Effects of Isotemporal Substitution Analysis of Sedentary Behavior, Sleep, and Physical Activity on Physical Performance in Older Adults.

Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease (AD). In 2022, the number of new patients diagnosed with PD was estimated to increase by 50% in the United State alone and the total prevalence is projected to reach one million in 2030. Accordingly, there is interest in advancing new therapeutic strategies to address this disease. Postmortem analysis of patient brain tissues reveals the accumulation of aggregates known as Lewy bodies which are composed of abnormally phosphorylated α-synuclein. These proteinase-resistant aggregates are one of the primary pathological hallmarks of PD and they correlate with the extent of the degeneration of dopaminergic neurons in the brain. Currently, Levodopa (L-DOPA) is the most prescribed FDA-approved treatment for improving the quality of life for patients with PD, by transiently replenishing dopamine in the brain to restore motor control. However, the lack of direct intervention against the progressive α-synuclein pathologies results in the irreversible loss of dopaminergic neurons. Therefore, identifying a disease-modifying strategy that can effectively block the formation of toxic phosphorylated α-synuclein aggregates remains a critical need for patients. The O-linked β--acetylglucosaminylation (O-GlcNAcylation) modification of nuclear and cytoplasmic proteins has gained considerable interest as a strategy to combat various neurodegenerative diseases due to the protective effects arising from increased O-GlcNAc that relieves cellular stresses and neurodegeneration. β--acetylglucosamine (GlcNAc) is a monosaccharide synthesized from glucose and glutamine via the hexosamine biosynthetic pathway (HBP) to generate, as an end product, the high-energy nucleotide sugar uridine diphosphate GlcNAc (UDP-GlcNAc). The enzyme O-GlcNAc transferase (OGT) uses UDP-GlcNAc as a substrate to modify proteins by attaching a GlcNAc unit onto the hydroxyl group of certain serine and threonine residues. The O-linked GlcNAc can be subsequently removed by the enzyme O-GlcNAcase (OGA), which recovers the hydroxyl group. Pharmacological elevation of O-GlcNAcylation is found to preserve neurons, strengthen synaptic plasticity, relieve neuroinflammation, and prevent cognitive decline in various cell and animal models of neurodegenerative diseases. Notably, AD patients exhibit hyperphosphorylation of neuronal tau protein amid compromised glucose metabolisms. Clinical studies using the fluorodeoxyglucose (FDG)-positron emission tomography (PET) as outlined by the Alzheimer's Disease Neuroimaging Initiative (ADNI) suggest diminished glucose uptake precedes tau hyperphosphorylation and cognitive decline in patients of familial AD. Most importantly, the level of O-GlcNAc-modified proteins appears markedly reduced in the brains of AD patients. These findings collectively support a protective role of O-GlcNAcylation in the brain that may delay or attenuate the intensity of neurodegeneration. Central to several of these studies, has been the use of the high-quality small-molecule OGA inhibitor Thiamet-G, which has seen common use as a research tool for cell and preclinical studies. In PC-12 cells overexpressing human tau protein, Thiamet-G reduces tau phosphorylation while elevating the level of O-GlcNAc-modified proteins. Due to Thiamet-G being a blood-brain-barrier penetrant inhibitor with high potency and specificity against OGA (K = 2.1 nM) [Cekic, ChemSci], chronic delivery of Thiamet-G by oral dosing in drinking water is readily feasible. This tool compound has therefore been used in various rodent models of tauopathy, where oral dosing or intracranial injection of Thiamet-G reduced levels of tau hyperphosphorylation and neurofibrillary tangles. Thus, OGA inhibition shows robust and reproducible protective effects in cell and animal models of tauopathies.