ABSTRACT
Oligodendrocyte precursor cells (OPCs) comprise 5-8â¯% of the adult glial cell population and stand out as the most proliferative cell type in the central nervous system (CNS). OPCs are responsible for generating oligodendrocytes (OLs), the myelinating cells of the CNS. However, OPC functions decline as we age, resulting in impaired differentiation and inadequate remyelination. This review explores the cellular and molecular changes associated with OPC aging, and their impact on OPC differentiation and functionality. Furthermore, it examines the impact of OPC aging within the context of multiple sclerosis and Alzheimer's disease, both neurodegenerative conditions wherein aged OPCs exacerbate disease progression by impeding remyelination. Moreover, various pharmacological interventions targeting pathways related to senescence and differentiation are discussed as potential strategies to rejuvenate aged OPCs. Enhancing our understanding of OPC aging mechanisms holds promise for developing new therapies to improve remyelination and repair in age-related neurodegenerative disorders.
Subject(s)
Brain , Cell Differentiation , Cellular Senescence , Oligodendrocyte Precursor Cells , Humans , Oligodendrocyte Precursor Cells/metabolism , Oligodendrocyte Precursor Cells/physiology , Cellular Senescence/physiology , Animals , Brain/metabolism , Brain/pathology , Cell Differentiation/physiology , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Multiple Sclerosis/pathology , Multiple Sclerosis/metabolism , Aging/physiology , Aging/metabolism , Aging/pathology , Oligodendroglia/metabolism , Remyelination/physiologyABSTRACT
Microglia activity can drive excessive synaptic loss during the prodromal phase of Alzheimer's disease (AD) and is associated with lowered cyclic adenosine monophosphate (cAMP) due to cAMP phosphodiesterase 4B (PDE4B). This study aimed to investigate whether long-term inhibition of PDE4B by A33 (3 mg/kg/day) can prevent synapse loss and its associated cognitive decline in APPswe/PS1dE9 mice. This model is characterized by a chimeric mouse/human APP with the Swedish mutation and human PSEN1 lacking exon 9 (dE9), both under the control of the mouse prion protein promoter. The effects on cognitive function of prolonged A33 treatment from 20 days to 4 months of age, was assessed at 7-8 months. PDE4B inhibition significantly improved both the working and spatial memory of APPswe/PSdE9 mice after treatment ended. At the cellular level, in vitro inhibition of PDE4B induced microglial filopodia formation, suggesting that regulation of PDE4B activity can counteract microglia activation. Further research is needed to investigate if this could prevent microglia from adopting their 'disease-associated microglia (DAM)' phenotype in vivo. These findings support the possibility that PDE4B is a potential target in combating AD pathology and that early intervention using A33 may be a promising treatment strategy for AD.
Subject(s)
Alzheimer Disease , Cognition , Cyclic Nucleotide Phosphodiesterases, Type 4 , Disease Models, Animal , Mice, Transgenic , Microglia , Phosphodiesterase 4 Inhibitors , Animals , Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism , Mice , Alzheimer Disease/drug therapy , Alzheimer Disease/pathology , Cognition/drug effects , Phosphodiesterase 4 Inhibitors/pharmacology , Phosphodiesterase 4 Inhibitors/therapeutic use , Phosphodiesterase 4 Inhibitors/administration & dosage , Microglia/drug effects , Microglia/metabolism , Microglia/pathology , Presenilin-1/genetics , Presenilin-1/metabolism , Humans , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/metabolism , MaleABSTRACT
OBJECTIVES: Schizophrenia is a psychiatric disorder affecting 1% of the population. Accumulating evidence indicates that neuroinflammation is involved in the pathology of these disorders by altering neurodevelopmental processes and specifically affecting glutamatergic signalling and astrocytic functioning. The aim of this study was to curate interactive biological pathways involved in schizophrenia for the identification of novel pharmacological targets implementing pathway, gene ontology, and network analysis. METHODS: Neuroinflammatory pathways were created using PathVisio and published in WikiPathways. A transcriptomics dataset, originally created by Narla et al. was selected for data visualisation and analysis. Transcriptomics data was visualised within pathways and networks, extended with transcription factors, pathways, and drugs. Network hubs were determined based on degrees of connectivity. RESULTS: Glutamatergic, immune, and astrocytic signalling as well as extracellular matrix reorganisation were altered in schizophrenia while we did not find an effect on the complement system. Pharmacological agents that target the glutamate receptor subunits, inflammatory mediators, and metabolic enzymes were identified. CONCLUSIONS: New neuroinflammatory pathways incorporating the extracellular matrix, glutamatergic neurons, and astrocytes in the aetiology of schizophrenia were established. Transcriptomics based network analysis provided novel targets, including extra-synaptic glutamate receptors, glutamate transporters and extracellular matrix molecules that can be evaluated for therapeutic strategies.
