Neurovascular dysfunction, inflammation and endothelial activation: implications for the pathogenesis of Alzheimer's disease

Abstract

Alzheimer's disease (AD) is an age-related disorder characterized by progressive cognitive decline and dementia. Alzheimer's disease is an increasingly prevalent disease with 5.3 million people in the United States currently affected. This number is a 10 percent increase from previous estimates and is projected to sharply increase to 8 million by 2030; it is the sixth-leading cause of death. In the United States the direct and indirect costs of Alzheimer's and other dementias to Medicare, Medicaid and businesses amount to more than $172 billion each year. Despite intense research efforts, effective disease-modifying therapies for this devastating disease remain elusive. At present, the few agents that are FDA-approved for the treatment of AD have demonstrated only modest effects in modifying clinical symptoms for relatively short periods and none has shown a clear effect on disease progression. New therapeutic approaches are desperately needed. Although the idea that vascular defects are present in AD and may be important in disease pathogenesis was suggested over 25 years ago, little work has focused on an active role for cerebrovascular mechanisms in the pathogenesis of AD. Nevertheless, increasing literature supports a vascular-neuronal axis in AD as shared risk factors for both AD and atherosclerotic cardiovascular disease implicate vascular mechanisms in the development and/or progression of AD. Also, chronic inflammation is closely associated with cardiovascular disease, as well as a broad spectrum of neurodegenerative diseases of aging including AD. In this review we summarize data regarding, cardiovascular risk factors and vascular abnormalities, neuro- and vascular-inflammation, and brain endothelial dysfunction in AD. We conclude that the endothelial interface, a highly synthetic bioreactor that produces a large number of soluble factors, is functionally altered in AD and contributes to a noxious CNS milieu by releasing inflammatory and neurotoxic species.

Figure 1

Diagram of hypothesis. In response to a persistent or intermittent stimulus, such as cerebral hypoxia, brain endothelial cells become activated. Activated endothelial cells are highly synthetic and release a host of factors that can affect the activation of nearby cells. Despite the continued presence of the stimulus, no new vessel growth occurs. Because no new vessels are formed there are no feedback signals to shut off vascular activation endothelial cells, as occurs in physiologic angiogenesis. In AD reversible endothelial activation becomes irreversible endothelial dysfunction. The vascular products of a permanently dysfunctional endothelium could cause neuronal injury/death directly or via activation of microglia and/or astrocytes. (blue line) = feedback inhibition, (yellow lighting bolt) = Endothelial cell products