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.

Demonstration of impaired neurovascular coupling responses in TG2576 mouse model of Alzheimer’s disease using functional laser speckle contrast imaging

“…In healthy subject during times of increased neural activity, a homeostatic mechanism termed neurovascular coupling (functional hyperemia) matches the localized demand for glucose and oxygen with increased blood supply to ensure normal brain function. Neurovascular coupling is a feed-forward mechanism which requires the coordinated cellular interaction between neurons, astrocytes, pericytes, vascular endothelial and smooth muscle cells (Petzold and Murthy 2011;Stobart et al 2013;Wells et al 2015;Chen et al 2014;Tarantini et al 2016). A large body of evidence derived from both clinical and experimental studies demonstrate that aging significantly impairs neurovascular coupling responses, which likely contribute to cognitive decline in the elderly (Balbi et al 2015;Fabiani et al 2013;Sorond et al 2013;Tong et al 2012;Toth et al 2014;Zaletel et al 2005;Park et al 2007).…”

“…A large body of evidence derived from both clinical and experimental studies demonstrate that aging significantly impairs neurovascular coupling responses, which likely contribute to cognitive decline in the elderly (Balbi et al 2015;Fabiani et al 2013;Sorond et al 2013;Tong et al 2012;Toth et al 2014;Zaletel et al 2005;Park et al 2007). There is also growing evidence for microvascular pathophysiological alterations having a causal role in the development of cognitive decline associated with Alzheimer's disease (AD) (Tarantini et al 2016;Snyder et al 2015). …”

Cerebromicrovascular dysfunction predicts cognitive decline and gait abnormalities in a mouse model of whole brain irradiation-induced accelerated brain senescence

“…During periods of intense neuronal activity, there is a requirement for rapid increases in oxygen and glucose delivery. This is ensured by neurovascular coupling (functional hyperemia), a vital mechanism of regulation of CBF that maintains optimal microenvironment of cerebral tissue by adjusting local blood flow to local neuronal activity in a moment-to-moment manner (Attwell et al 2010;Tarantini et al 2015Tarantini et al , 2016Toth et al 2016;Toth et al 2014aToth et al , 2015aToth et al , 2015bToth et al , 2017Tucsek et al 2014). There is increasing evidence that neurovascular dysfunction is causally related to cognitive decline in models of aging (Tarantini et al 2015(Tarantini et al , 2016), yet, the effects of WBI on cerebromicrovascular function have never been investigated.…”

Pharmacologically induced impairment of neurovascular coupling responses alters gait coordination in mice

“…There is growing evidence that functional impairment of the neurovascular unit develops early during aging before manifestation of other pathologies (Balbi et al 2015), and that it importantly contributes to age-related impairment of brain function (Tarantini et al 2016;Toth et al 2017). The energetic demand of active neurons is high and their proper function depends on constant, tightly controlled delivery of oxygen and nutrients via the microcirculatory network.…”

“…There are numerous agerelated vascular pathologies underlying VCID. It has become evident that in addition to pathologies affecting the larger cerebral arteries (e.g., atherosclerosis promoting cerebral ischemia) and cerebral microvessels (including arteriosclerosis, blood-brain barrier disruption, microvascular rarefaction, microvascular amyloid deposition, microhemorrhages) (Tucsek et al 2014a(Tucsek et al , b, 2017Ungvari et al 2017b), functional impairment of cerebral microvessels resulting in dysregulation of cerebral blood flow (CBF) also has a critical role in the agerelated decline of brain function Tarantini et al 2016;Toth et al 2017;Zlokovic 2011).…”