Abstract
BackgroundAlzheimer’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.ResultsUsing 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.ConclusionThese 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.
Highlights
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)
Icv‐delivering clusterin peptide D‐[113–122] improved memory dysfunction of Tg6799 transgenic mouse We firstly investigated whether clusterin peptide D-[113– 122] infusion could improve the memory dysfunction of Tg6799 transgenic mouse by Morris water maze test
These results suggested that clusterin peptide D-[113–122] was able to improve memory impairment in AD transgenic mouse
Summary
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). Alzheimer’s disease (AD) is a common neurodegenerative disease in elderly It is characterized by abnormal amyloid deposition such as amyloid plaque and cerebral amyloid angiopathy (CAA), neurofibrillary tangle and neuron loss. Named apolipoprotein J, is a major glycoprotein firstly identified in ram rete testis fluid [7] and recently shown to play an important role in AD [8]. Clusterin was shown to bind low density lipoprotein receptor-2 (LRP-2) to facilitate Aβ clearance [16, 17]. This pathway could cooperate with Apolipoprotein E, another well-known risk factor of AD to maintain vascular clearance of Aβ [18, 19]
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