Maintaining protein homeostasis, or proteostasis, is essential to cell function and survival, and is orchestrated by a complex network of cellular processes, regulating the synthesis, folding, trafficking, degradation and clearance of intracellular, extracellular and secreted proteins.

Proteostasis can, however, be significantly altered with age, resulting in an increased risk of developing degenerative diseases. Brain cells, especially neurons, are particularly sensitive to proteotoxic stresses, such as those triggered by proteostasis imbalances. This is the case in age-related neurodegenerative diseases such as Alzheimer’s.

Alzheimer’s disease – a neurodegenerative pathology leading to progressive impairment of cognitive functions (memory, language, reasoning) – is characterized by intracerebral accumulation of soluble β‑amyloid (Aβ) oligomers, followed by insoluble fibrils, progressive appearance of abnormally ubiquitinylated neurofibrillary tangles and chronic inflammation – a process attributable to a degradation/clearing defect involving the ubiquitin‑proteasome system. A key player in intracellular protein degradation, the proteasome plays a major role in maintaining proteostasis by selectively eliminating short‑lived, damaged or malformed proteins that have previously been ubiquitinylated – a post‑translational modification by ubiquitin enabling the proteasome to recognize and then destroy the proteins thus tagged. The systematic presence of ubiquitinylated, but undegraded, inclusions in fact reflects a reduction in proteasome activity due to (and contributing to) the presence of toxic Aβ oligomers – a dysfunction central to the etiology of the disease.

The involvement of the ubiquitin‑proteasome system in the pathophysiological process of Alzheimer’s disease opens up new therapeutic perspectives, both preventive and curative. In this respect, there is growing interest in potential synergistic approaches combining proteasome activators, immunoproteasome inhibitors (involved in inflammation), and modulators of β‑amyloid peptide aggregation.

Beyond conventional pharmacological approaches, non‑medicinal interventions combining a balanced diet, regular physical exercise and cognitive training have both preventive and therapeutic potential. In particular, the fact that a suitable diet – for example, of the traditional Mediterranean type – and specific nutritional supplements can counteract the pathophysiological mechanisms of the disease, offers the possibility of preventing, delaying or managing its progression.

Natural compounds such as oleuropein (an olive polyphenol – a key player in the Mediterranean diet) and betulinic acid (a birch bark triterpene – present in the traditional Nordic diet) are known to activate the proteasome and delay cellular aging. Aglycone oleuropein (deprived of glucose) also inhibits the aggregation of Aβ peptides into toxic oligomers. Similarly, betulinic acid reduces the formation of neurotoxic oligomers. Furthermore, the administration of epigallocatechin gallate (a polyphenol found in green tea) and ferulic acid (a plant phenolic compound) reduces certain manifestations of Alzheimer’s disease, such as spatial memory deficits, in an animal model, but this has yet to be confirmed in humans. These compounds are also thought to have beneficial effects on other aspects of the disease, such as Aβ oligomer synaptotoxicity and neuroinflammation.

These active compounds found in certain foods or nutritional supplements, along with other natural substances of interest, could eventually become essential ingredients in balanced diets for seniors.

Disclaimer: This information is provided for guidance only and is not a substitute for medical advice.

References: Simon PYR, Bus J, David R. Alzheimer’s disease, amyloid‑β peptides and ubiquitin‑proteasome system: therapeutic perspectives. Med Sci (Paris). 2023;39(8‑9):643‑649. Med Sci (Paris). 2023;39(8-9):643-649.
https://pubmed.ncbi.nlm.nih.gov/37695154/
Simon PYR, David R. Alzheimer’s disease, β-amyloid peptides, and ubiquitin-proteasome system: nutritherapeutic insights. Neurodegener Dis. 2025;25:76-87.
https://pubmed.ncbi.nlm.nih.gov/40132562/
Almeida MF, Farizatto KLG, Almeida RS, Bahr BA. Lifestyle strategies to promote proteostasis and reduce the risk of Alzheimer’s disease and other proteinopathies. Ageing Res Rev. 2024;93:102162.
https://pubmed.ncbi.nlm.nih.gov/38070831/