Epigenetic Blockade of Hippocampal SOD2 Via DNMT3b-Mediated DNA Methylation: Implications in Mild Traumatic Brain Injury-Induced Persistent Oxidative Damage

Balasubramanian, Nagalakshmi; Sagarkar, Sneha; Choudhary, Amit; Kokare, Dadasaheb M.; Sakharkar, Amul J.

doi:10.1007/s12035-020-02166-z

Cited by 17 publications

(16 citation statements)

References 97 publications

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“…Total RNA was extracted from cortical tissues of WT, htau +/- and htau -/- mice brains using TRIzol reagent (Ambion, Life Technologies, USA) as described previously [26]. The DNA contaminants from the extracted RNA were eliminated using a DNA-free™ DNA Removal Kit (Life Technologies, USA).…”

Section: Methodsmentioning

confidence: 99%

Behavioral dysregulation and monoaminergic deficits precede memory impairments in human tau-overexpressing (htau) mice

Khan

Selvakumar

Balasubramanian

et al. 2022

Preprint

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Alzheimer’s disease (AD) poses an ever-increasing public health concern as the population ages, affecting more than 6 million Americans. AD patients present with mood and sleep changes in the prodromal stages that may be partly driven by loss of monoaminergic neurons in brainstem, but a causal relationship has not been firmly established. The goal of the present study was to evaluate depressive and anxiety-like behaviors in a mouse model of human tauopathy (htau mice) at 4 and 6 months of age prior to the onset of cognitive impairments and correlate these behavior changes with tau pathology, neuroinflammation, and monoaminergic dysregulation in the DRN and LC. We observed depressive-like behaviors at 4 months of age in male and female htau mice and hyperlocomotion in male htau mice. At 6 months, male htau mice developed anxiety-like behavior in the EZM, whereas hyperlocomotion had resolved by this time point. Depressive-like behaviors in the social interaction test persisted at 6 months but were resolved in the sucrose preference test. There was also a significant reduction in number and density of 5-HT-immunoreactive neurons in the rostral DRN in htau mice at 4 months and 5-HT neuronal density was negatively correlated with the intensity of phosphorylated tau staining in this subregion. Additionally, we found evidence of microglial activation in the mid and caudal DRN and astrocytic activation in the rostral DRN. 5-HT neuronal activity was reduced in the DRN and accompanied by downregulation of Tph2 and Sert, whereas genes that promote neuroinflammation and tau phosphorylation were upregulated. Finally, there was enhanced ptau202/205 staining and microglial activity in the LC of htau mice and reduced TH optical density, although the number and density of TH+ neurons were not altered. In total, these results suggest that tau pathology in the DRN and the resulting loss of serotonergic neurotransmission may drive depressive-like behaviors in the early stages of AD, whereas anxiety-like behaviors develop later and may result from neurodegeneration in other regions.

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Section: Methodsmentioning

confidence: 99%

Behavioral dysregulation and monoaminergic deficits precede memory impairments in human tau-overexpressing (htau) mice

Khan

Selvakumar

Balasubramanian

et al. 2022

Preprint

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“…The brains were extracted and the olfactory bulb (OB), orbitofrontal cortex (OFC), nucleus accumbens (NAc), amygdala (AMY), thalamus (TH), hypothalamus (HT), hippocampus (HP), dorsal raphe nucleus (DRN), locus coeruleus (LC), and nucleus of the solitary tract (NTS) were dissected. Total RNA from the above-mentioned brain regions was isolated using TRIzol reagent (Ambion, USA) followed by DNA-free™ DNA Removal Kit (Life Technologies, USA) as described previously (Balasubramanian et al, 2021). RNA was then quantified using NanoDrop 1000 Spectrophotometer (Thermo Scientific, USA).…”

Section: Methodsmentioning

confidence: 99%

Repeated ethanol exposure and withdrawal alters ACE2 expression in discrete brain regions: Implications for SARS-CoV-2 infection

