Abstract
The lack of effective disease-modifying therapeutics to tackle Alzheimer’s disease (AD) is unsettling considering the actual prevalence of this devastating neurodegenerative disorder worldwide. Intermittent hypoxic conditioning (IHC) is a powerful non-pharmacological procedure known to enhance brain resilience. In this context, the aim of the present study was to investigate the potential long-term protective impact of IHC against AD-related phenotype, putting a special focus on cognition and mitochondrial bioenergetics and dynamics. For this purpose, six-month-old male triple transgenic AD mice (3×Tg-AD) were submitted to an IHC protocol for two weeks and the behavioral assessment was performed at 8.5 months of age, while the sacrifice of mice occurred at nine months of age and their brains were removed for the remaining analyses. Interestingly, IHC was able to prevent anxiety-like behavior and memory and learning deficits and significantly reduced brain cortical levels of amyloid-β (Aβ) in 3×Tg-AD mice. Concerning brain energy metabolism, IHC caused a significant increase in brain cortical levels of glucose and a robust improvement of the mitochondrial bioenergetic profile in 3×Tg-AD mice, as mirrored by the significant increase in mitochondrial membrane potential (ΔΨm) and respiratory control ratio (RCR). Notably, the improvement of mitochondrial bioenergetics seems to result from an adaptative coordination of the distinct but intertwined aspects of the mitochondrial quality control axis. Particularly, our results indicate that IHC favors mitochondrial fusion and promotes mitochondrial biogenesis and transport and mitophagy in the brain cortex of 3×Tg-AD mice. Lastly, IHC also induced a marked reduction in synaptosomal-associated protein 25 kDa (SNAP-25) levels and a significant increase in both glutamate and GABA levels in the brain cortex of 3×Tg-AD mice, suggesting a remodeling of the synaptic microenvironment. Overall, these results demonstrate the effectiveness of the IHC paradigm in forestalling the AD-related phenotype in the 3×Tg-AD mouse model, offering new insights to AD therapy and forcing a rethink concerning the potential value of non-pharmacological interventions in clinical practice.
Highlights
With a worldwide population that is aging at a rapid pace, the prevalence of Alzheimer’s disease (AD) is reaching alarming proportions emerging as one of the major global epidemics of the21st century [1]
Ten weeks after the implementation of Intermittent hypoxic conditioning (IHC) protocol, the effect of this non-pharmacological strategy on AD-related behavioral and cognitive manifestations was assessed by performing the open-field and Morris water maze (MWM) tests
In the open-field test, the 3×Tg-AD mice exhibited an increased anxiety-like behavior when compared with the control wild-type (WT)
Summary
With a worldwide population that is aging at a rapid pace, the prevalence of AD is reaching alarming proportions emerging as one of the major global epidemics of the21st century [1]. AD is currently the most common type of dementia, affecting more than 44 million people worldwide [2,3,4], this number being projected to triplicate by 2050. Within this scenario, AD represents a major frontier in medical research, a major challenge for the pharmaceutical industry, and a burden for society. AD has been conceptualized as a continuum that begins with a long asymptomatic or preclinical phase that typically progresses to dementia [5]. The AD signature is defined by the presence of extracellular deposition of Aβ peptide in senile plaques and the intracellular accumulation of neurofibrillary tangles containing hyperphosphorylated tau protein [9]
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