MEMANTINE ATTENUATES VASCULAR AMYLOID β DEPOSITS AND SPONTANEOUS HEMORRHAGES IN MOUSE MODELS OF CEREBRAL AMYLOID ANGIOPATHY

Abstract

The pathological hallmark of cerebral amyloid angiopathy (CAA) is cerebrovascular amyloid beta (Aβ) deposits. Although effective treatment for preventing Aβ deposits on cerebrovascular smooth muscle cells is needed, therapy for CAA is understudied. N methyl-D-aspartate receptor partial agonist has been used for patients with AD for improving cognitive impairments. Nevertheless, therapeutic effects of memantine for CAA are unclear. In the present study, we investigated whether memantine attenuates CAA using mice models of CAA (APP23 mice). Heterozygous APP23 mice were allocated to either the memantine or placebo group, and age matched wild-type littermates as control. Memantine hydrochloride was dissolved in drinking water (20 mg/ kg/ day). Memantine treatments were started at 6 months of age and continued for 12 months. To evaluate memantine effects on CAA severities, we quantified the numbers of CAA-affected vessels in leptomeningeal and cortical arteries, and also quantified the numbers of cerebral hemorrhages by berlin blue staining. We measured soluble and insoluble Aβ40 and Aβ42 levels by ELISA, and mRNA and protein levels (Amyloid precursor protein [APP], BACE-1, Presenillin-1, ADAM10, Insulin degrading enzyme [IDE]) by real-time PCR and western blot, respectively. Cognitive functions were assessed by Morris water maze. We found that memantine treatment reduced Aβ deposits in leptomeningeal and cortical arteries, and the numbers of cerebral hemorrhages in cortex of APP23 mice. Soluble and insoluble Aβ40 levels in cortex and hippocampus were lower, and IDE mRNA and protein levels in hippocampus were higher in memantine-treated APP23 mice compared with those treated with vehicle. Memantine also improved both escape latency and path length during acquisition phase and augmented preferences for the target quadrant during probe trial in memantine-treated APP23 mice. Memantine treatment reduced vascular Aβ deposits and spontaneous hemorrhages in APP23 mice brain. The attenuations of CAA severities by memantine may result from the degradations of Aβ via increase of IDE levels.