Interaction of oxidative stress and neurotrauma in ALDH2 mice causes significant and persistent behavioral and pro-inflammatory effects in a tractable model of mild traumatic brain injury

Knopp, Rachel C.; Lee, Sue; Hollas, Michael A.; Nepomuceno, Emily; González, D.; Tam, Kevin A.; Aamir, Daniyal; Pierce, Emily; BenAissa, Manel; Thatcher, Gregory R. J.

doi:10.1016/j.redox.2020.101486

Cited by 20 publications

(26 citation statements)

References 79 publications

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“…6a. Young adult rodents have an innate curiosity toward novelty, thus in this task, they show an increased preference for the novel/target arm [85,118]. However, as animals age, it is not well understood how this preference changes as a function of age and diet.…”

Section: Late-life Eod Fasting Enhances Musculoskeletal Systemsmentioning

confidence: 99%

Late-life intermittent fasting decreases aging-related frailty and increases renal hydrogen sulfide production in a sexually dimorphic manner

et al. 2021

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Global average life expectancy continues to rise. As aging increases the likelihood of frailty, which encompasses metabolic, musculoskeletal, and cognitive deficits, there is a need for effective anti-aging treatments. It is well established in model organisms that dietary restriction (DR), such as caloric restriction or protein restriction, enhances health and lifespan. However, DR is not widely implemented in the clinic due to patient compliance and its lack of mechanistic underpinnings. Thus, the present study tested the effects of a somewhat more clinically applicable and adoptable DR regimen, every-other-day (EOD) intermittent fasting, on frailty in 20-month-old male and female C57BL/6 mice. Frailty was determined by a series of metabolic, musculoskeletal, and cognitive tasks performed prior to and toward the end of the 2.5-month dietary intervention. Late-life EOD fasting attenuated overall energy intake, hypothalamic inflammatory gene expression, and frailty in males. However, it failed to reduce overall caloric intake and had a little positive effect in females. Given that the selected benefits of DR are dependent on augmented production of the gasotransmitter hydrogen sulfide (H2S) and that renal H2S production declines with age, we tested the effects of EOD fasting on renal H2S production capacity and its connection to frailty in males. EOD fasting boosted renal H2S production, which positively correlated with improvements in multiple components of frailty tasks. Therefore, late-life initiated EOD fasting is sufficient to reduce aging-related frailty, at least in males, and suggests that renal H2S production capacity may modulate the effects of late-life EOD fasting on frailty.

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Section: Late-life Eod Fasting Enhances Musculoskeletal Systemsmentioning

confidence: 99%

Late-life intermittent fasting decreases aging-related frailty and increases renal hydrogen sulfide production in a sexually dimorphic manner

et al. 2021

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“…LPS injection provides a well-characterized mouse model of acute systemic and central inflammation . We have observed that ALDH2 KO mice lacking expression of mitochondrial aldehyde dehydrogenase-2 (Aldh2) show an amplified response to LPS and other insults, providing a useful preclinical model for drug discovery . Aldh2 is a major enzymic contributor to detoxification of lipid peroxidation products (e.g., 4-hydroxynonenal), which are known to contribute to enhanced oxidative stress in aging and are elevated in T2D and in ADRD brains .…”

Section: Resultsmentioning

confidence: 99%

“…In ALDH2 KO mice fed HFD for 4 weeks, cotreatment with F4 led to reduction in levels of TNFα, COX2, and IL6 in the brain, reaching significance for TNFα and COX2 (Figure 6G). Since ALDH2 KO mice show significant cognitive deficits in the Novel Object Recognition task (NOR) from 4M−14M of age, 37 we tested 3M-old KO mice alongside WT littermates in NOR at three time points: before initiating HFD, after 1 week, and 2 weeks on HFD (Figure 6H). In some mouse strains, HFD causes cognitive impairment, 41 and we observed in NOR in ALDH2 KO mice fed HFD for 2 weeks, a significant deficit measured by the discrimination index (DI = time with novel object − time with familiar object ÷ total time).…”

Section: ■ Resultsmentioning

confidence: 99%

“…ALDH2 KO mice lack mitochondrial Aldh2, an enzyme that detoxifies lipid peroxidation products leading to oxidative stress and a mild cognitive deficit from 4 months of age. 37 In HFD-fed mice, lipid peroxidation products and protein adducts are elevated; furthermore, Aldh2 has been reported to protect mice from HFD-induced adverse effects. 57 We observed that pro-inflammatory markers in the brain of ALDH2 KO mice fed HFD were attenuated by administration of F4.…”

Section: ■ Discussionmentioning

confidence: 99%

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Discovery of Nonlipogenic ABCA1 Inducing Compounds with Potential in Alzheimer’s Disease and Type 2 Diabetes

Aissa

Lewandowski

Ratia

et al. 2021

ACS Pharmacol. Transl. Sci.

