Premium
[O3–08–03]: CEREBROSPINAL FLUID MEASURES OF BLOOD BRAIN BARRIER INTEGRITY IN PSEN1 ‐RELATED ALZHEIMER's DISEASE
Author(s) -
Ringman John M.,
Sweeney Melanie D.,
Sagare Abhay,
Chang Chui Helena,
Zlokovic Berislav
Publication year - 2017
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2017.07.346
Subject(s) - psen1 , medicine , cerebrospinal fluid , blood–brain barrier , biomarker , fibrinogen , lumbar puncture , dementia , population , pericyte , pathology , oncology , alzheimer's disease , disease , gastroenterology , central nervous system , biology , genetics , amyloid precursor protein , environmental health , endothelial stem cell , in vitro
Background: The pathological hallmark of cerebral amyloid angiopathy (CAA) is cerebrovascular amyloid beta (Ab) deposits. Although effective treatment for preventing Ab 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 withAD for improving cognitive impairments.Nevertheless, therapeutic effects of memantine for CAA are unclear. In the present study, we investigatedwhethermemantine attenuatesCAAusingmicemodels of CAA (APP23 mice). Methods: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 Ab40 and Ab42 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. Results: We found that memantine treatment reduced Ab deposits in leptomeningeal andcortical arteries, and thenumbers of cerebral hemorrhages in cortex of APP23 mice. Soluble and insoluble Ab40 levels in cortex and hippocampuswere lower, and IDEmRNAandprotein 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 memantinetreated APP23 mice. Conclusions: Memantine treatment reduced vascular Ab deposits and spontaneous hemorrhages in APP23 mice brain. The attenuations of CAA severities by memantine may result from the degradations of Ab via increase of IDE levels.