Fas Apoptosis Inhibitory Molecule Blocks and Dissolves Pathological Amyloid-β Species

Abstract

A number of neurodegenerative diseases are associated with the accumulation of misfolded proteins, including Alzheimer’s disease (AD). In AD, misfolded proteins such as tau and amyloid-β (Aβ) form pathological insoluble deposits. It is hypothesized that molecules capable of dissolving such protein aggregates might reverse disease progression and improve the lives of afflicted AD patients. Here we report new functions of the highly conserved mammalian protein, Fas Apoptosis Inhibitory Molecule (FAIM). We found that FAIM-deficient Neuro 2A cells accumulate Aβ oligomers/fibrils. We further found that recombinant human FAIM prevents the generation of pathologic Aβ oligomers and fibrils in a cell-free system, suggesting that FAIM functions without any additional cellular components. More importantly, recombinant human FAIM disaggregates and solubilizes established Aβ fibrils. Our results identify a previously unknown, completely novel candidate for understanding and treating irremediable, irreversible, and unrelenting neurodegenerative diseases.

Small Heat Shock Proteins Collaborate with FAIM to Prevent Accumulation of Misfolded Protein Aggregates

“…We previously showed that FAIM protein possesses heat shock protein (HSP)-like chaperone activity given that FAIM prevents amyloid-β and SOD1 aggregation in an in vitro cell-free system [ 3 , 4 ]. Some HSPs respond to stress conditions by upregulating their expression [ 8 ].…”

“…FAIM-S and sHSPs are known to inhibit β-amyloid fibrillization/aggregation in vitro [ 4 , 15 , 16 ]. To examine whether FAIM-S and HSP27 have an additive effect on the prevention of aggregation, we utilized the in vitro β-amyloid fibrillization/aggregation model.…”

“…We previously reported that FAIM, similar to HSP27, prevents the formation of cytotoxic protein aggregates after cellular stress, which protects cells from loss of viability [ 2 , 17 , 18 ]. Subsequent studies demonstrated that FAIM can antagonize SOD1 and amyloid-β aggregation using an in vitro cell-free model, indicating that FAIM may have chaperone-like activity similar to HSPs [ 3 , 4 ]. The work described herein finds a FAIM protein shift (or translocation) after stress similar to sHSPs.…”

“…We previously found that fas apoptosis inhibitory molecule (FAIM) protects cells from stress induced cell death by preventing protein aggregation similar to HSPs [ 2 ]. Moreover, FAIM possesses a chaperone-like activity given that it prevents the de novo formation of aggregates from SOD1-G93A and amyloid-β in cell-free systems [ 3 , 4 ]. FAIM was originally cloned as a FAS antagonist in mouse primary B lymphocytes [ 5 ].…”