Interaction of intracellular β amyloid peptide with chaperone proteins

Abstract

Expression of the human β amyloid peptide (Aβ) in transgenic Caenorhabditis elegans animals can lead to the formation of intracellular immunoreactive deposits as well as the formation of intracellular amyloid. We have used this model to identify proteins that interact with intracellular Aβ in vivo . Mass spectrometry analysis of proteins that specifically coimmunoprecipitate with Aβ has identified six likely chaperone proteins: two members of the HSP70 family, three αB-crystallin-related small heat shock proteins (HSP-16s), and a putative ortholog of a mammalian small glutamine-rich tetratricopeptide repeat-containing protein proposed to regulate HSP70 function. Quantitative reverse transcription–PCR analysis shows that the small heat shock proteins are also transcriptionally induced by Aβ expression. Immunohistochemistry demonstrates that HSP-16 protein closely colocalizes with intracellular Aβ in this model. Transgenic animals expressing a nonaggregating Aβ variant, a single-chain Aβ dimer, show an altered pattern of coimmunoprecipitating proteins and an altered cellular distribution of HSP-16. Double-stranded RNA inhibition of R05F9.10, the putative C. elegans ortholog of the human small glutamine-rich tetratricopeptide-repeat-containing protein (SGT), results in suppression of toxicity associated with Aβ expression. These results suggest that chaperone function can play a role in modulating intracellular Aβ metabolism and toxicity.

Proteasomal adaptation to environmental stress links resistance to proteotoxicity with longevity in Caenorhabditis elegans

“…aip-1(RNAi) accelerated the mean onset of paralysis from 11.3 Ϯ 0.2 days in mock RNAi to 7.6 Ϯ 0.2 days in aip-1(RNAi) animals. A similar effect was observed in hsf-1(RNAi) (mean onset of paralysis, 7.5 Ϯ 0.2 days) (20) (Fig. 2C).…”

Crystallin proteins and amyloid fibrils

“…Furthermore, the Hsp16 proteins co-localized and coimmunoprecipitated with Aβ(1-42) in this model [89] and increased expression of Hsp16 partially suppressed the Aβ-mediated toxicity [90]. It was concluded that sHsps such as Hsp16 may act to reduce Aβ toxicity by interacting directly with the Aβ peptide and altering its oligomerization pathways, thereby reducing the formation of some toxic species [90].…”

“…In a series of elegant papers using transgenic Caenorhabditis elegans worms, the expression of human Aβ(1-42) was found to lead to the induction of Hsp16 proteins (sHsps that are homologs of αB-crystallin in vertebrates) [89]. Furthermore, the Hsp16 proteins co-localized and coimmunoprecipitated with Aβ(1-42) in this model [89] and increased expression of Hsp16 partially suppressed the Aβ-mediated toxicity [90].…”

Overexpression of small glutamine‐rich TPR‐containing protein promotes apoptosis in 7721 cells

“…In a Caenorhabditis elegans model for Alzheimer disease, SGT was found to be present in protein complexes including b-amyloid peptide, several chaperones and chaperone-like protein. Furthermore, when SGT was knockdown by dsRNA, the toxic effect of exogenous expression of b-amyloid peptide was significantly reduced, implying that SGT may be involved in b-amyloid peptide-dependent pathogenicity in this model system [10]. On the other hand, rat SGT promoted the chaperone activity of Hsc70 in a tripartite complex containing the cysteine string protein (Csp) and Hsc70, which is thought to participate in vesicle-mediated neuronal signal transduction [11].…”