Signal transduction abnormalities in Alzheimer's disease: evidence of a pathogenic stimuli.
Hippocampal and select cortical neuronal populations in Alzheimer's disease exhibit phenotypic changes characteristic of cells re-entering the cell division cycle. Therefore, in this study, we investigated whether components, known to trigger cellular proliferation and differentiation, upstream of the ras/mitogen-activated kinase pathway, could contribute to the activation of a signal transduction cascade in Alzheimer's disease. We found that proteins implicated in signal transduction from cell surface receptors via the ras pathway, namely Grb2 and SOS-1, were altered in cases of Alzheimer's disease in comparison to age-matched controls. SOS is increased in susceptible pyramidal neurons, while Grb2 shows more subtle alterations in subcellular distribution. Importantly, both SOS-1 and Grb2 show considerable overlap with early cytoskeletal abnormalities suggesting that the alteration in signal transduction molecules is a concurrent, if not preceding, event in the pathogenesis of Alzheimer's disease. Taken together with the cell cycle abnormalities previously reported, these findings suggest that a signal derived from the cell surface contributes to a stimulus for neurons in Alzheimer's disease to re-enter the cell cycle.
McShea
A
A
Institute of Pathology, Case Western Reserve University, 2085 Adelbert Road, Cleveland, OH 44106, USA.
Zelasko
D A
DA
Gerst
J L
JL
Smith
M A
MA
D048868:Adaptor Proteins, Signal Transducing; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000209:etiology* / Q000378:metabolism / Q000473:pathology*; D002453:Cell Cycle; D005625:Frontal Lobe / Q000378:metabolism / Q000473:pathology; D051380:GRB2 Adaptor Protein; D020662:Guanine Nucleotide Exchange Factors; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D011506:Proteins / Q000378:metabolism; D015398:Signal Transduction; D020663:ras Guanine Nucleotide Exchange Factors; D016875:tau Proteins / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D020662:Guanine Nucleotide Exchange Factors; D011506:Proteins; D020663:ras Guanine Nucleotide Exchange Factors; D016875:tau Proteins