Traumatic brain injury (TBI) is associated with mortality and morbidity worldwide. Accumulating pre-clinical and clinical data suggests TBI is the leading extrinsic cause of progressive neurodegeneration. Neurological deterioration after either a single moderate-severe TBI or repetitive mild TBI often resembles dementia in aged populations; however, no currently approved therapies adequately mitigate neurodegeneration. Inflammation correlates with neurodegenerative changes and cognitive dysfunction for years post-TBI, suggesting a potential association between immune activation and both age- and TBI-induced cognitive decline. Inflammaging, a chronic, low-grade sterile inflammation associated with natural aging, promotes cognitive decline. Cellular senescence and the subsequent development of a senescence associated secretory phenotype (SASP) promotes inflammaging and cognitive aging, although the functional association between senescent cells and neurodegeneration is poorly defined after TBI. In this mini-review, we provide an overview of the pre-clinical and clinical evidence linking cellular senescence with poor TBI outcomes. We also discuss the current knowledge and future potential for senotherapeutics, including senolytics and senomorphics, which kill and/or modulate senescent cells, as potential therapeutics after TBI.

In addition to being a steroid hormone, 17β-estradiol (E₂) is also a neurosteroid produced in neurons in various regions of the brain of many species, including humans. Neuron-derived E₂ (NDE₂) is synthesized from androgen precursors via the action of the biosynthetic enzyme aromatase, which is located at synapses and in presynaptic terminals in neurons in both the male and female brain. In this review, we discuss evidence supporting a key role for NDE₂ as a neuromodulator that regulates synaptic plasticity and memory. Evidence supporting an important neuromodulatory role of NDE₂ in the brain has come from studies using aromatase inhibitors, aromatase overexpression in neurons, global aromatase knockout mice, and the recent development of conditional forebrain neuron-specific knockout mice. Collectively, these studies demonstrate a key role of NDE₂ in the regulation of synapse and spine density, efficacy of excitatory synaptic transmission and long-term potentiation, and regulation of hippocampal-dependent recognition memory, spatial reference memory, and contextual fear memory. NDE₂ is suggested to achieve these effects through estrogen receptor-mediated regulation of rapid kinase signaling and CREB-BDNF signaling pathways, which regulate actin remodeling, as well as transcription, translation, and transport of synaptic proteins critical for synaptic plasticity and function.

Astrocytes and neurons in the male and female brains produce the neurosteroid brain-derived 17β-estradiol (BDE₂) from androgen precursors. In this review, we discuss evidence that suggest BDE₂ has a role in a number of neurological conditions, such as focal and global cerebral ischemia, traumatic brain injury, excitotoxicity, epilepsy, Alzheimer’s disease, and Parkinson’s disease. Much of what we have learned about BDE₂ in neurological disorders has come from use of aromatase inhibitors and global aromatase knockout mice. Recently, our group developed astrocyte- and neuron-specific aromatase knockout mice, which have helped to clarify the precise functions of astrocyte-derived 17β-estradiol (ADE₂) and neuron-derived 17β-estradiol (NDE₂) in the brain. The available evidence to date suggests a primarily beneficial role of BDE₂ in facilitating neuroprotection, synaptic and cognitive preservation, regulation of reactive astrocyte and microglia activation, and anti-inflammatory effects. Most of these beneficial effects appear to be due to ADE₂, which is induced in most neurological disorders, but there is also recent evidence that NDE₂ exerts similar beneficial effects. Furthermore, in certain situations, BDE₂ may also have deleterious effects, as recent evidence suggests its overproduction in epilepsy contributes to seizure induction. In this review, we examine the current state of this quickly developing topic, as well as possible future studies that may be required to provide continuing growth in the field.

