Exploring links between 2‐oxoglutarate‐dependent oxygenases and Alzheimer's disease

Abstract

Hypoxia, that is, an inadequate oxygen supply, is linked to neurodegeneration and patients with cardiovascular disease are prone to Alzheimer's disease (AD). 2‐Oxoglutarate and ferrous iron‐dependent oxygenases (2OGDD) play a key role in the regulation of oxygen homeostasis by acting as hypoxia sensors. 2OGDD also have roles in collagen biosynthesis, lipid metabolism, nucleic acid repair, and the regulation of transcription and translation. Many biological processes in which the >60 human 2OGDD are involved are altered in AD patient brains, raising the question as to whether 2OGDD are involved in the transition from normal aging to AD. Here we give an overview of human 2OGDD and critically discuss their potential roles in AD, highlighting possible relationships with synapse dysfunction/loss. 2OGDD may regulate neuronal/glial differentiation through enzyme activity‐dependent mechanisms and modulation of their activity has potential to protect against synapse loss. Work linking 2OGDD and AD is at an early stage, especially from a therapeutic perspective; we suggest integrated pathology and in vitro discovery research to explore their roles in AD is merited. We hope to help enable long‐term research on the roles of 2OGDD and, more generally, oxygen/hypoxia in AD. We also suggest shorter term empirically guided clinical studies concerning the exploration of 2OGDD/oxygen modulators to help maintain synaptic viability are of interest for AD treatment.

The interaction between ageing and Alzheimer's disease: insights from the hallmarks of ageing

“…Oxygen homeostasis is essential for maintaining cell function. 2-Oxoglutarate and ferrous iron-dependent oxygenases (2OGDDs) are hypoxia sensors that play an essential role in regulating oxygen homeostasis [ 147 ]. Several 2OGDD-related cellular processes are altered in the brains of AD patients.…”

Activation of the muscle-to-brain axis ameliorates neurocognitive deficits in an Alzheimer’s disease mouse model via enhancing neurotrophic and synaptic signaling

“…Of these, 12 were down-regulated and only 3 were up-regulated, reflecting the high degree of disease-association built into the panel footprint [31][32][33]. Two of these genes were associated with protein aggregation (Kctd1, potassium channel tetramerization domain containing 1) [34] and Aβ amyloidosis formation (Phyhip, phytanoyl-CoA 2-hydroxylase interacting protein) [35], consistent with our findings of reduced plaque abundance in the CNS of 5xFAD;HSACre mice (Figure 1C-F). Strikingly, many of the other down-regulated genes coded for multiple hits on the synaptic regulatory network, including, Stxbp5l (a syntaxin-binding protein), protein kinase C related genes Prkca and Prkcb, Arhgef9 and Mef2c.…”

Examining the Role of a Functional Deficiency of Iron in Lysosomal Storage Disorders with Translational Relevance to Alzheimer’s Disease

“…In addition to mitochondrial function, other iron-related processes and iron-dependent enzymatic activities may be affected when available iron is depleted, such as enzymes for myelin synthesis (or remyelination) and Fe(II)/2-oxoglutarate-dependent (Fe/2OG) oxygenases [23][24][25]. If a functional iron deficiency affects the activities of the family of Fe/2OG oxygenases, then there can be widespread implications since these enzymes are When available iron levels fall, cells respond by various means: attempting to acquire more iron, limiting the export of iron, increasing the release of iron from stores (e.g., ferritinophagy), and increasing the recycling of iron (e.g., mitophagy), etc.…”

“…If a functional iron deficiency affects the activities of the family of Fe/2OG oxygenases, then there can be widespread implications since these enzymes are involved with transcription regulation, repair of nucleic acids, oxygen sensing, lipid metabolism, etc. [25]. Eventually, altered levels and/or activities of proteins can impact a variety of CNS functions, including decreased synaptic activity, impaired dendritic growth, diminished learning, and even neuronal death [1].…”