Hypoxia‐mediated alteration in cholesterol oxidation and raft dynamics regulates BDNF signalling and neurodegeneration in hippocampus

Abstract

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 β (Trkβ) 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 Trkβ from non‐raft to raft regions. Supplementation of vitamin E during hypoxic exposure on the other hand reduced cholesterol oxidation and increased translocation of Trkβ 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.

7-Ketocholesterol in disease and aging

“…Many neurodegenerative diseases have been linked to oxidative stress, including Amyotrophic lateral sclerosis (ALS) [78,139,140], Parkinson's (PD) [[141], [142], [143], [144]], Alzheimer's (AD) [79,140,145], Huntington's (HD) [146], vascular dementia [79], and multiple sclerosis (MS) [140,147,148]. 7KC has been shown to be highly cytotoxic to neuronal cells and is therefore suspected to be involved in the progression of some, if not all, of these neurological diseases [20,57,85,149]. Oxysterols, unlike cholesterol, can cross the blood brain barrier (BBB) and accumulate in brain tissue [150,151], ultimately causing neurodegeneration.…”

Cognitive Protective Mechanism of Crocin Pretreatment in Rat Submitted to Acute High‐Altitude Hypoxia Exposure

“…It was reported that the hippocampus was seriously damaged, and the number of pyramidal cells was decreased in rat under acute highaltitude hypoxia [29]. Moreover, exposure to hypoxia leads to chromatinic condensation and neurodegeneration in the hippocampus [30]. Our results showed that the neurons in the hippocampus of rats were disordered and deformed, and Nissl body was decreased significantly after 72 h rapidly of acute hypoxia exposure at high altitude.…”

Serum BDNF Levels Are Reduced in Patients with Disorders of Consciousness and Are Not Modified by Verticalization with Robot-Assisted Lower-Limb Training

“…p75NTR is expressed widely during synaptogenesis and subsequently downregulated in the adult brain. However, it is upregulated after brain injuries, including TBIs and cerebral hypoxia, and the resulting overexpression may cause neuronal death via different intracellular pathways in several conditions [29][30][31][32]. The reduction of serum BDNF levels in patients with UWS and those in an MCS may reflect a persistent impaired balance of interactions between BDNF and Trk and between proBDNF and p75NTR, as a consequence of brain injury.…”