ABSTRACT
Failed regeneration of myelin around neuronal axons following central nervous system damage contributes to nerve dysfunction and clinical decline in various neurological conditions, for which there is an unmet therapeutic demand. Here, we show that interaction between glial cells - astrocytes and mature myelin-forming oligodendrocytes - is a determinant of remyelination. Using in vivo/ ex vivo/ in vitro rodent models, unbiased RNA sequencing, functional manipulation, and human brain lesion analyses, we discover that astrocytes support the survival of regenerating oligodendrocytes, via downregulation of the Nrf2 pathway associated with increased astrocytic cholesterol biosynthesis pathway activation. Remyelination fails following sustained astrocytic Nrf2 activation in focally-lesioned male mice yet is restored by either cholesterol biosynthesis/efflux stimulation, or Nrf2 inhibition using the existing therapeutic Luteolin. We identify that astrocyte-oligodendrocyte interaction regulates remyelination, and reveal a drug strategy for central nervous system regeneration centred on targeting this interaction.
Subject(s)
Astrocytes , NF-E2-Related Factor 2 , Male , Mice , Animals , Humans , Astrocytes/metabolism , NF-E2-Related Factor 2/genetics , NF-E2-Related Factor 2/metabolism , Central Nervous System/metabolism , Oligodendroglia/metabolism , Myelin Sheath/metabolism , Nerve Regeneration/physiology , Cholesterol/metabolismABSTRACT
Alzheimer's disease (AD) alters astrocytes, but the effect of Aß and Tau pathology is poorly understood. TRAP-seq translatome analysis of astrocytes in APP/PS1 ß-amyloidopathy and MAPTP301S tauopathy mice revealed that only Aß influenced expression of AD risk genes, but both pathologies precociously induced age-dependent changes, and had distinct but overlapping signatures found in human post-mortem AD astrocytes. Both Aß and Tau pathology induced an astrocyte signature involving repression of bioenergetic and translation machinery, and induction of inflammation pathways plus protein degradation/proteostasis genes, the latter enriched in targets of inflammatory mediator Spi1 and stress-activated cytoprotective Nrf2. Astrocyte-specific Nrf2 expression induced a reactive phenotype which recapitulated elements of this proteostasis signature, reduced Aß deposition and phospho-tau accumulation in their respective models, and rescued brain-wide transcriptional deregulation, cellular pathology, neurodegeneration and behavioural/cognitive deficits. Thus, Aß and Tau induce overlapping astrocyte profiles associated with both deleterious and adaptive-protective signals, the latter of which can slow patho-progression.
Subject(s)
Alzheimer Disease/genetics , Amyloid beta-Protein Precursor/genetics , Astrocytes/metabolism , Brain/metabolism , Neuroprotection/genetics , tau Proteins/genetics , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Amyloid beta-Protein Precursor/metabolism , Animals , Astrocytes/cytology , Brain/pathology , Disease Models, Animal , Female , Gene Expression Profiling , Gene Expression Regulation , Homozygote , Humans , Mice , Mice, Transgenic , NF-E2-Related Factor 2/genetics , NF-E2-Related Factor 2/metabolism , Phenotype , Phosphorylation , Proteostasis/genetics , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/metabolism , Signal Transduction , Trans-Activators/genetics , Trans-Activators/metabolism , tau Proteins/metabolismABSTRACT
Forebrain neurons have relatively weak intrinsic antioxidant defenses compared to astrocytes, in part due to hypo-expression of Nrf2, an oxidative stress-induced master regulator of antioxidant and detoxification genes. Nevertheless, neurons do possess the capacity to auto-regulate their antioxidant defenses in response to electrical activity. Activity-dependent Ca2+ signals control the expression of several antioxidant genes, boosting redox buffering capacity, thus meeting the elevated antioxidant requirements associated with metabolically expensive electrical activity. These genes include examples which are reported Nrf2 target genes and yet are induced in a Nrf2-independent manner. Here we discuss the implications for Nrf2 hypofunction in neurons and the mechanisms underlying the Nrf2-independent induction of antioxidant genes by electrical activity. A significant proportion of Nrf2 target genes, defined as those genes controlled by Nrf2 in astrocytes, are regulated by activity-dependent Ca2+ signals in human stem cell-derived neurons. We propose that neurons interpret Ca2+ signals in a similar way to other cell types sense redox imbalance, to broadly induce antioxidant and detoxification genes.
Subject(s)
Antioxidants/metabolism , Neurons/metabolism , Neurons/physiology , Animals , Calcium Signaling/genetics , Humans , NF-E2-Related Factor 2/genetics , Oxidation-Reduction , Signal Transduction/geneticsABSTRACT
Facial recognition is a fundamental feature of primate social interaction. However, the location and number of neurons that are solely dedicated to the recognition of faces and facial features are not well known. The following mini review describes a paper by Perrett and colleagues that identifies and describes a subpopulation of neurons in the superior temporal sulcus that appear to be strongly tuned to faces and facial features. This paper holds great value for undergraduate teaching, as it is a foundational paper within the literature of face recognition. It is an example of a publication that stands the test of time, promotes the birth of many new fields of research and displays easy to understand experimentation with profound results.
