Intraventricular infusion of clusterin ameliorated cognition and pathology in Tg6799 model of Alzheimer's disease

• Published in: BMC neuroscience Vol. 19; no. 1; p. 2
• Main Authors: Qi, Xue-Mei, Wang, Cheng, Chu, Xing-Kun, Li, Gen, Ma, Jian-Fang
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 25.01.2018; BioMed Central; BMC
• Subjects: Alzheimer Disease - drug therapy; Alzheimer's disease; Amyloid; Amyloid beta-Peptides - metabolism; Amyloid beta-protein; Analysis; Animals; Blood-Brain Barrier - drug effects; Brain - drug effects; Cerebral Amyloid Angiopathy - drug therapy; Clusterin; Clusterin - administration & dosage; Clusterin - pharmacology; Cognition - drug effects; Development and progression; Disease Models, Animal; Genetic aspects; Infusions, Intraventricular; LRP-2; Mice, Transgenic; Physiological aspects; China; Amyloid; LRP-2; Alzheimer’s disease; Clusterin
• ISSN: 1471-2202; 1471-2202
• DOI: 10.1186/s12868-018-0402-7

Alzheimer's disease (AD) is characterized by the deposition of amyloid-β (Aβ) in brain parenchyma and cerebral blood vessels as cerebral amyloid angiopathy (CAA). Clusterin, a chaperon protein associated with Aβ aggregation, toxicity and transport through blood-brain barrier, may play a key role in the development of AD. Recently, clusterin peptide D-[113-122] was shown to mimic clusterin's function and exerted therapeutic effect in atherosclerosis. In this study, we investigated whether this clusterin peptide also affected (Aβ) deposition in AD transgenic mouse. Using a micropump, synthetic peptide 113-122 of clusterin protein (20 μg/200 μl) was infused into the lateral ventricle of 8-month 5 × FAD transgenic mouse model (Tg6799), for 2 weeks. Water-maze testing showed an improved cognitive function of the Tg6799 mice treated with clusterin. Immunocytochemistry and quantitative analysis revealed that intraventricular (icv) administration of clusterin peptide in Tg6799 mouse reduced Aβ plaques as well the severity of cerebral amyloid angiopathy. Enzyme-linked immunosorbent assay demonstrated a decreased in the soluble levels of Aβ (Aβ40 and Aβ42) in the brain. Western-blot revealed an increased level of LRP-2 after clusterin peptide treatment. These results suggest that icv infusion of clusterin peptide D-[113-122] offers a promising therapeutic approach to reduce Aβ deposition as well as CAA. The LRP2-mediated clearance system might be involved in the mechanism of these effects.