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Na,K-ATPase mRNA levels and plaque load in Alzheimer's disease

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Abstract

The expression of Na,K-ATPase α1- and α3-mRNAs was analyzed byin situ hybridization in the superior frontal cortex and cerebellum of brains from five Alzheimer's disease (AD), five nondemented age-matched, and three young control subjects. Brains with well-preserved RNA, tested by Northern hybridization of immobilized RNA with [32P]-labeled human β-actin riboprobe, were chosen for analysis.In situ hybridization was performed on formalin-fixed, 5 μm-thick Paraplast sections with [35S]-labeled riboprobes prepared by in vitro transcription of the respective linearized clones: a 537-bpEcoRI-PstI fragment of α1-cDNA and a 342-bpPstI-EcoRI fragment of α3-cDNA. In cortex, grains related to mRNA were measured by density per unit area in five cortical columns separated by 1.0–1.2 cm in each of two adjacent sections. Each cortical column of 180-μm width was divided into four depths orthogonal to the pial surface between the pia and the white matter. Amyloid plaques were counted in the same regions of adjacent sections. In addition, α3-mRNA grain clusters over individual pyramidal neurons within depth 4 were analyzed. We found the following significant changes (p<0.05):

  1. 1.

    Increases in total α1-mRNA by 13–19% in AD compared to young and by 7–12% in AD compared to age-matched controls.

  2. 2.

    Decrease in total α3-mRNA by 31–38% in AD compared to young and age-matched controls.

  3. 3.

    Decrease in α3-mRNA content over individual pyramidal perikarya by 14% in normal aged brains without plaques compared to young controls, and by 44% in AD relative to young controls and by 35% compared to age-matched controls.

No significant difference (p<0.2) was found with respect to α1- or α3-mRNA in cerebellar cortex or individual Purkinje cells among any of the groups. In addition, there was a trend toward an inverse correlation between the levels of α3-mRNA and of diffuse plaques, but not of neuritic plaques, in AD cases. In conclusion:

  1. 1.

    The increases in α1-mRNA in AD may be related to an increased reactive gliosis.

  2. 2.

    The declines in α3-mRNA per individual neuron found in normal aging occur prior to the formation of diffuse plaques and are greatly accelerated in AD.

  3. 3.

    The declines in α3-mRNA per neuron found in normal aging may predispose to or potentiate AD pathogenesis.

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Chauhan, N.B., Lee, J.M. & Siegel, G.J. Na,K-ATPase mRNA levels and plaque load in Alzheimer's disease. J Mol Neurosci 9, 151–166 (1997). https://doi.org/10.1007/BF02800498

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