Vascular Cognitive Impairment: Information from Animal Models on the Pathogenic Mechanisms of Cognitive Deficits

Abstract

Vascular cognitive impairment (VCI) is the second most common cause of cognitive deficit after Alzheimer’s disease. Since VCI patients represent an important target population for prevention, an ongoing effort has been made to elucidate the pathogenesis of this disorder. In this review, we summarize the information from animal models on the molecular changes that occur in the brain during a cerebral vascular insult and ultimately lead to cognitive deficits in VCI. Animal models cannot effectively represent the complex clinical picture of VCI in humans. Nonetheless, they allow some understanding of the important molecular mechanisms leading to cognitive deficits. VCI may be caused by various mechanisms and metabolic pathways. The pathological mechanisms, in terms of cognitive deficits, may span from oxidative stress to vascular clearance of toxic waste products (such as amyloid beta) and from neuroinflammation to impaired function of microglia, astrocytes, pericytes, and endothelial cells. Impaired production of elements of the immune response, such as cytokines, and vascular factors, such as insulin-like growth factor 1 (IGF-1), may also affect cognitive functions. No single event could be seen as being the unique cause of cognitive deficits in VCI. These events are interconnected, and may produce cascade effects resulting in cognitive impairment.

GPR39 Localization in Aging Human Brain and Correlation of Expression and Polymorphism with Vascular Cognitive Impairment

“…Based on this and other observations, Waller et al concluded that microglial activation is a prominent feature of age-associated white matter lesions [35]. As the resident brain immune cell, microglia may be increased in number or activated by oxidative stress associated with SVD, which contributes to the pathogenesis of dementia [36]. Our finding that a high percentage of microglia in the aging brain express GPR39, and that the density of GPR39-positive cells is increased in the white matter of MCI dlPFC implicates GPR39 in the neuroinflammation underlying aging-related cognitive decline.…”

The Emerging Roles of Ferroptosis in Vascular Cognitive Impairment

“…Thus, CCH caused by continuously reducing CBF is the common pathomechanism of VCI, which not only reduces the supply of oxygen and nutrients, but also leads to the accumulation and deposition of harmful molecules in the brain. The sustained low cerebral blood supply caused impairment of structure and function of the blood–brain barrier (BBB) and neuronal tissue loss and finally manifests as a cognitive deficit (Dichgans and Leys, 2017; Hort et al, 2019). So far, however, no effective treatments have been applied to prevent the progression of the disease, which has led to serious social burden (Kalaria, 2016; Venkat et al, 2018).…”

The Influence of Virus Infection on Microglia and Accelerated Brain Aging

“…Physiological aging of the healthy brain is an age-dependent biological process and consists of deterioration of structure and function [ 7 , 8 , 9 , 10 , 11 , 12 ]. However, brain aging can be accelerated by multiple factors, due to traumatic events [ 13 , 14 ], following neurovascular conditions [ 15 , 16 , 17 ], or related to specific brain diseases, including Alzheimer’s and Parkinson’s disease. Accelerated brain aging is often related to enhanced neurodegeneration, which includes loss of neuronal cell structure and function due to (1) metabolic changes [ 18 ], (2) neuronal cell death [ 19 ] (3) decline in the neuronal network [ 20 ], (4) neuronal functional deficiency [ 21 ], (5) decline in neuronal regeneration [ 22 , 23 , 24 ], or (6) a combination of the mentioned reasons.…”