Alzheimer's disease (AD) is the leading cause of dementia. Amyloid plaques in the brain remain a pathological feature of AD. These plaques are primarily composed of amyloid β-protein (Aβ). It has been postulated that glycogen synthase kinase-3β (GSK3β) activity might exert a central role in the development of AD. GSK3β activity has been implicated in tau phosphorylation, APP processing, Aβ production and neurodegeneration. Quetiapine is frequently used to treat psychoses in AD patients at the late stage and has inhibitory effects on GSK3β activity in mouse brains after acute/subchronic treatment. Therefore, the proposed hypothesis is that chronic quetiapine administration after amyloid plaque onset reduces AD like pathology and alleviates AD like behaviours in APP/PS1 transgenic mice by inhibiting GSK3β activity.
APP/PS1 transgenic mice were treated with quetiapine (2.5, 5 mg/kg/day) in drinking water starting from 3.5 months of age, for a period of 8 months. One week after behaviour testing, mice were sacrificed at 12 months of age. Half of the hemispheres were rapidly frozen for immunoblot and ELISA analyses and the other half were fixed with 4% paraformaldehyde for histological analyses.
Quetiapine treatment reduced amyloid plaques formation in the cortex and hippocampus of AD mice. It also improved the behavioural deficits in these mice, including attenuating impaired memory and anxiety-like phenotypes. In addition, chronic quetiapine administration inhibited GSK3β, which resulted in reduced production of Aβ in cortices and hippocampi of transgenic mice. Quetiapine treatment also significantly decreased the activation of astrocytes and attenuated synapse integrity impairment in transgenic mice. These findings suggest that early application of quetiapine can alleviate memory deficits and pathological changes in the APP/PS1 transgenic mouse model of AD, and further support that modulation of GSK3β activity by quetiapine may be a therapeutic option for AD.
| Identifer | oai:union.ndltd.org:MANITOBA/oai:mspace.lib.umanitoba.ca:1993/4736 |
| Date | 14 July 2011 |
| Creators | Zhu, Shenghua |
| Contributors | Li, Xin-Min (Human Anatomy and Cell Science) Kong, Jiming (Human Anatomy and Cell Science), Vrontakis, Maria (Human Anatomy and Cell Science) He, Jue (Psychiatry) |
| Source Sets | University of Manitoba Canada |
| Language | en_US |
| Detected Language | English |
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