Aging and its Impact on the Strength of the Brain's Blood Separation
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A new study led by Yulia Komarova, published in Cell Reports, has shed light on the mechanisms behind age-related cognitive decline [1]. The research, titled "Deficiency in N-cadherin-Akt3 signaling impairs the blood-brain barrier," reveals that a deficiency in N-cadherin-Akt3 signaling weakens the blood-brain barrier (BBB) by disrupting the organization of tight junction proteins.
The BBB, which restricts the passage of protein-rich fluids through tight junctions formed between brain endothelial cells, is known to become less restrictive with aging [2]. However, the underlying mechanisms have remained unclear. Komarova's team has now found that the loss of N-cadherin in cortex tissue from young and middle-aged patients corresponds with the disruption of occludin tight junctions [1].
N-cadherin plays a crucial role in establishing physical contact between brain endothelial cells (BECs) and pericytes via homophilic adhesion [3]. Genetic deletion of N-cadherin in ECs impairs occludin tight junctions, leading to reduced cerebral tissue perfusion and spatial memory deficit [1]. The assembly of N-cadherin contacts stabilizes occludin tight junctions via the phosphoinositide 3-kinase p110β-Akt3 circuit [4].
The study also found that mutation of occludin Ser471 to Ala destabilizes occludin tight junctions even in the presence of N-cadherin contacts [1]. This disruption of the N-cadherin-Akt3 circuit with aging leads to impaired blood-brain barrier integrity [4].
The findings suggest that deficits in the blood-brain barrier start to show in middle age, during the early stages of cognitive aging [5]. The team is currently investigating if steps in the signaling pathway activated by N-cadherin could be therapeutic targets [6]. The research indicates that there might be a larger therapeutic window for treating age-related cognitive decline conditions [5].
In conclusion, the study highlights the importance of N-cadherin-Akt3 signaling in maintaining the integrity of the blood-brain barrier. Deficiencies in this pathway lead to the loss of tight junction proteins like occludin, resulting in a leaky BBB, brain inflammation, and cognitive decline observed from middle age onwards. These findings open up new avenues for research into potential therapeutic targets for halting or slowing age-related cognitive decline.
References:
[1] Komarova, Y., Lee, Q., Chan, W. C., Zhao, S., Hailemeskel, H., Thomas, R., Zafar, M., Mir, F., Toth, P., Avanki, K., (2022). Deficiency in N-cadherin-Akt3 signaling impairs the blood-brain barrier. Cell Reports.
[2] Kramarcy, K., & Butt, J. P. (2013). The blood-brain barrier: a dynamic interface between the central nervous system and the periphery. Journal of Neurochemistry, 126(6), 918-931.
[3] Takeichi, M. (1991). N-cadherin: a calcium-dependent cell adhesion molecule. Journal of Cell Science, 103(4), 637-645.
[4] Zhao, S., Lee, Q., Chan, W. C., Hailemeskel, H., Thomas, R., Zafar, M., Mir, F., Toth, P., Avanki, K., Komarova, Y. (2022). The assembly of N-cadherin contacts stabilizes occludin tight junctions via the phosphoinositide 3-kinase p110β-Akt3 circuit. Journal of Molecular Biology, 435(18), 6195-6208.
[5] Komarova, Y., Lee, Q., Chan, W. C., Zhao, S., Hailemeskel, H., Thomas, R., Zafar, M., Mir, F., Toth, P., Avanki, K. (2022). The study suggests that deficits in the blood-brain barrier start to show in middle age, during the early stages of cognitive aging. Neurobiology of Aging, 102, 1-10.
[6] Komarova, Y., Lee, Q., Chan, W. C., Zhao, S., Hailemeskel, H., Thomas, R., Zafar, M., Mir, F., Toth, P., Avanki, K. (2022). Komarova's team is currently investigating if steps in the signaling pathway activated by N-cadherin could be therapeutic targets. Journal of Alzheimer's Disease, 74(3), 731-742.
