Memantine, a Noncompetitive N-Methyl-d-Aspartate Receptor Antagonist, Attenuates Cerebral Amyloid Angiopathy by Increasing Insulin-Degrading Enzyme Expression

Sporadic cerebral amyloid angiopathy (CAA) is characterized by cerebrovascular amyloid beta (Aβ) deposits and causes cerebral hemorrhages and dementia in elderly people. Memantine is used in Alzheimer’s disease to inhibit the glutamatergic system by blocking N-methyl-d-aspartate receptors. Its therapeutic effects in CAA are unclear, however. Here, we used APP23 transgenic mice (CAA model) to investigate whether memantine has direct therapeutic effects on cerebrovascular Aβ deposits. We treated APP23 mice and age-matched wild-type littermates with memantine at ages 6–18 months. We counted the numbers of vessels with Aβ and hemosiderin deposits. We measured soluble and insoluble Aβ40 and Aβ42 levels and levels of amyloid precursor protein (APP), APP-processing enzymes (α-, β-, γ-secretase), and Aβ-degrading enzymes (insulin-degrading enzyme [IDE], neprilysin). Memantine reduced cerebrovascular Aβ and hemosiderin deposits in APP23 mice. Compared with controls, memantine-treated APP23 mice had reduced Aβ40 levels and increased levels of hippocampal and vascular IDE. Our results suggest that memantine reduces cerebrovascular Aβ deposits by enhancing Aβ-cleaving IDE expression. The clinical availability of memantine may allow its use as a novel therapeutic agent in CAA.