Neuronal O-GlcNAcylation Improves Cognitive Function in the Aged Mouse Brain

Abstract

Mounting evidence in animal models indicates potential for rejuvenation of cellular and cognitive functions in the aging brain. However, the ability to utilize this potential is predicated on identifying molecular targets that reverse the effects of aging in vulnerable regions of the brain, such as the hippocampus. The dynamic post-translational modification O-linked N-Acetylglucosamine (O-GlcNAc) has emerged as an attractive target for regulating aging-specific synaptic alterations as well as neurodegeneration. While speculation exists about the role of O-GlcNAc in neurodegenerative conditions, such as Alzheimer's disease, its role in physiological brain aging remains largely unexplored. Here, we report that countering age-related decreased O-GlcNAc transferase (OGT) expression and O-GlcNAcylation ameliorates cognitive impairments in aged mice. Mimicking an aged condition in young adults by abrogating OGT, using a temporally controlled neuron-specific conditional knockout mouse model, recapitulated cellular and cognitive features of brain aging. Conversely, overexpressing OGT in mature hippocampal neurons using a viral-mediated approach enhanced associative fear memory in young adult mice. Excitingly, in aged mice overexpressing neuronal OGT in the aged hippocampus rescued in part age-related impairments in spatial learning and memory as well as associative fear memory. Our data identify O-GlcNAcylaton as a key molecular mediator promoting cognitive rejuvenation.

The aged hematopoietic system promotes hippocampal‐dependent cognitive decline

“…Correspondingly, we assessed the levels of CREB phosphorylation (pCreb) and observed a decrease in Het HSC‐reconstituted young mice compared with Iso controls (Figure 1f,g). Moreover, we observed decreased expression of the synaptic markers AMPAR and the NMDA receptor subunit NR2B (Figure 1f,g), both of which have previously been shown to decline with hippocampal aging (Shi et al, 2007; Wheatley et al, 2019). At a structural level, we examined dendritic spine density in granule cell neurons and observed a decrease in Het HSC‐reconstituted young mice (Figure 1h,i).…”

The Dysregulation of OGT/OGA Cycle Mediates Tau and APP Neuropathology in Down Syndrome

“…Our analysis in Ts2Cje mice showed a persistent reduction of total GlcNAc bound to protein in each area of the hippocampal region, suggesting the alteration of O-GlcNAcylation homeostasis as an early molecular event that could increase susceptibility to neurodegenerative phenotypes. Previous reports demonstrated that decreased protein O-GlcNAcylation in the hippocampal region drives synaptic and cognitive decline in the aging brain, facilitating later onset of dementia [97]. Among the proposed mechanisms through which loss of O-GlcNAcylation promotes neurodegenerative processes, the extensive interplay of this PTM with protein phosphorylation has special relevance [38,45,58].…”

Age-related loss of neural stem cell O-GlcNAc promotes a glial fate switch through STAT3 activation

“…From a therapeutic perspective, while decreased O-GlcNAcylation has been implicated in Alzheimer’s disease pathology and neurodegeneration ( 18 , 19 ), we recently demonstrated that increasing neuronal O-GlcNAcylation ameliorates age-related cognitive decline ( 17 ). Similarly, others have shown that inhibiting STAT3 signaling ameliorates cognitive deficits in mouse models of Alzheimer’s disease, in part by preventing astrogliosis ( 36 ).…”

“…The posttranslational modification O-linked β- N-a cetylglucosamine (O-GlcNAc), a dynamic form of intracellular protein glycosylation, is quickly emerging as a potent regulator of brain aging ( 15 – 17 ). Recently, we identified age-related changes in O-GlcNAcylation associated with neuronal dysfunction in old mice ( 17 ).…”

“…The posttranslational modification O-linked β- N-a cetylglucosamine (O-GlcNAc), a dynamic form of intracellular protein glycosylation, is quickly emerging as a potent regulator of brain aging ( 15 – 17 ). Recently, we identified age-related changes in O-GlcNAcylation associated with neuronal dysfunction in old mice ( 17 ). Moreover, the catalytic enzymes responsible for the addition and removal of O-GlcNAc, O-GlcNAc transferase (Ogt), and O-GlcNAcase (Oga), have been implicated in Alzheimer’s disease ( 15 , 18 , 19 ), Parkinson’s disease ( 20 ), and even lifespan regulation ( 21 , 22 ).…”