Hemoglobin (Hb) is the oxygen transport protein in erythrocytes. In blood, Hb is a tetramer consisting of two Hb-alpha (Hb-α) chains and two Hb-beta (Hb-β) chains. A number of studies have also shown that Hb-α is also expressed in neurons in both the rodent and human brain. In the current study, we examined for age-related regulation of neuronal Hb-α and hypoxia in the hippocampus and cerebral cortex of intact male and female mice. In addition, to confirm the role and functions of neuronal Hb-α, we also utilized lentivirus CRISPR interference-based Hb-α knockdown (Hb-α CRISPRi KD) in the non-ischemic and ischemic mouse hippocampus and examined the effect on neuronal oxygenation, as well as induction of hypoxia-inducible factor-1α (HIF-1α) and its downstream pro-apoptotic factors, PUMA and NOXA, and on neuronal survival and neurodegeneration. The results of the study revealed an age-related decrease in neuronal Hb-α levels and correlated increase in hypoxia in the hippocampus and cortex of intact male and female mice. Sex differences were observed with males having higher neuronal Hb-α levels than females in all brain regions at all ages. In vivo Hb-α CRISPRi KD in the mouse hippocampus resulted in increased hypoxia and elevated levels of HIF-1α, PUMA and NOXA in the non-ischemic and ischemic mouse hippocampus, effects that were correlated with a significant decrease in neuronal survival and increased neurodegeneration. As a whole, these findings indicate that neuronal Hb-α decreases with age in mice and has an important role in regulating neuronal oxygenation and neuroprotection.

17β-estradiol (E2) is produced in the brain as a neurosteroid, in addition to being an endocrine signal in the periphery. The current animal models for studying brain-derived E₂ include global and conditional non-inducible knockout mouse models. The aim of this study was to develop a tamoxifen (TMX)-inducible astrocyte-specific aromatase knockout mouse line (GFAP-ARO-iKO mice) to specifically deplete the E₂ synthesis enzymes and aromatase in astrocytes after their development in adult mice. The characterization of the GFAP-ARO-iKO mice revealed a specific and robust depletion in the aromatase expressions of their astrocytes and a significant decrease in their hippocampal E₂ levels after a GCI. The GFAP-ARO-iKO animals were alive and fertile and had a normal general brain anatomy, with a normal astrocyte shape, intensity, and distribution. In the hippocampus, after a GCI, the GFAP-ARO-iKO animals showed a major deficiency in their reactive astrogliosis, a dramatically increased neuronal loss, and increased microglial activation. These findings indicate that astrocyte-derived E₂ (ADE₂) regulates the ischemic induction of reactive astrogliosis and microglial activation and is neuroprotective in the ischemic brain. The GFAP-ARO-iKO mouse models thus provide an important new model to help elucidate the roles and functions of ADE₂ in the brain.

Alzheimer’s disease (AD) is increasingly recognized as a neurodegenerative disorder characterized by central insulin resistance and cerebral hypometabolism. The steroid hormone, 17β-estradiol (E2), interacts closely with insulin signaling pathways and is locally synthesized in the brain by the enzyme aromatase. However, the spatial and temporal dynamics of brain aromatase during AD progression and its relationship to central insulin resistance remain poorly understood. Using the 5xFAD mouse model, we examined whole-brain, regional, and neuron/astrocyte-specific alterations in aromatase expression along disease progression. Whole-brain aromatase expression remained unchanged at 2 months of age but progressively declined at 5 and 9 months, inversely correlating with amyloid-β plaque burden. Regional analysis of the cortex, hippocampal CA1, and hypothalamus revealed progressive aromatase loss in all regions; notably, the hypothalamus exhibited a significant decline at the earliest disease stage examined, preceding comparable changes in the cortex and hippocampus, while an age-related decline cannot be fully excluded, as only a single-aged wild-type (WT) control was used. Cell-level analysis revealed a progressive reduction in neuronal aromatase expression, whereas astrocytic aromatase displayed a biphasic response, increasing during early disease stages before declining at later stages. In parallel, neuronal insulin-resistance signaling increased progressively with disease advancement and was negatively correlated with neuronal aromatase expression across all regions examined (r = −0.82 to −0.87). Collectively, these findings demonstrate progressive regional and neuron/astrocyte-specific alterations in brain aromatase during the progression of amyloid pathology, identifying early hypothalamic vulnerability as a feature of AD-associated altered insulin signaling.