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Selective liver X receptor (LXR) agonists have been extensively pursued as therapeutics for Alzheimer's disease and related dementia (ADRD) and, for comorbidities such as type 2 diabetes (T2D) and cerebrovascular disease (CVD), disorders with underlying impaired insulin signaling, glucose metabolism, and cholesterol mobilization. The failure of the LXR-focused approach led us to pursue a novel strategy to discover nonlipogenic ATP-binding cassette transporter A1 (ABCA1) inducers (NLAIs): screening for ABCA1-luciferase activation in astrocytoma cells and counterscreening against lipogenic gene upregulation in hepatocarcinoma cells. Beneficial effects of LXRβ agonists mediated by ABCA1 include the following: control of cholesterol and phospholipid efflux to lipid-poor apolipoproteins forming beneficial peripheral HDL and HDL-like particles in the brain and attenuation of inflammation. While rare, ABCA1 variants reduce plasma HDL and correlate with an increased risk of ADRD and CVD. In secondary assays, NLAI hits enhanced cholesterol mobilization and positively impacted in vitro biomarkers associated with insulin signaling, inflammatory response, and biogenic properties. In vivo target engagement was demonstrated after oral administration of NLAIs in (i) mice fed a high-fat diet, a model for obesity-linked T2D, (ii) mice administered LPS, and (iii) mice with accelerated oxidative stress. The lack of adverse effects on lipogenesis and positive effects on multiple biomarkers associated with T2D and ADRD supports this novel phenotypic approach to NLAIs as a platform for T2D and ADRD drug discovery.

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“…Alternatively, the use of a ‘2-hit’ model could unmask more robust changes at a younger age in this particular model, as previous evidence has demonstrated the effectiveness of using a secondary insult in models of traumatic brain injury (TBI), Parkinson’s disease, and even schizophrenia to detect complex or less-sensitive processes [ 78–81 ]. In fact, a previous study using this animal model in combination with mild (TBI) recently reported significant increases in inflammatory cytokines, as well as sustained cognitive deficits, when compared to sham controls [ 82 ]. In this work, administration of anti-inflammatory agents post-TBI ameliorated both inflammatory and cognitive impairments of the Aldh2 –/– mice.…”

Section: Discussionmentioning

confidence: 99%

Neuronal Calcium Imaging, Excitability, and Plasticity Changes in the Aldh2–/– Mouse Model of Sporadic Alzheimer’s Disease

Ghoweri

Gagolewicz

Frazier

et al. 2020

JAD

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Background: Dysregulated signaling in neurons and astrocytes participates in pathophysiological alterations seen in the Alzheimer’s disease brain, including increases in amyloid-β, hyperphosphorylated tau, inflammation, calcium dysregulation, and oxidative stress. These are often noted prior to the development of behavioral, cognitive, and non-cognitive deficits. However, the extent to which these pathological changes function together or independently is unclear. Objective: Little is known about the temporal relationship between calcium dysregulation and oxidative stress, as some reports suggest that dysregulated calcium promotes increased formation of reactive oxygen species, while others support the opposite. Prior work has quantified several key outcome measures associated with oxidative stress in aldehyde dehydrogenase 2 knockout (Aldh2–/–) mice, a non-transgenic model of sporadic Alzheimer’s disease. Methods: Here, we tested the hypothesis that early oxidative stress can promote calcium dysregulation across aging by measuring calcium-dependent processes using electrophysiological and imaging methods and focusing on the afterhyperpolarization (AHP), synaptic activation, somatic calcium, and long-term potentiation in the Aldh2–/– mouse. Results: Our results show a significant age-related decrease in the AHP along with an increase in the slow AHP amplitude in Aldh2–/– animals. Measures of synaptic excitability were unaltered, although significant reductions in long-term potentiation maintenance were noted in the Aldh2–/– animals compared to wild-type. Conclusion: With so few changes in calcium and calcium-dependent processes in an animal model that shows significant increases in HNE adducts, Aβ, p-tau, and activated caspases across age, the current findings do not support a direct link between neuronal calcium dysregulation and uncontrolled oxidative stress.

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Interaction of oxidative stress and neurotrauma in ALDH2 mice causes significant and persistent behavioral and pro-inflammatory effects in a tractable model of mild traumatic brain injury

Cited by 20 publications

References 79 publications

Late-life intermittent fasting decreases aging-related frailty and increases renal hydrogen sulfide production in a sexually dimorphic manner

Late-life intermittent fasting decreases aging-related frailty and increases renal hydrogen sulfide production in a sexually dimorphic manner

Discovery of Nonlipogenic ABCA1 Inducing Compounds with Potential in Alzheimer’s Disease and Type 2 Diabetes

Neuronal Calcium Imaging, Excitability, and Plasticity Changes in the Aldh2–/– Mouse Model of Sporadic Alzheimer’s Disease

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