Fight Aging!

Overly reactive, senescent, and otherwise inflammatory microglia in the brain are implicated in the development of neurodegenerative conditions. Chronic inflammation in brain tissue disrupts neural function in numerous ways. Thus why not clear or replace microglia? There are established ways to remove these cells, allowing them to regenerative over a few weeks, but these have not yet made their way to human trials for neurodegenerative conditions, despite interesting results in animal models. The replacement of microglia via transplantation of hematopoietic cells is at a similar stage, wherein there are interesting results in animal models of various neurodegenerative conditions.

For a long time, reactive microglia have been considered a consequence of Alzheimer's disease (AD) pathology; however, they are now regarded as potentially playing a role in disease progression and maybe initiation. Sustained microglia inflammation has been identified as a contributor to AD pathogenesis, as the release of inflammatory cytokines, chemokines, and complement proteins increases amyloid-β (Aβ) production. In addition, microglia have been shown to be involved in the clearance of Aβ plaque, which is impaired in AD due to mutations in microglia-related genes, including P2ry12, Apoe, and Trem2. Furthermore, with impaired microglia clearance, debris and other byproducts are diverted for clearance to other brain cells, such as endothelial cells, which do not proliferate efficiently and exhibit similar dysfunction, resulting in cell death and impaired blood flow.

Thus, targeting microglia offers a potential therapeutic opportunity for AD. We have previously demonstrated that a single systemic transplant of wild-type hematopoietic stem and progenitor cells (HSPCs) led to long-term rescue in both mouse models for cystinosis, a lysosomal storage disease, and Friedreich's ataxia, a neurodegenerative disease. In Friedreich's ataxia mouse model, transplanted HSPCs engrafted and differentiated into microglia in the brain and spinal cord, and into macrophages in the dorsal root ganglions (DRGs), resulting in the preservation of the neurons and locomotor function. Efficient replacement of microglia in the central nervous system (CNS) by bone marrow stem cell transplantation has previously been described. Therefore, because microglia may play an important role in AD, we hypothesized that wild-type (WT) HSPC transplantation could result in the generation of healthy microglia that may have a beneficial impact on AD.

Our study showed that single systemic wild-type (WT) hematopoietic stem and progenitor cell (HSPC) transplantation rescued the AD phenotype in 5xFAD mice and that transplantation may prevent microglia activation. Indeed, complete prevention of memory loss and neurocognitive impairment and decrease of β-amyloid plaques in the hippocampus and cortex were observed in the WT HSPC-transplanted 5xFAD mice compared with untreated 5xFAD mice and with mice transplanted with 5xFAD HSPCs. Neuroinflammation was also significantly reduced. Transcriptomic analysis revealed a significant decrease in gene expression related to "disease-associated microglia" in the cortex and "neurodegeneration-associated endothelial cells" in the hippocampus of the WT HSPC-transplanted 5xFAD mice compared with diseased controls. This work shows that HSPC transplant has the potential to prevent AD-associated complications and represents a promising therapeutic avenue for this disease.

Link: https://doi.org/10.1016/j.celrep.2023.112956