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.

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.

阿茲海默症是一種隨著年齡老化有關的神經退化性疾病，其特徵主要為記憶喪失及認知功能失調。阿茲海默症有兩個主要的病理指標，包含了因為濤蛋白造成的神經纖維糾結以及乙型類澱粉蛋白堆積而成的老化斑塊。乙型類澱粉蛋白是由類澱粉前驅蛋白經β-分泌酶及γ-分泌酶連續裁切生成大小約4-kDa的胜肽。乙型類澱粉蛋白會相互堆積形成寡聚體，並且高分子量寡聚體進一步再堆積成不可溶性的乙型類澱粉蛋白纖維及老化斑塊。半乳糖凝集素-3是半乳糖凝集素家族的一員，目前已知半乳糖凝集素-3調節各種細胞的功能，例如發炎、腫瘤生長以及細胞間的黏附，而在癌症中則有促使癌細胞積聚的能力，然而在大腦中的作用仍尚不清楚。在本研究中，我們使用APP/PS1基因轉殖小鼠作為阿茲海默症的動物模型，並且在其大腦中研究半乳糖凝集素-3對於乙型類澱粉蛋白堆積的作用與機制。結果顯示在野生型小鼠的海馬迴中過度表現半乳糖凝集素-3會促進乙型類澱粉蛋白的堆積，而將乙型類澱粉蛋白注射在半乳糖凝集素-3基因剔除小鼠的海馬迴，則會觀察到乙型類澱粉蛋白寡聚合作用的減少。乙型類澱粉蛋白的注射也會增加海馬迴中半乳糖凝集素-3的表現。在APP/PS1小鼠的海馬迴可以觀察到半乳糖凝集素-3的表現量會隨著年齡增長而增加，而具有抑制發炎及免疫反應的PIAS1在APP/PS1小鼠海馬迴中的表現量則會隨著年齡增長而減少。在探討半乳糖凝集素-3調節乙型類澱粉蛋白寡具體作用的過程中，我們發現半乳糖凝集素-3基因剔除小鼠的海馬迴中能夠代謝乙型類澱粉蛋白的腦啡肽酶表現量是野生型小鼠的兩倍多。研究結果顯示半乳糖凝集素-3對於乙型類澱粉蛋白的堆積扮演了重要的角色以及可能在阿茲海默症的病理機制中具有重要的作用。 / Alzheimer’s disease (AD) is an age-related neurodegenerative disorder which is characterized by progressive loss of memory and other cognitive functions. The two pathological hallmarks of AD are extracellular amyloid plaque and flame-shaped neurofibrillary tangles of the tau protein. Aβ is a 4-kDa protein that is resulted from sequential cleavage of the amyloid precursor protein by beta-secretase and gamma-secretase. Once Aβ is produced, it will aggregate to form oligomers and high molecular weight (HMW) oligomers will further assemble to form large insoluble fibrils and plaque. Galectin-3 (Gal-3) is a member of the β-galactoside-binding galectin protein family. Gal-3 is known to regulate various cellular functions, such as inflammation, tumor progression and cell-cell adhesion. In cancer cell, Gal-3 enhances homotypic aggregation, but its role in the brain is much less known. In the present study, we examined the role and mechanism of Gal-3 in Aβ aggregation in the brain by adopting the APP/PS1 mice as an animal model of AD. Results revealed that overexpression of Gal-3 enhanced Aβ oligomerization, whereas Aβ injection into hippocampus of Gal-3 KO mice reduced Aβ oligomerization. Aβ injection also increased Gal-3 expression in the hippocampus. Gal-3 expression is also increased in APP/PS1 mice and this effect is more significant along with ageing. Meanwhile, the expression of protein inhibitor of activated STAT1 (PIAS1) that suppresses inflammation and immune response was decreased with ageing in APP/PS1 mice. We further found that the expression level of neprilysin, an enzyme that degrades Aβ, was increased for approximately two-folds in Gal-3 KO mice compared with WT mice. These results suggest that Gal-3 plays an important role in Aβ aggregation and possibly in the pathology of AD.