TY - JOUR
T1 - The formation of small aggregates contributes to the neurotoxic effects of tau45-230
AU - Afreen, Sana
AU - Ferreira, Adriana
N1 - Funding Information:
This work was supported by the National Institutes of Health USA grant # RO1NS090993 to AF, and grants # P30AG072977 and P30AG013854 to the Mesulan Center for Cognitive Neurology and Alzheimer's disease.
Publisher Copyright:
© 2021 Elsevier Ltd
PY - 2022/1
Y1 - 2022/1
N2 - Intracellular deposits of hyperphosphorylated tau are commonly detected in tauopathies. Furthermore, these aggregates seem to play an important role in the pathobiology of these diseases. In the present study, we determined whether the recently identified neurotoxic tau45-230 fragment also formed aggregates in neurodegenerative disorders. The presence of such aggregates was examined in brain samples obtained from Alzheimer's disease (AD) subjects by means of Western blot analysis performed under non-denaturing conditions. Our results showed that a mixture of tau45-230 oligomers of different sizes was easily detectable in brain samples obtained from AD subjects. Our data also suggested that tau45-230 oligomers could be internalized by cultured hippocampal neurons, mainly through a clathrin-mediated mechanism, triggering their degeneration. In addition, in vitro aggregation studies showed that tau45-230 modulated full-length tau aggregation thereby inducing the formation of smaller, and potentially more toxic, aggregates of this microtubule-associated protein. Together, these data identified alternative mechanisms underlying the toxic effects of tau45-230.
AB - Intracellular deposits of hyperphosphorylated tau are commonly detected in tauopathies. Furthermore, these aggregates seem to play an important role in the pathobiology of these diseases. In the present study, we determined whether the recently identified neurotoxic tau45-230 fragment also formed aggregates in neurodegenerative disorders. The presence of such aggregates was examined in brain samples obtained from Alzheimer's disease (AD) subjects by means of Western blot analysis performed under non-denaturing conditions. Our results showed that a mixture of tau45-230 oligomers of different sizes was easily detectable in brain samples obtained from AD subjects. Our data also suggested that tau45-230 oligomers could be internalized by cultured hippocampal neurons, mainly through a clathrin-mediated mechanism, triggering their degeneration. In addition, in vitro aggregation studies showed that tau45-230 modulated full-length tau aggregation thereby inducing the formation of smaller, and potentially more toxic, aggregates of this microtubule-associated protein. Together, these data identified alternative mechanisms underlying the toxic effects of tau45-230.
KW - Alzheimer's disease
KW - Clathrin-mediated endocytosis
KW - Neuronal degeneration
KW - Tau aggregates
KW - tau internalization
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U2 - 10.1016/j.neuint.2021.105252
DO - 10.1016/j.neuint.2021.105252
M3 - Article
C2 - 34856321
AN - SCOPUS:85120658454
VL - 152
JO - Neurochemistry International
JF - Neurochemistry International
SN - 0197-0186
M1 - 105252
ER -