REVIEW: RAGE-Mediated Effects of Formaldehyde in Alzheimer’s Disease

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Ilya G. Mikhailov^1,2,a*, Milana S. Mikhailova¹, Anton N. Shuvaev¹, Yana V. Gorina¹, Olga S. Belozor¹

¹Voino-Yasenetsky Krasnoyarsk State Medical University, 660022 Krasnoyarsk, Russia

²Siberian Federal University, 660041 Krasnoyarsk, Russia

^* To whom correspondence should be addressed.

Received: December 18, 2024; Revised: February 24, 2025; Accepted: February 28, 2025

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Alzheimer’s disease (AD) remains an incurable pathology with a huge socio-economic impact. One of the known mechanisms of AD pathogenesis is deposition of amyloid plaques as a result of beta-amyloid (Aβ) accumulation. The receptor for glycation end products (RAGE) plays an important role in the Aβ transport across the blood-brain barrier. Ligand interaction with RAGE regulates the expression of the amyloid precursor protein (APP), which plays a key role in the Aβ accumulation. In this review, we discuss the biochemical mechanisms underlying the toxic effects of exogenous formaldehyde in the hippocampus leading to the insulin resistance development, as well as molecular mechanisms of neuroinflammation contributing to the upregulation of RAGE expression. Accumulation of endogenous formaldehyde in the body can be a result of impaired metabolism. However, accumulation of exogenous formaldehyde has much more acute and dangerous consequences. Formaldehyde is one of the most important toxins; its maximum permissible concentration (MPC) is exceeded in many cities of Russia, as well as in the countries of East, South, and Southeast Asia, Central Africa, and North and South Americas. Formaldehyde plays an important role in the pathogenesis of neurodegenerative diseases, as its mechanism of action is closely linked to the increased Aβ accumulation. In people more susceptible to Aβ accumulation (due to age or genetic predisposition), exposure to exogenous formaldehyde may contribute to this process. The role of formaldehyde in neurodegenerative diseases has been already investigated. It was found that the level of air pollution correlates with the incidence of hyperglycemia, but the detailed mechanism of the following development of neurodegeneration remains unclear. This review highlights the importance of studying the relationship between environmental toxins and neurodegenerative diseases, which may lead to the development of therapeutic approaches for the protection of neurons from the effects of toxic substances in individuals susceptible to neurodegenerative diseases.

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KEY WORDS: Alzheimer’s disease, formaldehyde, receptor for advanced glycation end products (RAGE), amyloid precursor protein (APP), insulin resistance

DOI: 10.1134/S0006297924604593

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