PMID- 30308090 OWN - NLM STAT- MEDLINE DCOM- 20191028 LR - 20201209 IS - 1471-4159 (Electronic) IS - 0022-3042 (Linking) VI - 148 IP - 2 DP - 2019 Jan TI - Hypoxia-mediated alteration in cholesterol oxidation and raft dynamics regulates BDNF signalling and neurodegeneration in hippocampus. PG - 238-251 LID - 10.1111/jnc.14609 [doi] AB - Brain-derived neurotrophic factor (BDNF) which is primarily associated with neuronal survivability, differentiation and synaptic plasticity has been reported to mediate neurodegeneration in hypoxia through its p75 Neurotrophin receptors (p75NTR). The molecular events promoting BDNF-mediated pro-death signalling in hypoxia, however, still remain an enigma. This study attempts towards deciphering the signalling cascades involved in alteration of BDNF isoforms and its cognate receptor subtypes leading to neurodegeneration in hypoxia. Adult Sprague-Dawley rats were exposed to global hypobaric hypoxia simulating an altitude of 7620 m at standard temperature and humidity. Chronic hypoxic exposure for 7 days resulted in higher expression of pro-BDNF and alteration in N-linked glycosylation in hippocampus along with increased expression of endoplasmic reticulum stress markers viz., glucose-regulated protein (Grp78), calnexin and changes in the endoplasmic reticulum morphology. Our findings reveal enriched expression of p75NTR in lipid rafts and higher expression of tyrosine receptor kinase beta (Trkbeta) in non-raft regions following hypoxic exposure. Further investigations on membrane properties revealed decline in membrane fluidity along with increased cholesterol oxidation resulting in reduced translocation of Trkbeta from non-raft to raft regions. Supplementation of vitamin E during hypoxic exposure on the other hand reduced cholesterol oxidation and increased translocation of Trkbeta from non-raft to raft regions and promoted neuronal survival. Hence, our findings suggest a novel mechanism of cholesterol oxidation-induced alteration in raft dynamics which is promotes p75 receptor-mediated death signalling in hippocampal neurons during chronic hypoxia. CI - (c) 2018 International Society for Neurochemistry. FAU - Sharma, Deepti AU - Sharma D AD - Defence Institute of High Altitude Research, Defence Research and Development Organisation, Leh-Ladakh, India. FAU - Barhwal, Kalpana Kumari AU - Barhwal KK AD - All India Institute of Medical Sciences, Sijua, Bhubaneswar, OR, India. FAU - Biswal, Surya Narayan AU - Biswal SN AD - Defence Institute of High Altitude Research, Defence Research and Development Organisation, Leh-Ladakh, India. FAU - Srivastava, Anup Kumar AU - Srivastava AK AD - Indian Institute of Nano Science & Technology, Mohali, CH, India. FAU - Bhardwaj, Pushpendar AU - Bhardwaj P AD - Defence Institute of High Altitude Research, Defence Research and Development Organisation, Leh-Ladakh, India. FAU - Kumar, Ashish AU - Kumar A AD - Defence Institute of High Altitude Research, Defence Research and Development Organisation, Leh-Ladakh, India. FAU - Chaurasia, Om Prakash AU - Chaurasia OP AD - Defence Institute of High Altitude Research, Defence Research and Development Organisation, Leh-Ladakh, India. FAU - Hota, Sunil Kumar AU - Hota SK AUID- ORCID: 0000-0002-5079-0181 AD - Defence Institute of High Altitude Research, Defence Research and Development Organisation, Leh-Ladakh, India. LA - eng GR - Defence Research & Development Organization, Ministry of Defence, Govt of India/International PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20181207 PL - England TA - J Neurochem JT - Journal of neurochemistry JID - 2985190R RN - 0 (Bdnf protein, rat) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Nerve Tissue Proteins) RN - 0 (Protein Isoforms) RN - 0 (Receptors, Growth Factor) RN - 0 (Receptors, Nerve Growth Factor) RN - 136958-07-1 (Ngfr protein, rat) RN - 97C5T2UQ7J (Cholesterol) SB - IM MH - Animals MH - Apoptosis/physiology MH - Brain-Derived Neurotrophic Factor/*metabolism MH - Cholesterol/*metabolism MH - Hippocampus/metabolism/*physiopathology MH - Hypoxia/*physiopathology MH - Male MH - Membrane Microdomains/metabolism/pathology MH - Nerve Degeneration/*physiopathology MH - Nerve Tissue Proteins MH - Neurons/metabolism/pathology MH - Oxidation-Reduction MH - Protein Isoforms/metabolism MH - Rats MH - Rats, Sprague-Dawley MH - Receptors, Growth Factor MH - Receptors, Nerve Growth Factor/metabolism MH - Signal Transduction/physiology OTO - NOTNLM OT - brain-derived neurotrophic factor OT - cholesterol OT - endoplasmic reticulum OT - hypoxia OT - lipid Raft OT - membrane fluidity EDAT- 2018/10/12 06:00 MHDA- 2019/10/29 06:00 CRDT- 2018/10/12 06:00 PHST- 2018/04/16 00:00 [received] PHST- 2018/09/08 00:00 [revised] PHST- 2018/10/08 00:00 [accepted] PHST- 2018/10/12 06:00 [pubmed] PHST- 2019/10/29 06:00 [medline] PHST- 2018/10/12 06:00 [entrez] AID - 10.1111/jnc.14609 [doi] PST - ppublish SO - J Neurochem. 2019 Jan;148(2):238-251. doi: 10.1111/jnc.14609. Epub 2018 Dec 7.