Candidate molecular pathways of white matter vulnerability in the brain of normal aging rhesus monkeys

Abstract

Mammalian aging is associated with decline in cognitive functions. Studies searching for a cause of cognitive aging initially focused on neuronal loss but quantitative investigations of rat, monkey, and human brain using stereology demonstrated that in normal aging, unlike in neurodegenerative disease, neurons are not lost. Instead, electron microscopic and MRI studies in normal aging monkeys revealed age-related damage to myelin sheaths, loss of axons, and reduction in white matter volume which correlates with cognitive impairments. However, little is known about the cause of myelin defects or associated axon loss. The present study investigates the effect of age on signaling pathways between oligodendroglia and neurons using a custom PCR array to assess the expression of 87 genes of interest in cortical gray matter and white matter from the inferior parietal lobe (IPL) of normal rhesus monkeys ranging in age from 4.2 to 30.4 years old. From this array data, five target genes of interest were selected for further analysis to confirm gene expression and measure protein expression. The most interesting target gene identified is brain-derived neurotrophic factor (BDNF), which was the only gene that was altered at both mRNA and protein levels. In gray matter, BDNF mRNA was decreased. While the level of the mature form of the protein was unchanged, there was a specific decrease in the precursor form of BDNF. These alterations in the BDNF in gray matter could contribute to the vulnerability and loss of the axons with age.

Keywords: Aging; BDNF; Gene expression; Parietal cortex; Protein expression; White matter.

Fig. 1

Relative gene expression in the IPL cortical gray matter versus age. a BDNF, b NTRK2, and c ADAM19 were all standardized to the expression of 18S rRNA in 27 animals. While there was no significant change with age for NTRK2 (b), both BDNF (a), and ADAM19 (c) were significantly decreased with age in the cortical gray matter. *p < 0.05

Fig. 2

Relative gene expression in the IPL subcortical white matter versus age. a BDNF standardized to 18S rRNA in 27 animals, b NGFR standardized to RPL13A in 26 animals (AM079x did not amplify), c NTRK2 standardized to 18S rRNA in 26 animals (AM107b did not amplify), and d ADAM19 standardized to 18S rRNA in 27 animals. Only the expression of NGFR was significantly changed, showing an increase with age. *p < 0.05

Fig. 3

Protein expression in the IPL gray matter versus age. The levels of a proBDNF, b mature BDNF (mBDNF), and c TrkB full length (FL TrkB) and truncated (TR TrkB) forms are shown standardized to β-tubulin. Representative blots are shown for each antibody. Only proBDNF showed a significant change with age in protein expression. *p < 0.05

Fig. 4

Protein expression in the IPL white matter versus age. The levels of a mature BDNF, b proBDNF, c NGFR, and d TrkB full length (FL TrkB) and truncated (TR TrkB) forms standardized to myelin oligodendrocyte glycoprotein (MOG) are shown. Representative blots for each antibody are below each graph. There are no significant changes in any of the proteins with age in the subcortical white matter