Genetic reduction of Nrf2 exacerbates cognitive deficits in a mouse model of Alzheimer’s disease

Abstract

Aging is the major risk factor for several neurodegenerative diseases, including Alzheimer's disease (AD). However, the mechanisms by which aging contributes to neurodegeneration remain elusive. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a transcription factor that regulates expression of a vast number of genes by binding to the antioxidant response element. Nrf2 levels decrease as a function of age, and reduced Nrf2 levels have been reported in postmortem human brains and animal models of AD. Nevertheless, it is still unknown whether Nrf2 plays a role in the cognitive deficits associated with AD. To address this question, we used a genetic approach to remove the Nrf2 gene from APP/PS1 mice, a widely used animal model of AD. We found that the lack of Nrf2 significantly exacerbates cognitive deficits in APP/PS1, without altering gross motor function. Specifically, we found an exacerbation of deficits in spatial learning and memory, as well as in working and associative memory. Different brain regions control these behavioral tests, indicating that the lack of Nrf2 has a global effect on brain function. The changes in cognition were linked to an increase in Aβ and interferon-gamma (IFNγ) levels, and microgliosis. The changes in IFNγ levels are noteworthy as previously published evidence indicates that IFNγ can increase microglia activation and induce Aβ production. Our data suggest a clear link between Nrf2 and AD-mediated cognitive decline and further strengthen the connection between Nrf2 and AD.

Polydatin Prevents Lipopolysaccharide (LPS)-Induced Parkinson's Disease via Regulation of the AKT/GSK3β-Nrf2/NF-κB Signaling Axis

“…Nrf2 plays an integral role in microglia-mediated protection of neurons from inflammatory responses ( 47 , 48 ). Moreover, previous studies involving Nrf2-knockout mice have demonstrated that loss of Nrf2 can exacerbate neurodegenerative phenotypes ( 49 – 51 ). Additional studies have revealed that activation of Nrf2 downregulates neuroinflammatory responses in microglia ( 52 ).…”

Ameliorating mitochondrial dysfunction restores carbon ion-induced cognitive deficits via co-activation of NRF2 and PINK1 signaling pathway

“…Similar results of melatonin received the support of the glioma cells [87] and neural stem cells [88] . As we known, NRF2 as a regulator of oxidative stress also exerts neuroprotective roles in prevention of cognitive impairment [89] . Recently, the emerging role of NRF2 in mitochondrial function has been found, contributing to the overall mitochondrial homeostasis via affecting mitochondrial membrane potential and respiration, oxidative phosphorylation and the synthesis of ATP, mitochondrial biogenesis and mitochondrial integrity [24] , [25] , [90] .…”

NRF2 as a Therapeutic Target in Neurodegenerative Diseases

“…-More severe clinical course, increased glial activation and exacerbated spinal cord damage, increased proinflammatory cytokines, and axonal degeneration in response to EAE (Johnson et al, 2010;Larabee et al, 2016) AD -Enhanced Ab and tau pathology, increased glial activation, markers of oxidative stress and neurodegeneration, and exacerbated cognitive decline in transgenic mouse models (Branca et al, 2017;Rojo et al, 2017Rojo et al, , 2018) PD -Increased sensitivity to MPTP with enhanced dopaminergic cell loss and microglial activation (Chen et al, 2009;Rojo et al, 2010) -Increased vulnerability to 6-OH dopamine-induced cell loss (Jakel et al, 2007) -Increased inflammation, protein misfolding, and neuronal death in transgenic model of aSyn accumulation (Lastres-Becker et al, 2016) HD -Increased vulnerability to 3-NP and malonic acid-induced lesions in the striatum (Shih et al, 2005) Stroke -Increased infarct size, enhanced inflammatory response, and neurobehavioral deficits (Shih et al, 2005;Li et al, 2013) Note. NRF2 ¼ nuclear factor erythroid 2-related factor 2; MS ¼ multiple sclerosis; EAE ¼ experimental autoimmune encephalomyelitis; AD ¼ Alzheimer's disease; PD ¼ Parkinson's disease; MPTP ¼ 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine; HD ¼ Huntington's disease; 3-NP ¼ 3nitropropionic acid.…”