Youth-associated platelet-derived chemokine reverses brain aging through neuroimmune mechanisms

Abstract

Age-related loss of brain function has been seen as inevitable, yet recent work leveraging the systemic environment challenges this notion. Schroer et al. demonstrate that youth-associated platelet factor 4 (PF4) partially restores brain function in aged mice while reducing peripheral immune dysfunction, supporting periphery-based approaches to treat age-associated brain disorders.

Aging represents a looming public health threat given its role as the major risk factor for devastating neurodegenerative diseases, including Alzheimer’s disease, for which there are no effective therapies. Age-related changes in brain function, including cognitive and synaptic dysfunction, are accompanied by perturbations in populations of astrocytes, oligodendrocytes, and microglia that participate in neuronal processes. The past decade has seen growth in studies exploring blood-central nervous system (CNS) communication as a novel avenue to reduce the harmful burden of aging on brain integrity, yet much of this work has focused on the functional effects of these interventions [1]. Aged animals receiving young blood or plasma exhibit improved hippocampus-dependent memory and synaptic plasticity [2,3], but the impact on glia and the peripheral immune compartment and molecular details of these interactions from the perspective of specific drivers have been relatively unexplored.

The concept that the blood-brain barrier precludes exchange of proteins and cells between peripheral and CNS compartments has led to the notion that the brain does not engage in appreciable immune crosstalk with the periphery. While the purpose of a blood-brain barrier is not disputed, recent work has challenged the concept that there is limited uptake of blood-borne proteins by neural cells [4]. Several groups have shown that youth-associated proteins, including tissue inhibitor of metalloproteinases 2 (TIMP2) [3], growth and differentiation factor 11 (GDF11) [5], and osteocalcin [6], can reverse aspects of brain aging when provided systemically. Some of these factors interact with the cerebral vasculature, while others appear to evade the blood-brain barrier to infiltrate the brain, thereby mediating their effects on target cells in the hippocampus. Whether these cells receive appreciable signals from peripheral immune cells and the extent to which this is modulated by exposure to young blood has remained unclear. Cells of both the adaptive and innate immune system, including T cells and macrophages, are established regulators of brain aging processes, positioning them as ideal targets both for systemic intervention and for mechanistic exploration into the effects of youth-associated blood-borne molecules.

In the recent study by Schroer and colleagues [7], the authors first establish that there is significant activity within the platelet fraction of young blood that is sufficient to reduce markers of brain aging, including complement activation and microgliosis. These results extend the panel of young blood-mediated phenotypes beyond plasticity to now include neuroinflammation, while generating fresh questions about the nature of peripheral signals in young blood capable of signaling to microglia. Previous work had established that platelet factor 4 (PF4) is sufficient to improve adult neurogenesis following voluntary exercise in rodents [8], a plasticity phenotype commonly linked to the effects of young blood, raising the question of whether it may play a role in mediating the effects of young platelets. After establishing that PF4 levels are elevated in young blood, the authors show that systemic treatment of aged mice with PF4 recapitulates young platelet-induced changes in microglia while improving hippocampus-dependent memory. Surprisingly, HiBiT-tagged PF4 does not appreciably enter the brain following systemic injection, though a new study reports that histidine-tagged PF4 readily enters the hippocampus [9]. While orthogonal methods may help clarify the extent and mode of uptake of PF4 into the brain, the possibility that some of young platelet-mediated changes in the brain are driven by a factor acting in the periphery is compelling and creates fresh insights into the diversity of mechanisms of blood-borne factors for brain aging.

Many mechanisms could account for how a blood-borne factor transduces its effects to the hippocampus without direct action in the brain. CITE-seq was used to profile transcriptomic changes in peripheral immune cells following PF4 treatment, revealing a reversal of the myeloid to lymphoid ratio that occurs with aging. Furthermore, PF4 treatment partially restored inflammatory signatures in myeloid populations, including Type I interferon signaling. Perhaps most intriguing among peripheral changes following PF4 treatment is the shift in T cells and corresponding decrease in exhaustion and cytotoxic markers associated with these cells. Through independent or perhaps intersecting mechanisms, PF4 also appears to dampen expression of age-associated cytokines, including CyPA, TNF, and CCL2, some of which regulate blood-brain barrier integrity. Remarkably, PF4-mediated peripheral immune changes were accompanied by improvements in hippocampus-dependent cognitive function, changes that were not observed in mice lacking the major receptor for PF4, CXCR3. Owing to the periphery-enriched expression of CXCR3, the CNS effects of PF4 may be mediated by disrupted immune signaling in the blood, which has downstream effects on innate immune reactivity in the CNS (Figure 1).

Figure 1. Systemic PF4 treatment in aged mice mitigates peripheral and hippocampal inflammation to improve cognitive function.

Systemic treatment of aged mice with PF4 results in changes in innate and adaptive immune function in the periphery, including reduced levels of myeloid/neutrophil inflammatory signals and reduced age-related exhaustion and cytotoxic T cell markers with concomitant improvements in hippocampus-dependent learning and memory, synapse function, and microglial activation. Mice lacking CXCR3 exhibit a partial loss of PF4-mediated CNS benefits, raising the possibility that CXCR3-expressing T cells are critical for the effects of PF4. Changes in the CNS following PF4 treatment may be mediated by shifts in peripheral cytokines, immune cell infiltration, or direct action of PF4, though future studies will clarify the relative contributions of these mechanisms and PF4’s regulation of neuroimmune interactions in the CNS. Abbreviations: CXCR3, C-X-C Motif Chemokine Receptor 3; CNS, central nervous system; PF4, platelet factor 4. This figure was created with tools from BioRender.com.

The confluence of components of both adaptive and innate immunity to robustly affect hippocampal function following PF4 treatment motivates important directions for the field and compels exploration into noncanonical mechanisms linking the periphery and CNS. The effects of PF4 are presumably mediated via its binding to CXCR3 on peripheral immune cells, raising the possibility of neuroimmune crosstalk, either with mature neurons or with neural progenitor cells/neuroblasts. A recent study supports the latter possibility given that these cells appear to be indispensable for the effects of PF4 in aged mice [10]. Microglia may be sensing changes in infiltrating cytokines or alterations in infiltrating peripheral immune cells, resulting in shifts in subpopulations that more effectively respond to aging insults (Figure 1). The net result of these perturbations may be altered neuroimmune interactions that promote more youthful cognitive health [11].

The work by Schroer et al. [7] highlights new avenues for investigation of blood-borne factors that regulate CNS rejuvenation. Given PF4’s roles in coagulation, wound repair, and other peripheral processes, future work will need to characterize the impact of elevating PF4 on basic physiology—and in what contexts—as the factor is considered for treatment of age-related disorders. Beyond immune modulation approaches for cognitive rejuvenation implicated in the current study [7] and in previous work [12], targeting the G-protein coupled receptor CXCR3 itself with small molecules or targeting crucial downstream cytokines may also represent specific approaches to be considered for restoring CNS health in age-related brain disorders. With further investigations to characterize the peripheral-CNS mechanisms implicated here, the promise of targeting complex neuroimmune processes vulnerable to aging without invasive CNS procedures may well be within reach.