Axonal atrophy in aging is associated with a decline in neurofilament gene expression

Neurofilaments (Nfs) are major determinants of axonal caliber. Nf transcript levels increase during development and maturation, and are associated with an increase in Nf protein, Nf numbers, and caliber of axons. With aging there is axonal atrophy. In this study we asked whether the axonal atrophy of aging was associated with a decline in Nf transcript expression, Nf protein levels, and Nf numbers. Expression of transcripts for the three Nf subunits was evaluated in dorsal root ganglia (DRG) of Fischer-344 rats aged 3-32 months by Northern and in situ hybridization. There was an approximately 50% decrease in Nf subunit mRNA levels in DRG of aged (> 23 months) as compared to young and mature (3 and 12 months) rats, whereas expression of another neuronal mRNA, GAP-43, showed no decline. Western analysis showed a corresponding decrease in Nf subunit proteins and no decline in GAP-43. Morphometric analysis showed a 50% decrease in Nf numbers within axons. The decrease in Nf gene expression and Nf numbers was accompanied by a decrease in cross-sectional area and circularity of all myelinated fibers, with the largest fibers showing the most marked changes, and a shrinkage in the perikaryal area of large neurons. Furthermore, we found a concomitant decrease in the expression of transcripts for the nerve growth factor receptors trkA and p75 with aging. Although the mechanisms leading to the decrease in Nf gene expression with aging are not known, a decrease in the availability of growth factors, or the neuron's ability to respond to them, may play a role in this process.