Inhibition of amyloid beta oligomer accumulation by NU-9: A unifying mechanism for the treatment of neurodegenerative diseases data set

Protein aggregation is a hallmark of neurodegenerative diseases, which
connects these neuropathologies by a common phenotype. Various proteins
and peptides form aggregates that are poorly degraded, and their ensuing
pathological accumulation underlies these neurodegenerative diseases.
Similarities may exist in the mechanisms responsible for the buildup of
these aggregates. Therefore, therapeutics designed to treat one
neurodegenerative disease may be beneficial to others. In ALS models, the
compound NU-9 was previously shown to block neurodegeneration produced by
aggregation-inducing mutations of SOD-1 and TDP-43 [B. Genç et al., Clin.
Transl. Med. 11, e336 (2021)]. Here, we report that NU-9 also prevents the
accumulation of amyloid beta oligomers (AβOs), small peptide aggregates
that are instigators of Alzheimer’s disease neurodegeneration [M. Tolar et
al., Int. J. Mol. Sci. 22, 6355 (2021)). AβO buildup was measured by
immunofluorescence imaging of cultured hippocampal neurons exposed to
exogenous monomeric Aβ. In this model, AβO buildup occurs via cathepsin L-
and dynamin-dependent trafficking. This is prevented by NU-9 through a
cellular mechanism that is cathepsin B- and lysosome-dependent, suggesting
that NU-9 enhances the ability of endolysosomal trafficking to protect
against AβO buildup. This possibility is strongly supported by a
quantitative assay for autophagosomes that shows robust stimulation by
NU-9. These results contribute additional understanding to the mechanisms
of protein aggregation and suggest that multiple neurodegenerative
diseases might be treatable by targeting common pathogenic mechanisms
responsible for protein aggregation.