Impaired neurovascular coupling in aging and Alzheimer's disease: Contribution of astrocyte dysfunction and endothelial impairment to cognitive decline

Abstract

The importance of (micro)vascular contributions to cognitive impairment and dementia (VCID) in aging cannot be overemphasized, and the pathogenesis and prevention of age-related cerebromicrovascular pathologies are a subject of intensive research. In particular, aging impairs the increase in cerebral blood flow triggered by neural activation (termed neurovascular coupling or functional hyperemia), a critical mechanism that matches oxygen and nutrient delivery with the increased demands in active brain regions. From epidemiological, clinical and experimental studies the picture emerges of a complex functional impairment of cerebral microvessels and astrocytes, which likely contribute to neurovascular dysfunction and cognitive decline in aging and in age-related neurodegenerative diseases. This overview discusses age-related alterations in neurovascular coupling responses responsible for impaired functional hyperemia. The mechanisms and consequences of astrocyte dysfunction (including potential alteration of astrocytic endfeet calcium signaling, dysregulation of eicosanoid gliotransmitters and astrocyte energetics) and functional impairment of the microvascular endothelium are explored. Age-related mechanisms (cellular oxidative stress, senescence, circulating IGF-1 deficiency) impairing the function of cells of the neurovascular unit are discussed and the evidence for the causal role of neurovascular uncoupling in cognitive decline is critically examined.

Keywords: Cerebral circulation; Cerebrovascular; Functional hyperemia; Geroscience; Microcirculation; Neurovascular coupling; Senescence; VCI; VCID; Vascular aging.

Figure 1. Aging impairs neurovascular coupling responses: synergistic roles of astrocyte dysfunction and endothelial impairment

Shown is a schematic illustration of putative aging-induced alterations in glio-vascular coupling mechanisms, which may contribute to impaired functional hyperemia and thereby promote cognitive decline in the elderly. A complex interaction between neurons, astrocytes, microvascular smooth muscle and endothelial cells ensures adequate cerebral blood flow at all times. Neurotransmitters (e.g. glutamate) released from active excitatory synapses elicits elevations of [Ca²⁺]_i in astrocytes via G protein–coupled receptors, whereas P2X and NMDA receptors contribute to channel-mediated increases in [Ca²⁺]_i, initiating the propagation of a calcium waves through the astrocyte’s processes to the soma and to its microvascular end-feet wrapped around the smooth muscle cells. The surge in astrocyte end-feet [Ca²⁺]_i promotes ATP release and activates PLA₂ to release arachidonic acid (AA), which lead to the CYP450- and cyclooxygenase (COX)-mediated production of vasodilator eicosanoids (epoxyeicosatrienoic acids [EETs] and prostaglandins, respectively). Astrocyte-derived ATP promotes endothelial release of vasodilator NO via activation of P2Y1 receptors and also contributes to the propagation of the signal(Chen et al. 2014; Toth et al. 2015b). The aforementioned mechanisms together elicit smooth muscle relaxation in cerebral microvessels leading to localized hyperemia. The model predicts that the effects of aging on the neurovascular unit are manifest at multiple levels. Arrows indicate known age-related changes, whereas question marks highlight predicted aging effects yet to be verified experimentally. Of particular importance is the role of age-related oxidative stress as increased ROS production by NOX oxidases(Park et al. 2007) and mitochondrial sources can potentially affect both endothelial NO-mediated dilation and may play a critical role in dysregulation of eicosanoid synthesis. The model highlights the importance of new research investigating age-related alterations in astrocyte calcium signaling pathways. The schematic does not include the potential effects of aging on neuronal release of vasodilator mediators and/or alterations in astrocytic regulation of pericyte function and capillary dilation.

Figure 2. Imaging of neurovascular coupling events using two-photon microscopy

A. Wide-field two-photon max intensity Z-stack of the barrel cortex from a GLAST-Cre GCaMP3 mouse with GCaMP3 expressed in the astrocytes (green) and vascular network labeled with Rhodamine B-dextran (red). Images of a penetrating arteriole (p.a.) enwrapped by an endfoot (e.f.) prior to whiskers stimulation (0 second, top and at 3 seconds, bottom). B. Representative traces of arteriole diameter (left) and endfoot Ca2+ (right) in response to whiskers stimulation (grey bars). C. Wide-field two-photon max intensity Z-stack of the barrel cortex from TEK-Cre ArchT eGFP mouse with ArchT eGFP expressed in the endothelial cells (EC) (green) and astrocytes labeled with Rhod2-AM (red). Images of a cross section of a penetrating arteriole and a capillary with EC expressing ArchT eGFP (top) with, astrocytic endfoot and smooth muscle cell (SMC) labeled with Rhod2-AM (middle) and merge image (bottom).