Balasubramanian

James

Pushpavathi

et al. 2022

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Emerging evidence suggests that people with alcohol use disorders are at higher risk for SARS-CoV-2. SARS-CoV-2 engages angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) receptors for cellular entry. While ACE2 and TMPRSS2 genes are upregulated in the cortex of alcohol-dependent individuals, information on expression in specific brain regions and neural populations implicated in SARS-CoV-2 neuroinvasion, particularly monoaminergic neurons, is limited. We sought to clarify how chronic alcohol exposure affects ACE2 and TMPRSS2 expression in monoaminergic brainstem circuits and other putative SARS-CoV-2 entry points. C57BL/6J mice were exposed to chronic intermittent ethanol (CIE) vapor for 4 weeks and brains were examined using immunofluorescence. We observed increased ACE2 levels in the olfactory bulb and hypothalamus following CIE, which are known to mediate SARS-CoV-2 neuroinvasion. Total ACE2 immunoreactivity was also elevated in the raphe magnus (RMG), raphe obscurus (ROB), and locus coeruleus (LC), while in the dorsal raphe nucleus (DRN), ROB, and LC we observed increased colocalization of ACE2 with monoaminergic neurons. ACE2 also increased in the periaqueductal gray (PAG) and decreased in the amygdala. Whereas ACE2 was detected in most brain regions, TMPRSS2 was only detected in the olfactory bulb and DRN but was not significantly altered after CIE. Our results suggest that previous alcohol exposure may increase the risk of SARS-CoV-2 neuroinvasion and render brain circuits involved in cardiovascular and respiratory function as well as emotional processing more vulnerable to infection, making adverse outcomes more likely. Additional studies are needed to define a direct link between alcohol use and COVID-19 infection.

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“…Four weeks post injection, the mice were decapitated under isoflurane anesthesia and the brains were extracted and immediately flash frozen on dry ice. Micro-punches of the DRN were taken, and total RNA was isolated using TRIzol reagent (Ambion Life Technologies) as described previously [4]. DNA contamination was removed from the RNA using DNA-free DNA removal Kit (Life Technologies).…”

Section: Reverse Transcriptase Quantitative Pcr (Rt-qpcr)mentioning

confidence: 99%

Tau pathology in the dorsal raphe may be a prodromal indicator of Alzheimer’s disease

Pierson

Fiock

Wang

et al. 2022

Preprint

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Protein aggregation in brainstem nuclei is thought to occur in the early stages of Alzheimer's disease (AD), but its specific role in driving prodromal symptoms and disease progression is largely unknown. The dorsal raphe nucleus (DRN) contains a large population of serotonin (5-hydroxytryptamine; 5-HT) neurons that regulate mood, reward-related behavior, and sleep, all of which are disrupted in AD. We report here that tau pathology is present in the DRN of cognitively intact individuals 54-80 years of age, whereas synuclein and TDP-43 are relatively absent. Almost all AD cases had tau pathology in the DRN, whereas only a subset contained TDP-43 or synuclein, but not both. Mice overexpressing human P301L-tau in the DRN also exhibited depressive-like behaviors and hyperactivity without any deficits in spatial memory. There was a negative correlation between the density of Tph2-expressing neurons and phospho-tau (ptau) optical density in P301L-tauDRNmice, although mean Tph2 expression did not differ significantly from the controls. 5-HT neurons were hyperexcitable in P301L-tauDRNmice, and there was an increase in the amplitude of excitatory post-synaptic currents (EPSCs) which is suggestive of increased glutamatergic transmission. Astrocytic density was also elevated in the DRN and accompanied by an increase in GFAP expression, as well as changes inHtr2a, Htr2c,andHtr3agene expression. Additionally, tau pathology was detected in axonal processes in the thalamus, hypothalamus, amygdala, and caudate putamen, suggesting that tau may spread in an anterograde manner to regions outside the DRN. Together, these results suggest that tau pathology accumulates in the DRN in a subset of individuals over 50 years and may lead to prodromal AD symptoms, 5-HT neuronal dysfunction, and activation of local astrocytes. The presence of tau pathology in the DRN combined with psychiatric assessments for depression may be a useful screening tool for individuals at risk for AD.

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Epigenetic Blockade of Hippocampal SOD2 Via DNMT3b-Mediated DNA Methylation: Implications in Mild Traumatic Brain Injury-Induced Persistent Oxidative Damage

Cited by 17 publications

References 97 publications

Behavioral dysregulation and monoaminergic deficits precede memory impairments in human tau-overexpressing (htau) mice

Behavioral dysregulation and monoaminergic deficits precede memory impairments in human tau-overexpressing (htau) mice

Repeated ethanol exposure and withdrawal alters ACE2 expression in discrete brain regions: Implications for SARS-CoV-2 infection

Tau pathology in the dorsal raphe may be a prodromal indicator of Alzheimer’s disease

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