ApoE4 undermines phrenic motor plasticity elicited by acute intermittent hypoxia with or without hypercapnia during the active phase

Abstract

Acute intermittent hypoxia (AIH) elicits respiratory motor plasticity and is emerging as a promising strategy to improve breathing and other (non-respiratory) movements in clinical disorders that end life due to respiratory insufficiency ( e.g., spinal cord injury & ALS). AIH-induced phrenic long-term facilitation (pLTF) is the most commonly studied form of respiratory motor plasticity and presents as a persistent increase in phrenic nerve activity after AIH. Specific factors ( e.g. aging, inflammation, hypoxia severity/duration) undermine AIH-induced pLTF; however, little information is available concerning the role of specific genes that regulate AIH-induced phrenic motor plasticity. Apolipoproteins (ApoE) are highly expressed in the central nervous system and function as lipid carriers. The ApoE gene is tri-allelic ( E2, E3 and E4); ApoE2 and E3 proteins are associated with neuroprotective and neuro-neutral phenotypes, respectively. ApoE4 impairs cortical and synaptic plasticity and is implicated in neurodegeneration, particularly Alzheimer’s Disease. Indeed, humans heterozygous for ApoE4 ( e.g., ApoE3/4) have reduced plasticity in diaphragm motor-evoked potentials versus non- ApoE4 carriers using an optimized protocol combining AIH with hypercapnia (AIHH; 15, 1 min O2=9.5%, CO2=5% episodes). To demonstrate causality, we tested the hypothesis that ApoE4 undermines AIH-induced pLTF vs ApoE3 in knock-in rats. Anesthetized, vagotomized, paralyzed and ventilated adult (3-4 months) male Sprague-Dawley rats with knock-in humanized (h) ApoE3 and (h) ApoE4 were presented with AIH (15,1 min hypoxic episodes; O2=9%; arterial PO2 = 40-50mmHg) or AIHH (inspired CO2=4%; arterial PCO2=50-55 mmHg). During the mid-active phase, AIH-induced pLTF was significantly greater in h ApoE3 (33±11%) vs h ApoE4 rats (-22±7%; p<0.001; both n=5). AIHH enhanced pLTF in h ApoE3 rats (60±11%; n=4) vs AIH, alone (p=0.046), but not h ApoE4 rats (-3±7%; n=3; p=0.970). These experiments demonstrate a causal relationship whereby ApoE4 undermines both AIH- and AIHH-induced pLTF during the active phase in rats. Since AIH has emerged as a promising neurotherapeutic to preserve/restore breathing in clinical disorders such as spinal cord injury and neuromuscular disease, understanding how genetic factors impact phrenic motor plasticity will help identify individuals most/least likely to respond to treatment. Such biomarkers are essential for success/failure in the translation of AIH/AIHH as a therapeutic modality. NIH (HL148030, HL149800 & T32HL134621), Craig H. Neilsen Foundation (JW) and UF Brain and Spinal Cord Injury Trust Fund (BSCIRTF). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.