Physical exercise during exposure to 40-Hz light flicker improves cognitive functions in the 3xTg mouse model of Alzheimer’s disease

Abstract

Background: Exercise promotes brain health and improves cognitive functioning in the elderly, while 40-Hz light flickering through the visual cortex reduces amyloid beta (Aβ) by stabilizing gamma oscillation. We examined whether exercise was associated with hippocampus-mediated improvement in cognitive functioning in the 3xTg-Alzheimer's disease (3xTg-AD) murine model following exposure to 40-Hz light flickering and exercise. Methods: We subjected 12-month-old 3xTg-AD mice to exercise and 40-Hz light flickering for 3 months to investigate spatial learning, memory, long-term memory, Aβ levels, tau levels, mitochondrial functioning including Ca 2+ retention and H 2 O 2 emission, apoptosis, and neurogenesis in the hippocampus. Results: Treatments had a positive effect; however, the combination of exercise and 40-Hz light flickering exposure was most effective in reducing Aβ and tau levels. Reducing Aβ and tau levels by combination of exercise and 40-Hz light flickering improves Ca 2+ homeostasis and reactive oxygen species such as H 2 O 2 in mitochondria and apoptosis including bax, bcl-2, cytochrome c, and cleaved caspase-3 and cell death, cell differentiation, and neurogenesis in the 3xTg-AD model of the hippocampus, resulting in improving cognitive impairment such as spatial learning, memory and long term memory. Conclusion: Our results show that exercising in a 40-Hz light flickering environment may improve cognitive functioning by reducing Aβ and tau levels, thereby enhancing mitochondrial function and neuroplasticity.

Induction of specific brain oscillations may restore neural circuits and be used for the treatment of Alzheimer's disease

“…40‐Hz stimulation in mouse models also exerts secondary benefits to other systems, including neuroimmune signalling and circadian function, and appears to be even more beneficial when applied simultaneously with exercise [102–104]. One month of daily hour‐long 40‐Hz light flicker rescues central clock gene expression deficits present in APP/PS1 mice, including CLOCK, BMAL1 and PER2, suggesting that gamma stimulation could be having a direct impact on the suprachiasmatic nucleus and underlying circadian rhythms [102].…”

Mutual Interactions between Brain States and Alzheimer’s Disease Pathology: A Focus on Gamma and Slow Oscillations

“…As summarised above, it is clear that a reduction in gamma power is associated with AD pathology, at least in mouse models. Leveraging this knowledge, various invasive and non-invasive neuromodulation approaches have been adopted to modify AD pathology ( Table 2 ) [ 88 , 89 , 90 , 91 , 157 , 158 , 159 , 160 ]. For example, Tsai and her colleagues have elegantly demonstrated that both invasive and non-invasive gamma stimulations can ameliorate AD pathology [ 86 , 89 , 90 , 91 ]: optogenetic induction of gamma oscillations in the hippocampus can reduce amyloid load by activating microglia [ 89 ].…”

The magics of 40 hertz

“…Anyone can buy such a device for self‐treatment at home. Moreover, it appears as if exercise improves effects of the 40‐Hz light flickering [9], suggesting future exercise bikes be equipped with light and sound flickering devices. And why stay with only two sensory inputs?…”