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

Circulating blood factors have an important impact on the homeostasis of the adult ventricular-subventricular (V-SVZ) and subgranular zones (SGZ), which contains neural stem cells (NSCs) crucial for sustained neurogenesis. Circulating sphingosine-1-phosphate (S1P) bound to apolipoprotein M (ApoM), a principal protein component of high-density lipoproteins (HDL), is an important circulating factor involved in various biological processes, but its specific role in neurogenic niches is poorly understood. Herein, we show that deficiency of the blood ApoM-S1P complex results in impairment of 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). Moreover, enhancement of the complex significantly improved these defects by activating S1P1 receptor signaling in NSCs of the V-SVZ. Thus, these data reveal new insights into the pathogenic mechanisms associated with early neuropathological features of AD and suggest the potential of using the blood ApoM-S1P complex as a diagnostic and therapeutic target for early AD. Overall design: To investigate the mechanism of ApoM-S1P-S1PR1 signaling in SVZ-NSCs, we treated SVZ-NSCs from both control mice and S1PR1-deficient mice with ApoM-HDL or ApoM+HDL