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

ABSTRACT: The present study examined the relationship between amyloid beta (A?)-peptide aggregation state and neurotoxicity in vivo using the rat retinal-vitreal model. Following single unilateral intravitreal injection of either soluble A?1-42 or A?1-42 preaggregated for different periods, retinal pathology was evaluated at 24 hours, 48 hours, and 1-month postinjection. Injection of either soluble A? (sA?) or preaggregated A? 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 sA? 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 A? after 1-month survival. Extending the preaggregation period from 4 to 8 days to obtain highly fibrillar A? species significantly increased the loss of choline acteyltransferase IR, but had no effect on PV-IR. These findings prompt the conclusion that A? assembly state has a significant impact on in vivo neurotoxicity by triggering distinct molecular changes within the cell.

SUBMITTER: Watts HR

PROVIDER: S-EPMC5436173 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

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

Watts H R HR Anderson Pjb P Ma D D Philpott K L KL Jen S M SM Croucher M M Jen L S LS Gentleman S M SM

Eye and brain 20100909

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 Aβ1-42 or Aβ1-42 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) ...[more]

PMID: 28539771

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Project description:The misfolding and aggregation of amyloid-? (A?) peptides into amyloid fibrils is regarded as one of the causative events in the pathogenesis of Alzheimer's disease (AD). Tanshinones extracted from Chinese herb Danshen (Salvia Miltiorrhiza Bunge) were traditionally used as anti-inflammation and cerebrovascular drugs due to their antioxidation and antiacetylcholinesterase effects. A number of studies have suggested that tanshinones could protect neuronal cells. In this work, we examine the inhibitory activity of tanshinone I (TS1) and tanshinone IIA (TS2), the two major components in the Danshen herb, on the aggregation and toxicity of A?1-42 using atomic force microscopy (AFM), thioflavin-T (ThT) fluorescence assay, cell viability assay, and molecular dynamics (MD) simulations. AFM and ThT results show that both TS1 and TS2 exhibit different inhibitory abilities to prevent unseeded amyloid fibril formation and to disaggregate preformed amyloid fibrils, in which TS1 shows better inhibitory potency than TS2. Live/dead assay further confirms that introduction of a very small amount of tanshinones enables protection of cultured SH-SY5Y cells against A?-induced cell toxicity. Comparative MD simulation results reveal a general tanshinone binding mode to prevent A? peptide association, showing that both TS1 and TS2 preferentially bind to a hydrophobic ?-sheet groove formed by the C-terminal residues of I31-M35 and M35-V39 and several aromatic residues. Meanwhile, the differences in binding distribution, residues, sites, population, and affinity between TS1-A? and TS2-A? systems also interpret different inhibitory effects on A? aggregation as observed by in vitro experiments. More importantly, due to nonspecific binding mode of tanshinones, it is expected that tanshinones would have a general inhibitory efficacy of a wide range of amyloid peptides. These findings suggest that tanshinones, particularly TS1 compound, offer promising lead compounds with dual protective role in anti-inflammation and antiaggregation for further development of A? inhibitors to prevent and disaggregate amyloid formation.

Dataset Information

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

Publications

Differential effects of amyloid-β peptide aggregation status on <i>in vivo</i> retinal neurotoxicity.

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