Abstract
Cerebrovascular dysfunction is re-emerging as a major component of aging, and may contribute to the risk of developing Alzheimer's disease (AD). Two important risk factors for cerebrovascular dysfunction are APOE and female sex, which are primarily researched in the context of high amyloid-β (Aβ) levels as found in AD. However, APOE4 and sex modulate Aβ-independent pathways that may induce cerebrovascular dysfunction as a downstream consequence. Therefore, testing the activity of factors that target cerebrovascular dysfunction in Aβ-independent models that incorporate APOE4 and female sex is crucial. We have previously demonstrated that peripheral administration of the epidermal growth factor (EGF) prevents cognitive dysfunction, cerebrovascular leakiness, and cerebrovascular coverage deficits in female mice that express APOE4 and overproduce Aβ, without affecting Aβ levels. These data raise the question of whether EGF protects the cerebrovasculature from general stress-induced damage. Therefore, the goal of this study was to determine whether EGF prevents Aβ-independent cerebrovascular dysfunction. In eight-month old mice that express human APOE, the interaction of APOE4 and female sex induced cognitive dysfunction, increased cerebrovascular leakiness and lowered vessel coverage. Importantly, in a prevention paradigm (from six to eight and a half months of age), EGF ameliorated cognitive decline and cerebrovascular deficits in female mice that express APOE4. Thus, developing treatment strategies based on EGF signaling could provide alternative therapeutic options for age-related cerebrovascular dysfunction and reduce AD risk.