Mouse models to study the effect of cardiovascular risk factors on brain structure and cognition

Abstract

Recent clinical data indicates that hemodynamic changes caused by cardiovascular diseases such as atherosclerosis, heart failure, and hypertension affect cognition. Yet, the underlying mechanisms of the resulting vascular cognitive impairment (VCI) are poorly understood. One reason for the lack of mechanistic insights in VCI is that research in dementia primarily focused on Alzheimer's disease models. To fill in this gap, we critically reviewed the published data and various models of VCI. Typical findings in VCI include reduced cerebral perfusion, blood-brain barrier alterations, white matter lesions, and cognitive deficits, which have also been reported in different cardiovascular mouse models. However, the tests performed are incomplete and differ between models, hampering a direct comparison between models and studies. Nevertheless, from the currently available data we conclude that a few existing surgical animal models show the key features of vascular cognitive decline, with the bilateral common carotid artery stenosis hypoperfusion mouse model as the most promising model. The transverse aortic constriction and myocardial infarction models may be good alternatives, but these models are as yet less characterized regarding the possible cerebral changes. Mixed models could be used to study the combined effects of different cardiovascular diseases on the deterioration of cognition during aging.

Figure 1

Most commonly used models for atherosclerosis, heart failure, and hypoperfusion to study the effect of cardiovascular risk factors on the brain. ApoE, apolipoprotein; BCAS, bilateral common carotid artery stenosis; BP, blood pressure; CBF, cerebral blood flow; TAC, transverse aortic constriction.

Figure 2

Proposed flow chart of disease progression primarily based on experimental data of the BCAS and TAC model. Because not a lot of successive studies have been performed, no clear distinction between cause and result of the different factors can be made. Aβ, amyloid β; ApoE, apolipoprotein; BBB, blood–brain barrier; BCAS, bilateral common carotid artery stenosis; TAC, transverse aortic constriction; WML, white matter lesion.