Translocation of amyloid precursor protein C-terminal fragment(s) to the nucleus precedes neuronal death due to thiamine deficiency-induced mild impairment of oxidative metabolism.
Thiamine deficiency (TD) is a model of neurodegeneration induced by mild impairment of oxidative metabolism. TD produces time-dependent glial activation, inflammation, oxidative stress, altered metabolism of amyloid precursor protein (APP), exacerbation of plaque formation from APP, and finally, selective neuron death in specific brain regions. The sub-medial thalamic nucleus (SmTN) is the most sensitive region to TD. Alteration in APP metabolism and nuclear translocation of carboxy-terminal fragments (CTF) of APP has been implicated in neuron death in other models of neurodegeneration. These experiments tested whether TD causes translocation of CTF into the nucleus of neurons in the SmTN that are destined to die after 9 days of TD by examining overlapping immunoreactivity (IR) of antibody APP 369 with either Alz90, 6E10 or 4G8 epitopes in the nuclei of the neurons in the SmTN. TD caused the accumulation of the CTF of APP in nuclei of SmTN neurons within 3 days of TD. These changes did not occur in the cortex which is spared in TD. Western blot analysis of nuclear fractions revealed a significant (61%; P < 0.026) increase in CTF 12 levels in TD SmTN (2.08 +/- 0.56) compared to control SmTN (1.29 +/- 0.41). Although TD increased CTF 15 levels in TD SmTN (1.95 +/- 0.73) compared to control SmTN (0.62 +/- 0.52) by 214%; P < 0.665 and decreased the full-length holo-APP levels in TD SmTN (0.32 +/- 0.30) compared to control SmTN (0.47 +/- 0.18) by 34%; P < 0.753, the differences were statistically insignificant. TD did not alter CTF 15 or CTF 12 levels in cortex. These findings demonstrate that changes in APP metabolism occur in early stages of TD, and they may play an important role in TD-induced selective neuronal loss.
Karuppagounder
Saravanan S
SS
Department of Neurology and Neuroscience, Weill Medical College of Cornell University, Burke Medical Research Institute, 785 Mamaroneck Avenue, White Plains, NY 10605, USA.
Xu
Hui
H
Pechman
David
D
Chen
Lian H
LH
DeGiorgio
Lorraine A
LA
Gibson
Gary E
GE
D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D016923:Cell Death / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism* / Q000502:physiology*; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009410:Nerve Degeneration / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology*; D010084:Oxidation-Reduction; D010446:Peptide Fragments / Q000378:metabolism; D020531:Subthalamic Nucleus / Q000378:metabolism / Q000473:pathology; D013832:Thiamine Deficiency / Q000473:pathology*; D014178:Translocation, Genetic
D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments