Alzheimer's disease presenilin-1 expression modulates the assembly of neurofilaments

Mutations in presenilin-1 gene are responsible for the majority of early-on set familial Alzheimer's disease casts. The function of this protein and th e mechanism underlying the pathogenicity of its mutations are still unclear . To elucidate the role of presenilin-1 in the Alzheimer's disease patholog y, we tested two such mutations (P117L and M146L) for their effect in stabl y transfected mouse neuroblastoma cell lines. Over-expression of the wild-t ype presenilin-1 gene induced formation of a well-extended. orderly organiz ed network consisting of neurofilaments assembled from the L and H subunits , while in cells with the mutant gene this network was markedly reduced to short filaments concentrated in structures resembling cups. Cells expressin g the mutant gene displayed altered processing of the transgene protein and neurofilament H, suggesting that presenilin-1 is the mediator of changes t argeted at neurofilaments, The two different mutations produced similar alt erations, implying that this is a common pathogenic mechanism. Presenilin-1 , neurofilament-H and tau proteins showed co-localization as evidenced by c onfocal microscopy, suggesting a possible physiological connection between these three proteins. Presenilin-1 appears to influence assembly of the H subunit into neurofilam ents and the subsequent formation of new neurites. Mutations impair this fu nction of presenilin-1, resulting in inhibition of neurite outgrowth. That presenilin-1 influences the assembly of neurofilaments may represent a nove l pathway through which presenilin-1 mutations are involved in Alzheimer's disease pathology. In this hypothesis, presenilin-1 mutations will be assoc iated with aberrant sprouting leading to synaptic loss, a key neuropatholog ical feature of Alzheimer's disease. (C) 2001 IBRO. Published by Elsevier S cience Ltd. All rights reserved.