Hypoxic Preconditioning Averts Sporadic Alzheimer's Disease-Like Phenotype in Rats: A Focus on Mitochondria.
Sónia C CorreiaMarco G AlvesPedro Fontes OliveiraGemma CasadesusJoseph LaMannaGeorge PerryPaula I MoreiraPublished in: Antioxidants & redox signaling (2022)
<b><i>Aims:</i></b> Brief episodes of sublethal hypoxia reprogram brain response to face possible subsequent lethal stimuli by triggering adaptive and prosurvival events-a phenomenon denominated hypoxic preconditioning (HP). To date, the potential therapeutic implications of HP to forestall sporadic Alzheimer's disease (sAD) pathology remain unexplored. Using a well-established protocol of HP and focusing on hippocampus as a first brain region affected in AD, this study was undertaken to investigate the potential protective effects of HP in a sAD rat model induced by the intracerebroventricular (icv) administration of streptozotocin (STZ) and to uncover the mitochondrial adaptations underlying this nonpharmacological strategy. <b><i>Results:</i></b> HP prevented the memory and learning deficits as well as tau pathology in the icvSTZ rat model. HP also attenuated icvSTZ-related reactive astrogliosis, as noted by increased glial fibrillary acidic protein immunoreactivity and myo-inositol levels. Notably, HP abrogated the icvSTZ-related impaired energy metabolism and oxidative damage. Particularly, HP averted increased lactate, glutamate, and succinate levels, and decreased mitochondrial respiratory chain function and mitochondrial DNA content. Concerning mitochondrial adaptations underlying HP-triggered tolerance to icvSTZ, preconditioned hippocampal mitochondria displayed an enhanced complex II-energized mitochondrial respiration, which resulted from a coordinated interaction between mitochondrial biogenesis and fusion-fission. Mitochondrial biogenesis was stimulated immediately after HP, whereas in a latter phase mitochondrial fusion-fission events are modulated favoring the generation of elongated mitochondria. <b><i>Innovation and Conclusion:</i></b> Overall, these results demonstrate for the first time that HP prevents the sAD-like phenotype, in part, by targeting mitochondria emerging as a preventive strategy in the context of AD. <i>Antioxid. Redox Signal</i>. 37, 739-757.
Keyphrases
- oxidative stress
- mitochondrial dna
- cell death
- randomized controlled trial
- ischemia reperfusion injury
- spinal cord injury
- diabetic rats
- reactive oxygen species
- traumatic brain injury
- cognitive decline
- multiple sclerosis
- endothelial cells
- type diabetes
- metabolic syndrome
- gene expression
- late onset
- endoplasmic reticulum
- high intensity
- insulin resistance
- spinal cord
- genome wide
- neuropathic pain
- mild cognitive impairment
- skeletal muscle
- early onset