Therapeutic modulation of cerebral microhemorrhage in a mouse model of cerebral amyloid angiopathy

Abstract

Background and purpose: The aging brain demonstrates frequent MRI and pathological evidence of cerebral microbleeds, which are often associated with cerebral amyloid angiopathy. To develop new therapeutic strategies for this disorder, we studied cerebral microhemorrhage in a well-characterized mouse model of cerebral amyloid angiopathy.

Methods: Tg2576 mice were studied at ages ranging from 2 to 21 months. Spontaneous and induced microscopic bleeding was analyzed with and without a passive anti-amyloid immunization regimen and dietary supplementation of ischemic stroke prevention medication dipyridamole.

Results: Areas of microhemorrhage were easily demonstrated and were significantly more prominent in the oldest mice and in animals treated with anti-amyloid immunotherapy. Dipyridamole supplementation in the diet generated plasma levels >790 ng/mL within the range seen clinically. Dipyridamole treatment did not worsen frequency and size of cerebral microscopic bleeding.

Conclusions: The Tg2576 mouse is a useful model to study progression and modification of spontaneous and immunotherapy-induced cerebral microhemorrhage. Absence of microhemorrhage worsening with dipyridamole treatment suggests a potential therapeutic role of this agent when ischemic and microhemorrhagic lesions coexist.

FIGURE 1

Tg2576 mice progressively accumulate microhemorrhages with aging. Number (A) and size (B) of microhemorrhages assessed in 15- and 24-month old Tg2576 mice fed regular mouse chow. (**- P<0.01; * - P< 0.05)

FIGURE 2

Dipyridamole diet (5 g/kg of chow) does not affect the number (A) nor the size (B) of spontaneous microhemorrhages in 15-month old Tg2576 mice receiving 3 months dipyridamole (DIP).

FIGURE 3

Immunotherapy effects on number (A) and size (B) of microhemorrhages. Twenty-one-month-old mice were treated for 11 weeks with control (high fat) diet, or with diet supplemented with dipyridamole (DIP; 5 g/kg chow). Two weeks after initiation of the diet, mice were given anti-Aβ40 antibody (Abody, 10mg/kg, i.p., weekly for 9 weeks). Significantly increased number of microhemorrhages after immunotherapy was seen with both diets, and significantly increased microhemorrhage size with control diet only. Representative photomicrographs were taken from cortex (C). Magnification: ×100. (**- P<0.01; * - P< 0.05).