Research reportSignal transduction abnormalities in Alzheimer's disease: evidence of a pathogenic stimuli
Introduction
The expression of mitosis-specific proteins in neuronal populations affected in Alzheimer's disease 17, 19, 21, 24, 25, 32, 43provides a mechanism, through aberrantly regulated mitotic kinases, for the increased phosphorylation of the cytoskeletal associated protein τ 4, 16, 18. One intriguing hypothesis is that the induction of cyclin-dependent kinases and subsequent phosphorylation of τ is a result of neuronal re-entry into the cell division cycle. However, given that there is no evidence of actual mitosis (i.e., mitotic figures), the presence of residual kinase activity likely represents growth arrest at a stage prior to M phase [22]. In this regard, we and others find elevated levels of cyclin-dependent kinase inhibitors generally associated with arrest of the cell division cycle including p16 3, 21and p21 [10]. Arrest of the cell cycle would adversely affect the viability of that cell by altering the capacity of the cell to transduce signals via gap junctions or ion channels—activities that oscillate during the cell cycle 5, 39and that are vitally important to neuronal function in relaying information. In support of this, cell cycle re-entry in postmitotic sympathetic neurons is associated with a dopamine-induced neuronal death model [30], suggesting that attempts to proliferate may form part of a universal pathological process in terminally differentiated neurons.
Son-of-sevenless-1 (SOS-1), a guanine nucleotide exchange factor for ras, couples to the growth-factor receptor bound protein 2 (Grb2) to form one of the primary components of a signal transduction cascade initiated proximal to the plasma membrane 6, 31. SOS-1 activates the ras/mitogen activated kinase (MAPK) pathway, that induces the expression of Cyclin D1 1, 9, Cyclin A [8], downregulates p27KIP1 [1], and is also associated with cellular proliferation in a wide variety of systems. To address whether a stimulus for proliferation, in neurons in Alzheimer's disease, originates proximal to the plasma membrane, we used immunocytochemical techniques to compare the expression of SOS-1 and Grb2 in the brains of control and Alzheimer's disease patients. Additionally, since we suspected that the activation of the ras pathway, by SOS-1, would ultimately lead to the engagement of the proliferative machinery of the cell cycle, and hence, the phosphorylation of τ by mitotic kinases, we correlated the expression of phosphorylated τ protein with SOS-1.
Section snippets
Brain tissue
Hippocampal, frontal cortex, and cerebellar brain tissue was obtained post-mortem from Alzheimer's disease (n=11, ages 57–91, post-mortem interval 2–9 h) and control (n=8, ages 53–82, post-mortem interval, 4–22 h) patients (based on clinical and pathological criteria established by CERAD and an NIA consensus panel) 14, 23. Tissue was fixed in methacarn (methanol:chloroform:acetic acid, 60:30:10), embedded in paraffin and 6 μm thick consecutive sections were prepared on silane-coated (Sigma, St.
Results
SOS-1 labeling is predominantly elicited as a punctate granular stain in neurons in Alzheimer's disease (Fig. 1A,B) but not age-matched control tissue (Fig. 1D). In Alzheimer's disease, SOS-1 was localized to neuronal populations affected by cytoskeletal abnormalities (i.e., neurofibrillary pathology), as well as apparently normal-looking pyramidal neurons (Fig. 1A,B). Comparison of regions affected by the disease (hippocampus and frontal cortex) vs. a region relatively spared (cerebellum)
Discussion
In these studies, we demonstrate that Grb2 and its ligand, SOS-1, are significantly altered in neurons of Alzheimer diseased brain compared to age-matched controls. One likely scenario, based on our data, is that the induction of SOS-1 affects the cellular location of Grb2, hence, explaining the confinement of Grb2 to the cell body in cases of Alzheimer's disease while it has a more diffuse distribution in controls, including neuronal processes. In contrast, SOS-1 is virtually undetectable in
Acknowledgements
This work was supported by the Howard Hughes Foundation (MAS, DAZ), the Alzheimer's Association (IIRG-98-136; MAS) and a Ruth Salta Student Fellowship (DAZ). The authors thank Ms. Dianne Kofskey for assistance with the Quantinet 570c system.
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