Altered subcellular location of phosphorylated Smads in Alzheimer's disease.
A number of growth factors and cytokines, such as transforming growth factor beta 1 (TGF-beta1), is elevated in Alzheimer's disease (AD), giving rise to activated intracellular mitogenic signaling cascades. Activated mitogenic signaling involving the mitogen-activated protein kinases (MAPKs) and other protein kinases might alter the phosphorylation states of structural proteins such as tau, resulting in hyperphosphorylated deposits. Many intracellular signaling proteins are potential targets of misregulated phosphorylation and dephosphorylation. Recently, a crosstalk between MAPKs and Smad proteins, both involved in mediating TGF-beta1 signaling, has been reported. Although TGF-beta1 has previously been shown to be involved in the pathogenesis of AD, the role of Smad proteins has not been investigated. In this study we thus analysed the subcellular distribution of phosphorylated Smad2 and Smad3 in the hippocampus of both normal and AD brains. Here we report on strong nuclear detection of phosphorylated Smad2 and Smad3 in neurons of control brains. In AD brains these phosphorylated proteins were additionally found in cytoplasmic granules in hippocampal neurons, within amyloid plaques and attached to neurofibrillary tangles. Our data suggest a critical role of Smad proteins in the pathogenesis of AD.
Ueberham
Uwe
U
Paul Flechsig Institute for Brain Research, Department of Neuroanatomy, University of Leipzig, Jahnallee 59, D-04109 Leipzig, Germany. uebu@medizin.uni-leipzig.de
Ueberham
Elke
E
Gruschka
Hildegard
H
Arendt
Thomas
T
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D001921:Brain / Q000473:pathology; D001923:Brain Chemistry / Q000502:physiology; D005260:Female; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D016874:Neurofibrillary Tangles / Q000473:pathology; D010766:Phosphorylation; D058225:Plaque, Amyloid / Q000473:pathology; D051785:Smad Proteins / Q000378:metabolism*; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism* / Q000473:pathology
D051785:Smad Proteins; D051899:Smad2 Protein; D051900:Smad3 Protein