Nrf2 Pathway Modulation in Alzheimer's Disease Therapeutics

Alzheimer’s disease (AD) is marked by progressive cognitive decline driven in part by oxidative stress and chronic neuroinflammation. The transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) regulates a battery of antioxidant and cytoprotective genes via binding to the antioxidant response element (ARE). In healthy brain tissue, Nrf2 resides in the cytoplasm bound to its inhibitor Keap1 and translocates to the nucleus upon oxidative challenge. In AD, Nrf2 activity is diminished, compromising endogenous defences against amyloid‐β toxicity and inflammatory mediators. Therapeutic strategies that restore or enhance Nrf2 signalling hold promise for slowing neurodegeneration by attenuating oxidative damage, suppressing proinflammatory cascades and preserving synaptic function. A range of small-molecule activators, electrophilic phytochemicals and protein–protein interaction inhibitors are under investigation for their ability to disrupt Keap1–Nrf2 binding, inhibit Nrf2 repressors and promote redox homeostasis. Recent preclinical and early clinical studies have begun to reveal the translational potential of Nrf2 modulation as a disease‐modifying approach in AD.

Research from Nature Portfolio

Antroquinonol, a ubiquinone derivative isolated from a medicinal fungus, has been shown in a transgenic mouse model of AD to penetrate the blood–brain barrier and activate Nrf2 signalling in hippocampal neurons. Chronic oral administration led to an increase in nuclear Nrf2, upregulation of downstream antioxidant enzymes and a marked reduction in amyloid-β deposits and histone deacetylase-2 levels. Treated animals demonstrated improved spatial learning and memory alongside decreased astrogliosis, highlighting the capacity of brain-permeable Nrf2 activators to mitigate core pathological features of AD.

Nrf2 Pathway Modulation in Alzheimer's Disease Therapeutics publication trend

The graph below shows the total number of articles in nrf2 pathway modulation in alzheimer's disease therapeutics across all publications each year (not limited to Nature Index journals).

Technical terms

Nrf2: A transcription factor that binds the antioxidant response element to induce genes involved in detoxification and antioxidant defence.

Keap1: A cytoplasmic protein that binds Nrf2 under resting conditions, targeting it for degradation.

Antioxidant Response Element (ARE): A DNA regulatory sequence in the promoter regions of Nrf2 target genes.

Oxidative Stress: An imbalance between reactive oxygen species production and antioxidant defences, leading to cellular damage.

Astrocyte/Microglia: Glial cell types in the central nervous system that mediate support functions, immune responses and redox homeostasis.

References

1. Antroquinonol Lowers Brain Amyloid-β Levels and Improves Spatial Learning and Memory in a Transgenic Mouse Model of Alzheimer’s Disease. Scientific Reports (2015).
2. Dimethyl fumarate improves cognitive impairment and neuroinflammation in mice with Alzheimer’s disease. Journal of Neuroinflammation (2024).
3. Nrf2/Bach1 signaling axis: A promising multifaceted therapeutic strategy for Alzheimer's disease. Neurotherapeutics (2025).
4. Coniferaldehyde attenuates Alzheimer's pathology via activation of Nrf2 and its targets. Theranostics (2020).
5. Direct Keap1-Nrf2 disruption as a potential therapeutic target for Alzheimer’s disease. PLOS Genetics (2017).