Small Vessels Are a Big Problem in Neurodegeneration and Neuroprotection

Abstract

The cerebral microcirculation holds a critical position to match the high metabolic demand by neuronal activity. Functionally, microcirculation is virtually inseparable from other nervous system cells under both physiological and pathological conditions. For successful bench-to-bedside translation of neuroprotection research, the role of microcirculation in acute and chronic neurodegenerative disorders appears to be under-recognized, which may have contributed to clinical trial failures with some neuroprotectants. Increasing data over the last decade suggest that microcirculatory impairments such as endothelial or pericyte dysfunction, morphological irregularities in capillaries or frequent dynamic stalls in blood cell flux resulting in excessive heterogeneity in capillary transit may significantly compromise tissue oxygen availability. We now know that ischemia-induced persistent abnormalities in capillary flow negatively impact restoration of reperfusion after recanalization of occluded cerebral arteries. Similarly, microcirculatory impairments can accompany or even precede neural loss in animal models of several neurodegenerative disorders including Alzheimer's disease. Macrovessels are relatively easy to evaluate with radiological or experimental imaging methods but they cannot faithfully reflect the downstream microcirculatory disturbances, which may be quite heterogeneous across the tissue at microscopic scale and/or happen fast and transiently. The complexity and size of the elements of microcirculation, therefore, require utilization of cutting-edge imaging techniques with high spatiotemporal resolution as well as multidisciplinary team effort to disclose microvascular-neurodegenerative connection and to test treatment approaches to advance the field. Developments in two photon microscopy, ultrafast ultrasound, and optical coherence tomography provide valuable experimental tools to reveal those microscopic events with high resolution. Here, we review the up-to-date advances in understanding of the primary microcirculatory abnormalities that can result in neurodegenerative processes and the combined neurovascular protection approaches that can prevent acute as well as chronic neurodegeneration.

Increased capillary stalling is associated with endothelial glycocalyx loss in subcortical vascular dementia

“…Recent studies have revealed the significance of capillary stalling in aging, stroke, Alzheimer's disease, polycythemia and thrombocythemia 3,4,5,6,11,21,22,23 . In fact, capillary stalling largely impacts on CBF, and cognitive functions can be improved by suppressing capillary stalling in Alzheimer's disease 6,24 .…”

“…Further, we examined the consequence of increased capillary stalling. We considered that alterations in the microcirculation, such as due to stalling, would reduce the efficiency of oxygen delivery to tissues that are presumably associated with the SVaD pathogenesis 21,35 .…”

Brain Microvascular Pericytes in Vascular Cognitive Impairment and Dementia

“…The cells have been variably called as ensheathing pericytes Grant et al, 2019), transition/transitional pericytes (Kisler et al, 2017a;Arango-Lievano et al, 2018), pre-capillary pericytes (Zimmermann, 1923), simply 'pericytes' or 'capillary pericytes' (Hall et al, 2014;Attwell et al, 2016;Cai et al, 2018;Khennouf et al, 2018;Grubb et al, 2020), smooth muscle-pericyte hybrids (Hartmann et al, 2015;Yang et al, 2017;Dalkara, 2019), arteriole SMC (aaSMC) (Vanlandewijck et al, 2018), or pre-capillary SMCs (Hill et al, 2015). At the same time, the vessels of proximal branches coming off penetrating arterioles are also differently defined as pre-capillary arterioles (Fernández-Klett et al, 2010;Hartmann et al, 2015;Hill et al, 2015;Berthiaume et al, 2018;Erdener and Dalkara, 2019;Grant et al, 2019), post-arteriole capillaries (Gould et al, 2016) or a part of capillaries (Hall et al, 2014;Attwell et al, 2016;Cai et al, 2018;Khennouf et al, 2018;Grubb et al, 2020).…”

“…Blood-brain barrier breakdown and microvessel dysfunction has been observed in various CNS disorders such as small vessel disease (SVD), ischemic acute stroke, intracerebral hemorrhage, Alzheimer's disease (AD), traumatic brain injury (TBI)/chronic traumatic encephalopathy (CTE), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Lewy body diseases (LBD), and epilepsy (Winkler et al, 2013;Coatti et al, 2019;Erdener and Dalkara, 2019;Geranmayeh et al, 2019). In particular, pericyte dysfunction is thought to be a critical factor for aggravating dementing diseases such as vascular cognitive impairment/dementia and AD (Sagare et al, 2013;Montagne et al, 2018;Nikolakopoulou et al, 2019).…”

Pericytes in Microvessels: From “Mural” Function to Brain and Retina Regeneration

“…Neurological diseases such as ischemic stroke, traumatic brain injury, Alzheimer's Disease (AD), amyotrophic lateral sclerosis and Parkinson's disease are characterized by pericyte dysfunction [64]. Hereafter, short description of pericyte involvement in ischemia-reperfusion and brain tumor is presented.…”