Alzheimer's disease alters oligodendrocytic glycolytic and ketolytic gene expression

Abstract

Introduction Sporadic Alzheimer's disease (AD) is strongly correlated with impaired brain glucose metabolism, which may affect AD onset and progression. Ketolysis has been suggested as an alternative pathway to fuel the brain. Methods RNA‐seq profiles of post mortem AD brains were used to determine whether dysfunctional AD brain metabolism can be determined by impairments in glycolytic and ketolytic gene expression. Data were obtained from the Knight Alzheimer's Disease Research Center (62 cases; 13 controls), Mount Sinai Brain Bank (110 cases; 44 controls), and the Mayo Clinic Brain Bank (80 cases; 76 controls), and were normalized to cell type: astrocytes, microglia, neurons, oligodendrocytes. Results In oligodendrocytes, both glycolytic and ketolytic pathways were significantly impaired in AD brains. Ketolytic gene expression was not significantly altered in neurons, astrocytes, and microglia. Discussion Oligodendrocytes may contribute to brain hypometabolism observed in AD. These results are suggestive of a potential link between hypometabolism and dysmyelination in disease physiology. Additionally, ketones may be therapeutic in AD due to their ability to fuel neurons despite impaired glycolytic metabolism.

Aβ initiates brain hypometabolism and network dysfunction via NOX2 activation: a potential onset mechanism of Alzheimer’s disease

“…Studies using PET ketone tracer 11C-acetoacetate (AcAc) reported that brain metabolism of ketones is unchanged in MCI and early AD 73,74 supporting the previous assumption that oxidative phosphorylation may still be normal in early AD. Finally, a recent study utilizing RNA-seq on post mortem AD brains showed impaired glycolytic pathways in neurons and astrocytes while the ketolytic pathways remained normal 75 . Altogether, this suggests that early brain hypometabolism in AD may be specific to glycolytic breakdown 76 and not in dysfunctional mitochondrial oxidative phosphorylation.…”

Ketones: potential to achieve brain energy rescue and sustain cognitive health during ageing

“…Using a 4-year longitudinal study in healthy older adults, we later showed that while declining regional brain glucose utilization (-6 to -12%) was paralleled by deteriorating cognitive performance, AcAc utilization remained unchanged over the same period (100) . A study in postmortem AD brains recently supported these in vivo observations by showing that while glycolytic gene expression was impaired in all cell types, ketolytic gene expression was normal in neurons, astrocytes and microglia but sub-normal in oligodendrocytes (101) . Overall, the impairment in brain energy metabolism in AD clearly seems to be specific to glucose, which opens the possibility of providing ketones as an alternative substrate to the brain to reduce or bypass the energetic deficit in AD caused by BGH.…”

Proteogenomics Reveals Orthologous Alternatively Spliced Proteoforms in the Same Human and Mouse Brain Regions with Differential Abundance in an Alzheimer’s Disease Mouse Model

“…RNA-Seq and proteomics based on mass spectrometry are widely used technologies that provide molecular-level insights into neurodegenerative diseases such as AD [ 53 , 54 , 55 , 56 ]. However, few studies have used an orthology approach to understand the diversity of AS manifestations in the CC and OB in humans and mice.…”

“…PKM2 is generally more abundant in embryonic stem cells [ 88 ] and organs with low energy demands, while PKM1 is more abundant in skeletal muscle, heart, and brain tissues [ 89 ]. A recent study demonstrated that AD alters glycolytic gene expression, including PKM , on oligodendrocytes [ 53 ]. Martire and colleagues found PKM1 overexpression in AD transgenic TgCRND8 mice at three months of age [ 90 ].…”

“…Martire and colleagues found PKM1 overexpression in AD transgenic TgCRND8 mice at three months of age [ 90 ]. Furthermore, recent studies have implicated PKM proteins as promising biomarkers for AD in cerebrospinal fluid [ 53 , 91 , 92 , 93 ]. Our analysis identified proteotypic peptides of PKM1 of humans (UniProt: P14618-2) and mice (UniProt: P52480-2) in MS/MS data from healthy CC and OB.…”