Plasma Transfusions from Fit Mice to Sedentary Mice Improve Cognitive Function via Increased Clusterin Levels

Plasma transfusions haven't performed well in either mouse or human studies when it comes to attempts to transfer youthful benefits to older individuals. This may be because dilution of harmful factors in old blood is more important than the provision of beneficial factors present in young blood, and a transfusion just doesn't provide enough dilution. In today's research materials, the goal is instead to transfer some of the benefits of exercise via factors present in the bloodstream of fit individuals that is absent in sedentary individuals. The initial results seem somewhat more positive.

Exercise is well established to improve cognitive function. This happens both in the short term, immediately following exercise, and over the long term as a consequence of improved fitness. One of the identified mechanisms involves upregulation of BDNF, which in turn boosts the pace of neurogenesis in brain regions responsible for memory. In the research here, scientists identify another beneficial signal molecule, clusterin. In this case the beneficial effect is a reduction in inflammation in brain tissue.

Blood from marathoner mice boosts brain function in their couch-potato counterparts

Investigators put either functional or locked running wheels into the cages of 3-month-old lab mice, which are metabolically equivalent to 25-year-old humans. A month of steady running was enough to substantially increase the quantity of neurons and other cells in the brains of marathoner mice when compared with those of sedentary mice. Next, the researchers collected blood from marathoner and, as controls, sedentary mice. Then, every three days, they injected other sedentary mice with plasma (the cell-free fraction of blood) from either marathoner or couch-potato mice. Each injection equaled 7% to 8% of the recipient mouse's total blood volume. (An equivalent amount in humans would be about 1/2 to 3/4 of a pint).

On two different lab tests of memory, sedentary mice injected with marathoner plasma outperformed their equally sedentary peers who received couch-potato plasma. In addition, sedentary mice receiving plasma from marathoner mice had more cells that give rise to new neurons in the hippocampus (a brain structure associated with memory and navigation) than those given couch-potato plasma transfusions.

Turning to an examination of proteins in the marathoner mice's blood, the team identified 235 distinct proteins, of which 23 were scarcer and 26 more abundant in marathoner compared with couch-potato mice. Several of these differentially expressed proteins were associated with the complement cascade - a set of about 30 blood-borne proteins that interact with one another to kick-start the immune response to pathogens. Removing a single protein, clusterin, from marathoner mice's plasma largely negated its anti-inflammatory effect on sedentary mice's brains. No other protein the scientists similarly tested had the same effect. Clusterin, an inhibitor of the complement cascade, was significantly more abundant in the marathoners' blood than in the couch potatoes' blood.

Further experiments showed that clusterin binds to receptors that abound on brain endothelial cells, the cells that line the blood vessels of the brain. These cells are inflamed in the majority of Alzheimer's patients, and research has shown that blood endothelial cells are capable of transducing chemical signals from circulating blood, including inflammatory signals, into the brain. Clusterin by itself, even though administered outside the brain, was able to reduce brain inflammation in two different strains of lab mice in which either acute bodywide inflammation or Alzheimer's-related chronic neuroinflammation had been induced.

Exercise plasma boosts memory and dampens brain inflammation via clusterin

Physical exercise is generally beneficial to all aspects of human and animal health, slowing cognitive ageing and neurodegeneration. The cognitive benefits of physical exercise are tied to an increased plasticity and reduced inflammation within the hippocampu, yet little is known about the factors and mechanisms that mediate these effects. Here we show that 'runner plasma', collected from voluntarily running mice and infused into sedentary mice, reduces baseline neuroinflammatory gene expression and experimentally induced brain inflammation.

Plasma proteomic analysis revealed a concerted increase in complement cascade inhibitors including clusterin (CLU). Intravenously injected CLU binds to brain endothelial cells and reduces neuroinflammatory gene expression in a mouse model of acute brain inflammation and a mouse model of Alzheimer's disease. Patients with cognitive impairment who participated in structured exercise for 6 months had higher plasma levels of CLU. These findings demonstrate the existence of anti-inflammatory exercise factors that are transferrable, target the cerebrovasculature and benefit the brain, and are present in humans who engage in exercise.

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