P1–417: Ectopic localization of phospho–Smad2 in the vulnerable neurons of Alzheimer's disease

Transforming growth factor–β (TGF–β), a multifunctional cytokine, has been widely suggested to play a role in the pathogenesis of Alzheimer's Disease (AD). Supporting this, levels of TGF–β are elevated in the cerebrospinal fluid, sera, and the brain of patients with AD. Since TGF–β is neuroprotective, whereas AD is typified by neurodegeneration, we speculated that defects in TGF–β signaling might abrogate its neuroprotective properties. To test our hypothesis, as well as to further define the role of TGF–β in AD, we investigated the expression of the active phosphorylated form of Smad2, a major downstream signaling molecule in the TGF–β pathway. The level and localization of phospho–Smad2 is determined in the brains of AD and age–matched control patients by immunocytochemistry. Consistent with an increase in TGF–β in AD, we found significant increases in phospho–Smad2 in hippocampal neurons of AD compared to age–matched control patients. However, in contrast to an expected nuclear localization, phosphorylated Smad2 in AD was predominantly, and ectopically, found in the cytoplasm, specifically co–localized with neurofibrillary tangles and granular vacuolar degeneration. Since the localization of phosphorylated Smad2 in the nucleus is required to regulate the transcription of target genes regulated by TGF–β, this ectopic localization of phosphorylated Smad2 in AD suggests a defect in the Smad–mediated signaling pathway of TGF–β. Therefore, although TGF–β is increased in AD, it is likely that TGF–β–mediated neuroprotection pathways become uncoupled and that this may lead to, or contribute to, the pathogenesis of AD. Work in the authors' laboratories is supported by the Alzheimer Association, National Institute of Health and Phillip Morris USA and Phillip Morris International.