AMYLOID-BETA PRECURSOR PROTEIN AND UBIQUITIN EPITOPES IN HUMAN AND EXPERIMENTAL DYSTROPHIC AXONS - ULTRASTRUCTURAL-LOCALIZATION

Dystrophic axons (DA) represent a major pathological feature of severa l neurodegenerative disorders, including infantile neuroaxonal dystrop hy (INAD) and Alzheimer disease. We have previously presented evidence that amyloid beta precursor protein (BPP) and ubiquitin (Ub) are pres ent in DA of different origin. We have now characterized the immunorea ctivity of DA experimentally induced in rat by the administration of p arabromophenylacetylurea (BPAU) and examined the subcellular localizat ion of Ub and BPP in BPAU-induced DA and in DA present in subjects aff ected by INAD. BPAU-induced DA strongly immunoreacted with antisera to Ub and to COOH- and NH2-terminal regions of BPP. Immunoblots of DA-en richted brain regions were consistent with an increase in the amount o f Ub and BPP in DA. Moreover, BPAU-induced DA immunoreacted with antib odies to PGP 9.5, a neuronal-specific Ub COOH-terminal hydrolase, and to the inducible heat shock protein 70. Antigenic characterization als o indicated that the tubulovesicular membranes within DA derive largel y from the smooth endoplasmic reticulum rather than from the Golgi sys tem or the synaptic vesicles. Subcellular immunolocalization of Ub and BPP in both INAD- and BPAU-induced DA revealed that Ub and BPP coloca lize in granulovesicluar material in both conditions. In INAD DA inten se Ub immunoreactivity was also detected in nonmembranous electron den se structures that were present only in these DA, probably because of the chronic course of INAD. Although BPP immunostaining may, be relate d to accumulation of BPP-containing membranes in DA, Ub immunostaining is likely to result from activation of the Ub system by the neuron in the attempt to remove excessive and possibly abnormal proteins. A sim ilar pathogenesis can be postulated for DA of Alzheimer disease.