Engagement of vascular early response genes typifies mild cognitive impairment

Introduction: Molecular responses in the brains of persons with mild cognitive impairment (MCI), the earliest transitional state between normal aging and early Alzheimer's disease (AD), are poorly understood. Methods: We examined AD-related neuropathology and transcriptome changes in the neocortex of individuals with MCI relative to controls and temporal responses to the mild hypoxia in mouse brains. Results: Subsets of vascular early response to hypoxia genes were upregulated in MCI prior to the buildup of AD neuropathology. Early activation of pro-angiogenic hypoxia-inducible factor signaling in response to mild hypoxia was detected in mouse brains similar to those that were altered in MCI. Protracted responses to hypoxia were characterized by activation of phosphoinositide 3-kinase (PI3K)-protein kinase B (Akt)-the mammalian target of rapamycin (mTOR) pathways in brain microvessel isolates. Discussion: These findings suggest that cerebrovascular remodeling is an important antecedent to the development of dementia and a component of the homeostatic response to reduced oxygen tension in aging prior to the onset of AD.