Cerebral Mitochondrial Function and Cognitive Performance during Aging: A Longitudinal Study in NMRI Mice

Abstract

Brain aging is one of the major risk factors for the development of several neurodegenerative diseases. Therefore, mitochondrial dysfunction plays an important role in processes of both, brain aging and neurodegeneration. Aged mice including NMRI mice are established model organisms to study physiological and molecular mechanisms of brain aging. However, longitudinal data evaluated in one cohort are rare but are important to understand the aging process of the brain throughout life, especially since pathological changes early in life might pave the way to neurodegeneration in advanced age. To assess the longitudinal course of brain aging, we used a cohort of female NMRI mice and measured brain mitochondrial function, cognitive performance, and molecular markers every 6 months until mice reached the age of 24 months. Furthermore, we measured citrate synthase activity and respiration of isolated brain mitochondria. Mice at the age of three months served as young controls. At six months of age, mitochondria-related genes (complex IV, creb-1, β-AMPK, and Tfam) were significantly elevated. Brain ATP levels were significantly reduced at an age of 18 months while mitochondria respiration was already reduced in middle-aged mice which is in accordance with the monitored impairments in cognitive tests. mRNA expression of genes involved in mitochondrial biogenesis (cAMP response element-binding protein 1 (creb-1), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1-α), nuclear respiratory factor-1 (Nrf-1), mitochondrial transcription factor A (Tfam), growth-associated protein 43 (GAP43), and synaptophysin 1 (SYP1)) and the antioxidative defense system (catalase (Cat) and superoxide dismutase 2 (SOD2)) was measured and showed significantly decreased expression patterns in the brain starting at an age of 18 months. BDNF expression reached, a maximum after 6 months. On the basis of longitudinal data, our results demonstrate a close connection between the age-related decline of cognitive performance, energy metabolism, and mitochondrial biogenesis during the physiological brain aging process.

Heat shock protein 22 modulates NRF1/TFAM-dependent mitochondrial biogenesis and DRP1-sparked mitochondrial apoptosis through AMPK-PGC1α signaling pathway to alleviate the early brain injury of subarachnoid hemorrhage in rats

“…Presently, we observed that exogenous hsp22 obviously augmented the AMPK phosphorylation at Thr172, whereas dorsomorphin evidently counteracted hsp22-mediated protection against EBI after SAH by worsening neurological impairment and brain edema, aggravating mitochondrial fission and the outbreak of oxidative stress, and suppressing mitochondrial biogenesis and apoptotic cascades. More fundamentally, it is well established that activating AMPK by phosphorylation at Thr172 site upregulates PGC1α in skeletal muscle [ 55 ] and cardiovascular system [ 56 ], as well as brain [ 57 ]. Accordingly, it's logical to conjecture that hsp22 may alter PGC1α activity by enhancing AMPK phosphorylation at the same site.…”

Ozone: a natural bioactive molecule with antioxidant property as potential new strategy in aging and in neurodegenerative disorders

“…Neurons rely almost exclusively on the mitochondria, which produce the energy required for most of the cellular processes, including synaptic plasticity and neurotransmitter synthesis. Mitochondrial disfunctions cause increase in ROS for lowered oxidative capacity and antioxidant defence, with consequent increased oxidative damage to protein and lipids, decreased ATP production and accumulation of DNA damage ( Garcia-Escudero et al, 2013 , Reutzel et al, 2020 ). Moreover, mitochondrial bioenergetic dysfunction and release of pro-apoptotic mitochondrial proteins into the cytosol initiate a variety of cell death pathways.…”

Intimate Relations—Mitochondria and Ageing

“…Nonsense, missense or frameshift mutations within the cytochrome b gene (MTCYB) are associated with complex III deficiency in muscle and a clinical presentation involving exercise intolerance [ 43 ]. In a longitudinal study of the NMRI mouse model of normal ageing, Reutzel et al [ 44 ] measured brain mitochondrial function, cognitive performance and molecular markers every 6 months until mice reached the age of 24 months using 3-month-old mice as normal controls. At 6 months, expression of several mitochondrially related genes (complex IV, creb-1, β-AMPK and Tfam) were significantly elevated but mitochondrial respiration was reduced already by 12 months and ATP levels by 18 months.…”

“…If anti-oxidant defenses are impaired with age, this might exacerbate the effect of increased ROS production. In the study of Reutzel et al [ 44 ] reductions in brain catalase and SOD2 were seen at 18 months in mouse, suggesting that anti-oxidant responses may be impaired by this age. Such a reduction in anti-oxidant defenses with age was also seen in the rat as suggested by lowered expression of the antioxidant enzymes peroxiredoxin III (Prx III) and superoxide dismutase 2 (SOD2) [ 291 ].…”