Neurotoxic APP C-terminal and beta-amyloid domains colocalize in the nuclei of substantia nigra pars reticulata neurons undergoing delayed degeneration.
Increased amyloid precursor protein (APP) expression and intracellular accumulation of its toxic fragments have been associated with acute neuronal death processes. However, the role of APP fragments in delayed neurodegeneration remains poorly understood. We have characterized the appearance of APP domains in rat substantia nigra pars reticulata (SNpR) neurons targeted for delayed degeneration following neurotoxic striatal lesion. From 4 to 8 days postlesion (dpl) SNpR neurons ipsilateral to the lesion showed marked cytosolic accumulation of full length APP. Moreover, the nuclei of affected neurons also showed intense immunoreactivity (IR) for APP C-terminal and beta-amyloid domains but not for an N-terminal sequence. These data suggested the presence of APP C-terminal fragment. The absence of nuclear IR for a beta1-40 specific antibody supports this conclusion. Ultrastructural analysis of nigral sections from 6 dpl rats using a beta-amyloid domain antibody showed pronounced accumulation of immunogold-silver reaction product in the nuclei of affected SNpR neurons that was absent in control, contralateral SNpR neurons. These findings suggest that intranuclear APP C-terminal fragment may play a role in genomic events contributing to delayed neuron degeneration in the SNpR.
DeGiorgio
L A
LA
Department of Neurology and Neuroscience, Weill College of Medicine of Cornell University, The Burke Medical Research Institute, 785 Mamaroneck Avenue, White Plains, NY 10605, USA. ldegiorg@burke.org
DeGiorgio
N
N
Milner
T A
TA
Conti
B
B
Volpe
B T
BT
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D007150:Immunohistochemistry; D008854:Microscopy, Electron; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology; D009498:Neurotoxins / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D051381:Rats; D013378:Substantia Nigra / Q000378:metabolism* / Q000473:pathology; D014018:Tissue Distribution
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D009498:Neurotoxins; D010446:Peptide Fragments