HDL-bound S1P affects the subventricular niche and early neuropathological features of Alzheimer’s disease

Byung Jo Choi, Ju Yeon Hong, Min Hee Park, Kang Ho Park, Wan Hui Han, Hee Ji Yoon, Hye Yoon Jung, Kyung Yeol Kim, Sun Ae Lee, Eun Young Lim, Jung Woo Hur, Im-Sook Song, So Yeon Jeon, Min-Koo Choi, Christina Christoffersen, Hee-Jin Kim, Seung Hyun Kim, Edward H. Schuchman, Jae-sung Bae () and Hee Kyung Jin ()
Additional contact information
Byung Jo Choi: Kyungpook National University
Ju Yeon Hong: Kyungpook National University
Min Hee Park: Kyungpook National University
Kang Ho Park: Kyungpook National University
Wan Hui Han: Kyungpook National University
Hee Ji Yoon: Kyungpook National University
Hye Yoon Jung: Kyungpook National University
Kyung Yeol Kim: Kyungpook National University
Sun Ae Lee: Kyungpook National University
Eun Young Lim: Kyungpook National University
Jung Woo Hur: Kyungpook National University
Im-Sook Song: Kyungpook National University
So Yeon Jeon: Dankook University
Min-Koo Choi: Dankook University
Christina Christoffersen: Blegdamsvej 9
Hee-Jin Kim: Hanyang University
Seung Hyun Kim: Hanyang University
Edward H. Schuchman: Icahn School of Medicine at Mount Sinai
Jae-sung Bae: Kyungpook National University
Hee Kyung Jin: Kyungpook National University

Nature Communications, 2025, vol. 16, issue 1, 1-22

Abstract: Abstract Circulating blood factors are critical for homeostasis of the adult ventricular-subventricular (V-SVZ) and subgranular zones, which contain neural stem cells (NSCs) crucial for sustained neurogenesis. Circulating sphingosine-1-phosphate (S1P) bound to apolipoprotein M (ApoM), a principal component of high-density lipoproteins, is involved in various biological processes, but its role in neurogenic niches is poorly understood. Herein, using Apom-/- mice, we show that blood ApoM-S1P deficiency impairs the SVZ-NSC pool, neurogenesis, ependymal cell polarity, and cerebrospinal fluid flow, leading to olfactory dysfunction and ventricular enlargement, early neuropathological features of Alzheimer’s disease (AD). Enhancing the complex significantly rescues these defects by activating S1P1 receptor signaling in SVZ-NSCs. Consistently, blood ApoM-S1P levels are reduced in early AD patients and correlate with olfactory deficits and ventricular enlargement. Similar abnormalities are recapitulated in young APP/PS1 mice and reversed by restoring blood ApoM-S1P levels. Thus, these data reveal pathogenic mechanisms underlying early neuropathological features of AD and identify the blood ApoM-S1P complex as a potential diagnostic and therapeutic target.

Date: 2025
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DOI: 10.1038/s41467-025-60750-0

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