Transforming growth factor-beta (TGF-beta), a multifunctional cytokine, has been 
widely suggested to play a role in the pathogenesis of Alzheimer's disease. 
Supporting this, levels of TGF-beta are elevated in the cerebrospinal fluid, 
sera, and brain of patients with Alzheimer's disease. Since TGF-beta is 
neuroprotective, whereas Alzheimer's disease is typified by neurodegeneration, 
we speculated that defects in TGF-beta signaling might abrogate its 
neuroprotective properties. Consistently with an increase in TGF-beta in 
Alzheimer's disease, we found significant increases in phospho-Smad2, a major 
downstream signaling molecule of TGF-beta, in hippocampal neurons of Alzheimer's 
disease compared with age-matched control patients. However, in contrast to an 
expected nuclear localization, phosphorylated Smad2 in Alzheimer's disease was 
predominantly, and ectopically, found in the neuronal cytoplasm, specifically 
colocalized with neurofibrillary tangles and granulovacuolar degeneration. Given 
that a nuclear localization is required to regulate the transcription of 
TGF-beta target genes to afford neuroprotection, the ectopic localization of 
phosphorylated Smad2 suggests a defect in the Smad-mediated signaling pathway of 
TGF-beta in Alzheimer's disease and consequent loss of neuroprotective function.