Cognitive decline continues to be one of greatest health threats affecting the elderly and it is therefore crucial to identify means by which to maintain cognitive integrity by protecting against, or even counteracting, the effects of aging. Presupposed dogma holds that the old brain is unable to combat the effects of aging due to a lack of inherent plasticity that facilitates permanent age-related functional impairments. However, our lab's recent work using heterochronic parabiosis (in which the circulatory systems of young and old animals are connected) has begun to challenge such dogma by showing that systemic exposure of an old animal to young blood can rejuvenate cognitive function in the aged brain. As we age, the hippocampus is a particularly vulnerable brain region to the effects of aging exhibiting synaptic dysfunction, a reduction in synaptic density, and decreased plasticity-related gene expression that collectively result in cognitive impairments. Historically, cognitive decline with age had been thought to result from neuronal loss. However, it has become clear that the dysfunction in the old brain in the absence of disease is not paralleled by cell death, bu by specific alterations in neuronal integrity at the synaptic level. The overall goal of this studyis to investigate targets that may be functional mediators of synaptic decline, and that hold therapeutic potential for rejuvenation studies. Recent published work and preliminary data from my thesis work have identified the enzyme O-linked N- Acetylglucosamine (O-GlcNAc) Transferase (OGT) as an attractive target for selectively regulating overall neuronal integrity and aging-specific synaptic and plasticity-related molecular alterations. OGT catalyzes the addition of O-GlcNAc to target protein residues and is highly expressed in the brain. It is present in two nucleocytoplasmic isoforms, ncOGT and sOGT, the former of which declines with age in the hippocampus. Interestingly, loss of OGT in C. elegans elicits aging phenotypes and results in shortened lifespan and loss of neuronal OGT in a genetic mouse model elicits early death. While aging drives susceptibility to neurodegenerative diseases, little is still known about the process of physiological brain aging. The goal of this proposal is therefore to elucidate the role of OGT in regulating neuronal function and aging-associated neuronal phonotypes in the adult hippocampus. I will investigate this using three Specific Aims: 1: Distinguish the role of total OGT and ncOGT in regulating overall neuronal integrity and aging-associated neuronal phenotypes in the adult hippocampus. 2: Investigate the role of ncOGT in mediating hippocampal-dependent cognitive function. 3: Characterize synaptic changes in O-GlcNAcylated proteins as a function of age and decreased ncOGT by electron transfer dissociation tandem mass spectrometry. Ultimately, I hope that by investigating the molecular mechanisms underlying brain aging, I can better understand how to rejuvenate cognitive function by harnessing latent plasticity within the aging brain.
The research described in this proposal aspires to identify new targets that may mediate cellular and cognitive decline in the aging brain, through both characterizations and functional studies. The results of this proposal will have significant translational potential, in that they will identify targets for future mechanistic pursuit to repai synaptic decline in the elderly, and thus functionally restore their capacity for learning and memory.
|Fan, Xuelai; Wheatley, Elizabeth G; Villeda, Saul A (2017) Mechanisms of Hippocampal Aging and the Potential for Rejuvenation. Annu Rev Neurosci 40:251-272|
|Smith, Lucas K; He, Yingbo; Park, Jeong-Soo et al. (2015) ?2-microglobulin is a systemic pro-aging factor that impairs cognitive function and neurogenesis. Nat Med 21:932-7|