuronal apoptosis, severe glial activation, immune reactivity, and blood retinal barrier breakdown. 6,[22][23][24] The aim of the present study was to clarify the relationship between Aβ aggregation state and neurotoxicity in vivo. To this end, we have compared Aβ 1-42 prepared under conditions that favor either (1) sAβ (monomers and small oligomers), or solutions that have been (2) preincubated for several days to increase fibril formation, or (3) preincubated for an extended period to obtain highly fibrillar Aβ species.…”

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confidence: 99%

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Differential effects of amyloid-beta peptide aggregation status on in vivo retinal neurotoxicity

Watts

Anderson

et al. 2010

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Abstract:The present study examined the relationship between amyloid beta (Aβ)-peptide aggregation state and neurotoxicity in vivo using the rat retinal-vitreal model. Following single unilateral intravitreal injection of either soluble Aβ 1-42 or Aβ 1-42 preaggregated for different periods, retinal pathology was evaluated at 24 hours, 48 hours, and 1-month postinjection. Injection of either soluble Aβ (sAβ) or preaggregated Aβ induced a rapid reduction in immunoreactivity (IR) for synaptophysin, suggesting that direct contact with neurons is not necessary to disrupt synapses. Acute neuronal ionic and metabolic dysfunction was demonstrated by widespread loss of IR to the calcium buffering protein parvalbumin (PV) and protein gene product 9.5, a component of the ubiquitin-proteosome system. Injection of sAβ appeared to have a more rapid impact on PV than the preaggregated treatments, producing a marked reduction in PV cell diameters at 48 hours, an effect that was only observed for preaggregated Aβ after 1-month survival. Extending the preaggregation period from 4 to 8 days to obtain highly fibrillar Aβ species significantly increased the loss of choline acteyltransferase IR, but had no effect on PV-IR. These findings prompt the conclusion that Aβ assembly state has a significant impact on in vivo neurotoxicity by triggering distinct molecular changes within the cell.

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Amyloid-Beta Peptide Is Toxic to Neurons In Vivo via Indirect Mechanisms

Cited by 63 publications

References 32 publications

Expression and activation of the farnesoid X receptor in the vasculature

Expression and activation of the farnesoid X receptor in the vasculature

Annular Oligomeric Amyloid Intermediates Observed by in Situ Atomic Force Microscopy

Differential effects of amyloid-beta peptide aggregation status on in vivo retinal neurotoxicity

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