Abstract
Molecular chaperones and co-chaperones, which are part of the protein quality control machinery, have been shown to regulate distinct aspects of Alzheimer’s Disease (AD) pathology in multiple ways. Notably, the co-chaperone STI1, which presents increased levels in AD, can protect mammalian neurons from amyloid-β toxicity in vitro and reduced STI1 levels worsen Aβ toxicity in C. elegans. However, whether increased STI1 levels can protect neurons in vivo remains unknown. We determined that overexpression of STI1 and/or Hsp90 protected C. elegans expressing Aβ(3–42) against Aβ-mediated paralysis. Mammalian neurons were also protected by elevated levels of endogenous STI1 in vitro, and this effect was mainly due to extracellular STI1. Surprisingly, in the 5xFAD mouse model of AD, by overexpressing STI1, we find increased amyloid burden, which amplifies neurotoxicity and worsens spatial memory deficits in these mutants. Increased levels of STI1 disturbed the expression of Aβ-regulating enzymes (BACE1 and MMP-2), suggesting potential mechanisms by which amyloid burden is increased in mice. Notably, we observed that STI1 accumulates in dense-core AD plaques in both 5xFAD mice and human brain tissue. Our findings suggest that elevated levels of STI1 contribute to Aβ accumulation, and that STI1 is deposited in AD plaques in mice and humans. We conclude that despite the protective effects of STI1 in C. elegans and in mammalian cultured neurons, in vivo, the predominant effect of elevated STI1 is deleterious in AD.
Highlights
Alzheimer’s disease (AD), the most common cause of dementia, afflicts close to 50 million people worldwide and the number of affected individuals is projected to grow by twofold every two decades [1]
We have previously shown that treatment with recombinant STI1 can protect cultured neurons from Aβ oligomers (AβOs) induced cell death, by preventing AβO mal-adaptative signalling via the prion protein [29]
The present experiments revealed the relationship between STI1 and Hsp90 in worm and mouse AD models of amyloidosis in vivo
Summary
Alzheimer’s disease (AD), the most common cause of dementia, afflicts close to 50 million people worldwide and the number of affected individuals is projected to grow by twofold every two decades [1]. One of the key receptors involved in Aβ toxicity is the prion protein (PrPC), which interacts with Aβ oligomers (AβOs) with high-affinity, and this interaction triggers metabotropic glutamate receptor 5 (mGluR5) maladaptive signalling in neurons [17–20]. PrPC functions as an extracellular scaffolding protein that interacts with multiple ligands and receptors [21–23]. Stress-inducible phosphoprotein 1 (STI1, STIP1, or mammalian homolog: Hsp organizing protein, HOP), a Hsp70/Hsp cochaperone, once secreted binds to PrPC, and protects mouse neurons against a number of insults [24–28]. Extracellular STI1 prevents toxic effects of AβOs, including neuronal death and decreased long-term potentiation, likely by interfering with AβO-PrPC interaction due to contiguous binding sites for STI1 and AβOs along PrPC [29]. Functional studies using a C. elegans model of Aβ indicate that knockdown of Hsp, STI1 and several other co-chaperones increases Aβ toxicity [30]. STI1 has been identified in a genome-wide transcriptome analysis as one of the top genes regulating ER transcriptome stress response in the brains of sporadic AD patients [31], and STI1 protein levels are upregulated in AD patient brains [29]
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