Infusion of Plasma from Exercised Mice Ameliorates Cognitive Dysfunction by Increasing Hippocampal Neuroplasticity and Mitochondrial Functions in 3xTg-AD Mice

Abstract

Alzheimer’s disease is the most common neurodegenerative brain disease causing dementia. It is characterized by slow onset and gradual worsening of memory and other cognitive functions. Recently, parabiosis and infusion of plasma from young mice have been proposed to have positive effects in aging and Alzheimer’s disease. Therefore, this study examined whether infusion of plasma from exercised mice improved cognitive functions related to the hippocampus in a 3xTg-Alzheimer’s disease (AD) model. We collected plasma from young mice that had exercised for 3 months and injected 100 µL of plasma into the tail vein of 12-month-old 3xTg-AD mice 10 times at 3-day intervals. We then analyzed spatial learning and memory, long-term memory, hippocampal GSK3β/tau proteins, synaptic proteins, mitochondrial function, apoptosis, and neurogenesis. In the hippocampus of 3xTg-AD mice, infusion of plasma from exercised mice improved neuroplasticity and mitochondrial function and suppressed apoptosis, ultimately improving cognitive function. However, there was no improvement in tau hyperphosphorylation. This study showed that plasma from exercised mice could have a protective effect on cognitive dysfunction and neural circuits associated with AD via a tau-independent mechanism involving elevated brain-derived neurotrophic factor due to exercise.

Mechanisms Underlying Non-Pharmacological Dementia Prevention Strategies: A Translational Perspective

“…Horowitz et al (30) showed that not only was neurogenesis increased in exercising WT mice, but even in inactive aged mice when administered with plasma from the exercised mice. Similar results were reported when 3xTg-AD mice were administered plasma from young, exercised mice (19). This denotes that there is a clear axis between the training-induced systemic changes and the brain.…”

“…Reflecting on the report, the effect on BDNF could be attributed to a Gpld1-uPA-plasminogen cascade. Finally, these effects were observed as an improved cognitive performance of the mice (19,30).…”

“…Extensive studies performed on dementia mouse models exposed to exercise training report positive outcomes in cognitive tests (10)(11)(12)(13)(14)(15)(16)(17)(18). Many of these studies report an increase of synaptic markers indicating preservation of synapses and their function in the brains of exercising mice (10)(11)(12)(13)(14)19). Additionally, desired alterations in AD-related pathology after a period of exercise in AD transgenic mice have been observed in several studies (10-12, 15, 20).…”

“…One common finding in several pre-clinical studies is the increased levels of the brain-derived neurotrophic factor (BDNF) as a result of physical activity (10,13,14,19,(29)(30)(31). BDNF expression is regulated to a great extent by other muscle-derived myokines, such as FNDC5 (fibronectin type III domain containing 5) and its cleavage product Irisin (32).…”

“…Complementary to neurogenesis, exercise might also alleviate cell death in the brain (14,15,19,24). This effect has been attributed to a decrease in pro-apoptotic markers like caspases, cytochrome c, and Bax, and additionally to an increase in anti-apoptotic markers like Bcl-2 (14,15,24,31).…”