Title: P3‐333: Targeting the hematopoietic system to treat Alzheimer's disease
Abstract: Strategies using bone marrow-derived cells (BMDC) as therapeutic agents for cerebral pathologies center on the beneficial effects of microglia. They are the brain resident macrophages, sole immunologic defenders of brain homeostasis and most important, of hematopoietic origin. A therapeutic role for these cells has been suggested in Alzheimer's disease (AD) using either bone marrow transplantation or hematopoietic cytokines. However, a controversy remains on the ability of BMDC to infiltrate into the CNS as previous experimental models always required the use of whole-body irradiation. A myeloablative chemotherapy regimen was adapted to replace whole-body irradiation. As no infiltration was seen in wild-type mice in a previous experiment, the regimen and bone marrow transplants were performed to APP/PS1 mice at 2 months of age, before they develop amyloid plaques and symptoms of Alzheimer's disease. They were sacrificed at 9 months of age, when signs of the pathology were fully developed. A similar protocol was also used in a curative model, between 6 and 9 months of age. The presence of Alzheimer's disease-like symptoms in mice was sufficient to induce an efficient migration of BMDC into the CNS. These cells were also highly efficient to treat the pathology, normalizing their behavior deficiencies and amyloid plaque load. Chemotherapy and irradiation were both equally efficient as a pretreatment for bone marrow transplant. These results demonstrate that although BMDC cannot migrate into the CNS in normal healthy conditions, they migrate to the sites of injury in conditions of cerebral pathology, such as Alzheimer's disease. These cells are highly efficient as a therapeutic agent to limit the deposition of amyloid plaques and the related cognitive decline. Taken together, our result suggest that treatments involving hematopoietic cytokines are prime candidates as new therapeutic strategies for Alzheimer's disease.