Mitochondrial Dysfunction and Neuroprotective Strategies in Alzheimer's Disease

Alzheimer’s disease is underpinned by progressive neuronal loss driven, in part, by failures in mitochondrial bioenergetics and quality control. Neuronal mitochondria normally generate adenosine triphosphate (ATP) through a tightly regulated electron transport chain while limiting the formation of reactive oxygen species (ROS). In Alzheimer’s pathogenesis, amyloid-β and tau assemblies localise to mitochondrial membranes, impairing respiratory chain complexes, triggering oxidative damage, dysregulating calcium homeostasis and activating apoptotic pathways. Early declines in mitochondrial membrane potential and ATP production compromise synaptic function and plasticity, exacerbating cognitive deficits. Strategies that restore mitochondrial integrity, bolster antioxidant defences, or modulate mitochondrial biogenesis have therefore emerged as promising therapeutic avenues. Approaches range from small-molecule antioxidants and metabolic cofactors to peptides derived from dietary proteins and engineered hybrids targeting multiple pathogenic mechanisms. In parallel, enhancement of innate clearance pathways in microglia and promotion of neuronal resilience via neurotrophic support represent complementary neuroprotective strategies. Together, these interventions aim to preserve synaptic connectivity, reduce neuroinflammation and delay disease progression. The global burden of Alzheimer’s, against an ageing population, underscores the urgency of translating mitochondrial-targeted discoveries into safe, scalable treatments.

Research from Nature Portfolio

Recent studies have shown that a novel pentapeptide derived from rice bran proteins markedly improves cognitive performance in dietary-stressed murine models. Oral administration of this peptide, termed rice-memolin, enhanced hippocampal neurogenesis, upregulated growth factors and engaged the cholinergic system to restore memory function. Mechanistic work linked its effects to modulation of neurotropic signalling and glucose metabolism, offering an innovative route to support mitochondrial health and synaptic plasticity in early Alzheimer’s pathology.

Mitochondrial Dysfunction and Neuroprotective Strategies in Alzheimer's Disease publication trend

The graph below shows the total number of articles in mitochondrial dysfunction and neuroprotective strategies in alzheimer's disease across all publications each year (not limited to Nature Index journals).

Technical terms

Electron transport chain (ETC): Series of protein complexes in the inner mitochondrial membrane responsible for ATP generation via oxidative phosphorylation.

Reactive oxygen species (ROS): Highly reactive molecules formed as by-products of mitochondrial respiration that can damage lipids, proteins and DNA.

Microglia: Resident immune cells of the central nervous system that clear debris and protein aggregates but may become dysregulated in Alzheimer’s disease.

Neurogenesis: Formation of new neurons from neural stem cells, occurring primarily in the hippocampus and essential for learning and memory.

Mitochondrial membrane potential: Electrochemical gradient across the inner mitochondrial membrane that drives ATP synthesis; its loss signals dysfunction.

References

1. Rice-memolin, a novel peptide derived from rice bran, improves cognitive function after oral administration in mice. Scientific Reports (2023).
2. Effects of α-Lipoic Acid on Phagocytosis of Oligomeric Beta-Amyloid1–42 in BV-2 Mouse Microglial Cells. Frontiers in Aging Neuroscience (2022).
3. Redox Active α-Lipoic Acid Differentially Improves Mitochondrial Dysfunction in a Cellular Model of Alzheimer and Its Control Cells. International Journal of Molecular Sciences (2022).
4. Hesperetin Nanocrystals Improve Mitochondrial Function in a Cell Model of Early Alzheimer Disease. Antioxidants (2021).