Chapter 110
Neurodegeneration — 16
When platelet factor 4 was infused to old mice, there was notable reduction of neuroinflammation, improved neurogenesis, better strength of connection between neurons (synaptic plasticity), and less blood-brain barrier breakdown. Along with all these favorable changes, there was substantial improvement in cognitive function. Similar effects have been seen with pulsatile administration of GnRH, both in mouse models and in men with cognitive impairment from Down syndrome.
Klotho is a hormone that circulates in the blood, increases with exercise, decreases with age, is linked to longevity, and, due to its size, is unable to cross the blood-brain barrier. One copy of the KLOTHO-VS gene (a variant of KLOTHO found in 20% of people) is associated with higher levels of klotho (the protein), longer life, improved brain volume, and cognitive function. In contrast, two copies decrease klotho levels. One copy has been associated with lower risk of Alzheimer’s in people with the APOE4 allele.
When klotho is given to mice, there is an improvement of synaptic plasticity, memory, and cognitive function. A single intravenous administration of a low dose of klotho given to rhesus monkeys enhanced their spatial delayed response, a key metric for memory and cognitive function, not seen at higher doses, and persisted for two weeks. Unsolved from these experiments was the mechanism by which klotho could achieve this improvement, since it cannot access the brain.
Platelet factor 4 (PF-4) levels increase when klotho is given to mice, along with other platelet factors, as occurs with exercise. PF-4 readily crosses the blood-brain barrier. Intravenous infusion of either klotho or PF-4 to both young and old mice improved cognition. In mice whose PF-4 gene was knocked out, there was still an effect of klotho infusion, telling us that PF-4 is not the only factor that can potentially work as a messenger for brain health.
There’s much more to the PF-4 story. PF-4 levels are higher in young mice and young people compared to their older counterparts. The PF-4 effect in mice, mediated through a cell receptor (CXCR3), reduced age-related hippocampal neuroinflammation, enhanced synaptic plasticity, and improved cognitive performance. The enhanced cognition with exercise in mice appeared to be mediated by platelets and replicated by intravenous infusion of PF-4, also demonstrating hippocampal neurogenesis in old mice. Use of PF-4 knockout mice showed this platelet factor was necessary and sufficient to achieve the beneficial brain effects. We’re making major headway for identifying specific factors from the young in experimental models, which may ultimately lead to clinical trials in older people to preserve cognitive function.