Lessons from a mouse model characterizing features of vascular cognitive impairment with white matter changes

Abstract

With the demographic shift in age in advanced countries inexorably set to progress in the 21st century, dementia will become one of the most important health problems worldwide. Vascular cognitive impairment is the second most common type of dementia after Alzheimer's disease and is frequently responsible for the cognitive decline of the elderly. It is characterized by cerebrovascular white matter changes; thus, in order to investigate the underlying mechanisms involved in white matter changes, a mouse model of chronic cerebral hypoperfusion has been developed, which involves the narrowing of the bilateral common carotid arteries with newly designed microcoils. The purpose of this paper is to provide a comprehensive summary of the achievements made with the model that shows good reproducibility of the white matter changes characterized by blood-brain barrier disruption, glial activation, oxidative stress, and oligodendrocyte loss following chronic cerebral hypoperfusion. Detailed characterization of this model may help to decipher the substrates associated with impaired memory and move toward a more integrated therapy of vascular cognitive impairment.

Figure 1

The procedure for BCAS and the microcoil. The microcoil is twined by rotating it around the CCA just proximal to the carotid bifurcation of a C57BL/6J mouse (a). Representative photographs of a FITC-perfused common carotid artery before (left) and after (right) placement of a microcoil (b). The microcoil is made from piano wire (wire diameter of 0.08 mm) with an inner diameter of 0.18 mm, pitch 0.50 mm, and total length 2.5 mm (c).

Figure 2

Cerebral blood flow after BCAS. This figure shows cerebral blood flow evaluated with laser Doppler flowmetry in mice at 2.5 months of age after the surgery using microcoils with diameter of 0.16 mm, 0.18 mm, 0.20 mm, and 0.22 mm. The data represent mean values expressed as a percentage of the preoperative value.

Figure 3

White matter changes after BCAS. Photomicrographs of Klüver-Barrera staining in the cerebral cortex (a, b), corpus callosum (c, d), and caudoputamen (e, f). The left column (a, c, e) indicates the brain from a sham-operated mouse, and the right column (b, d, f) indicates a brain after BCAS-operated mouse using microcoils with 0.18 mm diameter for 30 days. Note that the WM changes are the most intense in the medial part of the corpus callosum adjacent to the lateral ventricle (arrows). The histogram shows temporal profiles of the WM changes, the severity of which is semiquantitatively graded into four levels (g). Scale bar, 500 μm (a, b), 50 μm (c, d), and 25 μm (e, f).

Figure 4

A schematic illustration of oligovascular niche. In the “oligovascular niche,” crosstalk between endothelial cells and oligodendrocytes mediated by an exchange of soluble signals (e.g., trophic factors or chemical messengers) might play an important role in sustaining oligodendrocyte homeostasis and WM integrity. Since oxidative stress and inflammation caused by cerebral hypoperfusion would be detrimental for this niche, maintenance of white matter integrity or oligovascular protection could be achieved by proangiogenic, antioxidative, and anti-inflammatory interventions. OPC: oligodendrocyte precursor cell.