Cerebral microvascular pathology in aging and Alzheimer's disease

Abstract

The aging of the central nervous system and the development of incapacitating neurological diseases like Alzheimer's disease (AD) are generally associated with a wide range of histological and pathophysiological changes eventually leading to a compromised cognitive status. Although the diverse triggers of the neurodegenerative processes and their interactions are still the topic of extensive debate, the possible contribution of cerebrovascular deficiencies has been vigorously promoted in recent years. Various forms of cerebrovascular insufficiency such as reduced blood supply to the brain or disrupted microvascular integrity in cortical regions may occupy an initiating or intermediate position in the chain of events ending with cognitive failure. When, for example, vasoconstriction takes over a dominating role in the cerebral vessels, the perfusion rate of the brain can considerably decrease causing directly or through structural vascular damage a drop in cerebral glucose utilization. Consequently, cerebral metabolism can suffer a setback leading to neuronal damage and a concomitant suboptimal cognitive capacity. The present review focuses on the microvascular aspects of neurodegenerative processes in aging and AD with special attention to cerebral blood flow, neural metabolic changes and the abnormalities in microvascular ultrastructure. In this context, a few of the specific triggers leading to the prominent cerebrovascular pathology, as well as the potential neurological outcome of the compromised cerebral microvascular system are also going to be touched upon to a certain extent, without aiming at total comprehensiveness. Finally, a set of animal models are going to be presented that are frequently used to uncover the functional relationship between cerebrovascular factors and the damage to neural networks.

Astrocytes in Alzheimer's Disease

“…Morphological analysis also found pronounced vascular pathology in AD brains. 190 The elementary component of brain microcirculation is represented by a neurovascular unit, in which astrocytes integrate neurons, brain endothelium, pericytes, and vascular smooth muscle cells into a functionally independent entity. 23,188,189 In this structure, astrocytes assume the role of coordinating elements that establish the link between neuronal activity and local blood flow through several signaling cascades controlling vasoconstriction and vasodilatation.…”

Circulating IGF-1 deficiency exacerbates hypertension-induced microvascular rarefaction in the mouse hippocampus and retrosplenial cortex: implications for cerebromicrovascular and brain aging

“…In the brain, the number of endothelial cells is very similar to that of neurons (GarciaAmado and Prensa 2012) and nearly every neuron is supplied by its own capillary, with an average distance of 8-20 μm between the neuron and the microvessels. Importantly, there is strong evidence that aging is associated with a decline in cerebral capillary density ("microvascular rarefaction") and that decreases in cerebromicrovascular density contribute to the agerelated decline in regional cerebral blood flow (Mitschelen et al 2009;Riddle et al 2003;Khan et al 2001;Lynch et al 1999;Sonntag et al 1997;Martin et al 1991;Moeller et al 1996;Farkas and Luiten 2001;Kawamura et al 1993;Krejza et al 1999;Schultz et al 1999;Bentourkia et al 2000;Hagstadius and Risberg 1989;Pagani et al 2002). The resulting mismatch between energy supply and demand has been causally linked to significant cognitive impairment (reviewed in Sonntag et al 1997;Ingraham et al 2008;Sonntag et al 2000;Warrington et al 2011;Warrington et al 2012).…”

Nox2-Derived Reactive Oxygen Species Mediate Neurovascular Dysregulation in the Aging Mouse Brain

“…There is increasing evidence that the impairment in cerebrovascular function induced by aging is mediated by oxidative stress, but the cellular sources of reactive oxygen species (ROS) and the enzymatic systems generating them have not been defined (Faraci and Heistad, 1998;Farkas and Luiten, 2001). There are several potential sources of ROS in brain, including xanthine oxidase, mitochondrial enzymes, and enzymes involved in nitric oxide synthesis or arachidonic acid metabolism (Faraci, 2006).…”