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.

Inflammaging phenotype in rhesus macaques is associated with a decline in epithelial barrier-protective functions and increased pro-inflammatory function in CD161-expressing cells

“…Thus, despite a pathogenic role in certain disease settings, IL17 and IL-22 have key roles in gut mucosal homeostasis, suggesting that the decreased production in older macaques could contribute to the leaky gut phenotype based on plasma biomarkers of epithelial breach and microbial translocation. Future studies to explore the relationship of leaky gut-mediated inflammation with the impaired cognitive functions in older macaques as demonstrated by previous studies (Justice et al 2017;Robinson et al 2018;Shobin et al 2017) will provide key insights into the role of imbalance in gut mucosal immunity and the gut-brain axis in morbidity of aging individuals.…”

Sleep deprivation impairs cognitive performance, alters task-associated cerebral blood flow and decreases cortical neurovascular coupling-related hemodynamic responses

“…subclinical Alzheimer's diseases 62 and other pathological conditions) associated with a heightened inflammatory state may be more susceptible to the adverse effects of SD, exacerbating both neurovascular dysfunction and cognitive impairment. In fact, aging pathological conditions that promote accelerated aging were shown to induce significant changes in the phenotype and function of neurovascular unit 63 – 69 , which are expected to impact both NVC responses and cognitive function 68 , 69 . It is also likely that chronic sleep deficits may have more pronounced effects both on NVC and cognitive function than short-term SD.…”

Lipopolysaccharide exposure in a rat sepsis model results in hippocampal amyloid-β plaque and phosphorylated tau deposition and corresponding behavioral deficits

“…This does not exclude the possibility that other brain regions may also play a role in sepsis-induced neurocognitive compromise. Aging is known to be associated with myelin sheath defects, axonal loss, and a reduction in white matter volume (Robinson et al 2018). We have previously reported cortical deposition of Aβ plaques in the LPS-induced rat sepsis model (Wang et al 2018).…”