Neuritogenic-Neurotoxic Effects of Membrane-Associated Forms ofAmyloid Precursor Prot einNeill D. · Hughes D. · Leake A. · Morris C. · Jones D. · Oakley A. · Edwardson J. · Estibeiro P.
aInstitute for the Health of the Elderly, Newcastle General Hospital, Newcastle upon Tyne, bSouth Tyneside District Hospital, South Shields, cCentre for Genome Research, University of Edinburgh, Edinburgh, UK
The membrane-bound glycoprotein, amyloid precursor protein (APP), plays a central role in Alzheimer’s disease (AD). The present paper investigates the neuritogenic-neurotoxic properties of this protein and relates them to possible aetiopathological mechanisms in AD. Marked differences in neuritic differentiation were detected when comparing untransfected tetraploid mouse neuroblastoma cells (or vector only cells) with transfected cells overexpressing APP751. Transfected cells developed neurites quicker, and whereas all transfected cells differentiated, the degree of differentiation of untransfected cells was more variable. Fully differentiated transfected and untransfected cells had marked differences in neuritic morphology. Transfected cells had more neurites per cell, these being shorter and more branched than neurites on untransfected cells. The precocious differentiation of transfected cells was not maintained with neuritic process disintegration and cell death occurring from the seventh day onwards. Untransfected cells continued to extend their neuritic processes for up to five weeks. Membrane-associated forms of APP were responsible for these effects, rather than secreted APP or the β/A4-peptide. Combined data from Western blot and immunocytochemical procedures showed a prominent accumulation of APP-C-terminal fragments in the perinuclear region, neuritic varicosities and growth cones of transfected cells, suggesting their involvement in the neuritogenic-neurotoxic process. Similar neuritogenic-neurotoxic mechanisms occurring in vivo, in association with compensatory synaptoplastic responses in the aged brain, may be part of the pathological process in AD.
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