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NRF2 deficiency replicates transcriptomic changes in Alzheimer's patients and worsens APP and TAU pathology
Ana I Rojo1, Marta Pajares1, Patricia Rada2
1Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII. Instituto de Investigaciones Biomédicas "Alberto Sols" UAM-CSIC. Instituto de Investigación Sanitaria La Paz (IdiPaz), and Department of Biochemistry, Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain.
Abstract:
Failure to translate successful neuroprotective preclinical data to a clinical setting in Alzheimer's disease (AD) indicates that amyloidopathy and tauopathy alone provide an incomplete view of disease. We have tested here the relevance of additional homeostatic deviations that result from loss of activity of transcription factor NRF2, a crucial regulator of multiple stress responses whose activity declines with ageing. A transcriptomic analysis demonstrated that NRF2-KO mouse brains reproduce 7 and 10 of the most dysregulated pathways of human ageing and AD brains, respectively. Then, we generated a mouse that combines amyloidopathy and tauopathy with either wild type (AT-NRF2-WT) or NRF2-deficiency (AT-NRF2-KO). AT-NRF2-KO brains presented increased markers of oxidative stress and neuroinflammation as well as higher levels of insoluble phosphorylated-TAU and Aβ*56 compared to AT-NRF2-WT mice. Young adult AT-NRF2-KO mice exhibited deficits in spatial learning and memory and reduced long term potentiation in the perforant pathway. This study demonstrates the relevance of normal homeostatic responses that decline with ageing, such as NRF2 activity, in the protection against proteotoxic, inflammatory and oxidative stress and provide a new strategy to fight AD.
Insights
Declining nuclear factor erythroid 2-related factor 2 (NRF2) activity exacerbates Alzheimer's disease pathology. Restoring NRF2 function may offer a novel therapeutic strategy against neurodegeneration.
Area of Science:
- Neuroscience
- Molecular Biology
- Gerontology
Background:
- Alzheimer's disease (AD) treatments fail clinically, suggesting amyloid and tau pathology are insufficient explanations.
- Transcription factor NRF2, a key regulator of stress responses, declines with age, impacting homeostasis.
Purpose of the Study:
- To investigate the role of NRF2 in Alzheimer's disease pathogenesis.
- To determine if NRF2 deficiency exacerbates combined amyloid and tau pathology.
Main Methods:
- Transcriptomic analysis of NRF2-knockout (KO) mouse brains compared to human aging and AD brains.
- Generation of a mouse model combining amyloidopathy and tauopathy with either wild-type or NRF2-deficient backgrounds (AT-NRF2-WT and AT-NRF2-KO).
- Assessment of oxidative stress, neuroinflammation, protein aggregation (phosphorylated-TAU, Aβ*56), and cognitive function (spatial learning, memory, long-term potentiation).
Main Results:
- NRF2-KO mouse brains mirrored key dysregulated pathways in human aging and AD.
- AT-NRF2-KO mice showed increased oxidative stress, neuroinflammation, and insoluble TAU and Aβ*56 levels compared to AT-NRF2-WT mice.
- Young AT-NRF2-KO mice exhibited cognitive deficits and impaired synaptic plasticity.
Conclusions:
- Age-related decline in NRF2 activity compromises protection against proteotoxic, inflammatory, and oxidative stress in AD.
- NRF2 plays a critical role in mitigating AD pathology.
- NRF2 modulation presents a promising therapeutic avenue for Alzheimer's disease.
