Emerging Roles of Endothelial Nitric Oxide in Preservation of Cognitive Health

Abstract

eNOS (endothelial nitric oxide synthase) is critically important enzyme responsible for regulation of cardiovascular homeostasis. Under physiological conditions, constitutive eNOS activity and production of endothelial nitric oxide (NO) exert essential neurovascular protective functions. In this review, we first discuss the roles of endothelial NO in prevention of neuronal amyloid accumulation and formation of neurofibrillary tangles, hallmarks of Alzheimer disease pathology. Next, we review existing evidence suggesting that NO released from endothelium prevents activation of microglia, stimulates glycolysis in astrocytes, and increases biogenesis of mitochondria. We also address major risk factors for cognitive impairment including aging and ApoE4 (apolipoprotein 4) genotype with focus on their detrimental effects on eNOS/NO signaling. Relevant to this review, recent studies suggested that aged eNOS heterozygous mice are unique model of spontaneous cerebral small vessel disease. In this regard, we review contribution of dysfunctional eNOS to deposition of Aβ (amyloid-β) into blood vessel wall leading to development of cerebral amyloid angiopathy. We conclude that endothelial dysfunction manifested by the loss of neurovascular protective functions of NO may significantly contribute to development of cognitive impairment.

Keywords: amyloid; astrocyte; microglia; mitochondria; tau protein.

Figure 1.

Proteolytic cleavage of amyloid precursor protein (APP) by a nonamyloidogenic pathway (left) or an amyloidogenic pathway (right). In the nonamyloidogenic pathway, APP is cleaved by α-secretase thereby releasing the sAPPα ectodomain. Following α-secretase cleavage, γ-secretase releases the p3 fragment and the APP intracellular domain C59. In the amyloidogenic pathway, β-secretase (BACE1) cleaves APP and releases the sAPPβ ectodomain. Subsequent processing by γ-secretase generates the cytotoxic peptide, Aβ, as well as the C59.

Figure 2.

Schematic representation of the inhibitory effects of endothelial NO on expression of APP and BACE1, and production of Aβ in endothelial and neuronal cells.

Figure 3.

Schematic representation of the role of endothelial NO deficiency in stimulation of tau protein phosphorylation and formation of neurofibrillary tangles in neuronal cells.