Abeta-induced neuritic dystrophy requires ADF/cofilin-mediated actin filament reorganization.

HEREDIA L; CÁCERES A; LORENZO A

Sorrento - Italy

Congreso; VII International Conference on Alzheimer´s and Parkinson disease.; 2005

International Conference on Alzheimer´s and Parkinson disease

Amyloid beta (Abeta) plaques, neurofibrillary tangles and neuritic dystrophy are characteristic lesions of Alzheimer?s disease (AD).  In AD brain, dystrophic neurites are highly concentrated in fibrillar Abeta plaques, and are not found in neurodegenerative conditions that lack amyloid deposits, suggesting that neuronal dystrophy is a specific response to Abeta deposition that contribute to the pathogenesis of AD.  The molecular mechanism mediating neuronal and neuritic dystrophy is unknown.  In vitro, fibrillar Abeta (fAbeta), but not soluble Abeta, induces gross alterations in neuronal morphology, including altered caliber and tortuosity of neurites accompanied by a dramatic reduction in both, axonal and dendritic network.  In addition, Abeta-induced neuritic dystrophy is accompanied by increased levels of phosphorylated tau and abnormal accumulation of Amyloid beta Precursor protein (APP) in the cell surface.  These alterations are also characteristic features of dystrophic neurites in AD brain.  Abeta-induced neuritic alterations is also accompanied by a dramatic remodeling of the actin cytoskeleton, suggesting a role for actin in Abeta-induced dystrophy.  Actin-depolymerizing factor (ADF) and cofilin are actin binding proteins that play a critical role in actin filament organization and dynamics.  We have analyzed the involvement of ADF/cofilin, and its regulatory kinase, in fAbeta induced neuronal dystrophy using rat hippocampal cultures and a combination of biochemistry and confocal microscopy analysis.  Our data support a critical role of ADF/cofilin in fAbeta-induced dystrophy, and the significance of these observations for AD pathology will be discussed.