Sickle cell disease is one of the most common recessive inherited blood disorders in African Americans
affecting 70,000-100,000 individuals in the U.S. Sickle cell disease is caused by mutations in the ß-globin (p-
globin) gene, which leads to hemoglobin abnormalities. Sickle cell disease patients chronically suffer from
oxygen deprivation due to depressed oxygen-carrying capacity of hemoglobin S causing transient ischemic
attacks, and multiple organ dysfunction. Hypoperfusion following vaso-occlusion leads to insufficient blood
supply to the brain resulting in anaerobic metabolism, thus activating the inflammatory response. It is not
surprising that sickle cell disease -related vascular dementia may be prevalent. Sickle cell disease can decrease
memory and cognitive function including shortened attention spans, spatial function, and reading. These
pathologies are thought to be caused by the vascular obstructions caused by the sickle cell disease brain.
Vascular insufficiency can lead to loss of cerebral blood flow autoregulation and impaired cognitive function
related to chronic brain hypoxia. Altogether, these neurological sequelae of sickle cell disease mirrors vascular
dementia and similarities of Alzheimer's disease and related dementias (ADRD). Due to these similarities, we
compared the etiologies of sickle cell disease and ADRD, and examined the common mechanism(s) of these
inter-related events in vascular dementia.
We originally discovered that protein arginine methyltransferases (PRMT4) is enhanced in aged 3xTg-
AD mice v. younger counterparts, this makes the age-dependent PRMT4 a novel and relevant target against
ADRD. More importantly, PRMT4 is increased in female Townes mice, a model of sickle cell disease, leading to
subsequent investigations of PRMT4 in sickle cell disease. To our knowledge, this is the first time that PRMT4
has been identified in sickle cell disease (Townes mice). It is also well-known that sickle cell disease can trigger
vaso-occlusive crisis that can exacerbate brain hypoperfusion and disturb cerebral blood flow. We seek to
identify PRMT4-mediated neuroinflammatory markers to prevent blood brain barrier breakdown in the Townes
brain. Therefore, our central hypothesis is inhibition of PRMT4 (TP-064 or PRMT4-AAV) can enhance nitric oxide
signaling, neurovascular coupling, and preserve functional learning/memory in aged Townes female mice. We
describe PRMT4 inhibition as a therapeutic potential against sickle cell disease-related vascular dementia.