title: Functional interaction between amyloid-β precursor protein and peripherin neurofilaments: a shared pathway leading to Alzheimer's disease and amyotrophic lateral sclerosis?
abstract: OBJECTIVE
  The pathology of amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder affecting motor neurons, comprises aberrant accumulations of neurofilaments; mutations in the peripherin subunit of neurofilaments have been identified in some forms of ALS. Recently, the amyloid-β precursor protein (APP), a key element for the pathology of Alzheimer's disease (AD), was linked to ALS. Here, we provide evidence that the generation of the N-terminal fragment of APP, sAPP, relies on peripherin neurofilaments. This finding could relate to a novel molecular mechanism dysregulated in ALS and/or AD.
  
  
  RESULTS
  The production and the fate of sAPP were studied with the brainstem-derived, neuronal cell line, CAD, which expresses endogenous peripherin. We show that sAPP and C-terminal fragments (CTF) are generated to a large extent in the neuronal soma. We find that sAPP, but not CTF, associates with filamentous structures that delineate the nuclear lamina, extend to the cell periphery and immunostain for peripherin. The depletion of peripherin with siRNA eliminates the filamentous immunostaining of sAPP.
  
  
  CONCLUSIONS
  Our results indicate that a fraction of APP is cleaved by β-secretase in the soma and that the generated sAPP becomes associated with perinuclear peripherin neurofilaments. These findings link the metabolism of APP--which is dysregulated in AD--to the organization of neurofilaments--which is abnormal in ALS--and suggest a possible crosstalk/overlap between the molecular mechanisms of these diseases.
authors.affiliation: Department of Pharmacology and Physiology, Rutgers, The State University of New Jersey, New Jersey Medical School, Newark, N.J., USA.
authors.forename: Virgil
authors.initials: V
authors.lastname: Muresan
authors.forename: Christine
authors.initials: C
authors.lastname: Villegas
authors.forename: Zoia
authors.initials: Z
authors.lastname: Ladescu Muresan
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D051379:Mice; D009474:Neurons / Q000378:metabolism; D064531:Peripherins / Q000378:metabolism*
chemical_list: D016564:Amyloid beta-Protein Precursor; D064531:Peripherins; D053829:Amyloid Precursor Protein Secretases