Department of Neuroscience, Mayo Clinic, Collaborative Research Building CR03-010, 13400 E. Shea Blvd, Scottsdale, AZ, 85259, USA.
Neuroscience Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Scottsdale, AZ, 85259, USA.
Mol Neurodegener. 2020 Nov 27;15(1):71. doi: 10.1186/s13024-020-00416-1.
Accumulation of amyloid-β (Aβ) peptide in the brain is a pathological hallmark of Alzheimer's disease (AD). The clusterin (CLU) gene confers a risk for AD and CLU is highly upregulated in AD patients, with the common non-coding, protective CLU variants associated with increased expression. Although there is strong evidence implicating CLU in amyloid metabolism, the exact mechanism underlying the CLU involvement in AD is not fully understood or whether physiologic alterations of CLU levels in the brain would be protective.
We used a gene delivery approach to overexpress CLU in astrocytes, the major source of CLU expression in the brain. We found that CLU overexpression resulted in a significant reduction of total and fibrillar amyloid in both cortex and hippocampus in the APP/PS1 mouse model of AD amyloidosis. CLU overexpression also ameliorated amyloid-associated neurotoxicity and gliosis. To complement these overexpression studies, we also analyzed the effects of haploinsufficiency of Clu using heterozygous (Clu) mice and control littermates in the APP/PS1 model. CLU reduction led to a substantial increase in the amyloid plaque load in both cortex and hippocampus in APP/PS1; Clu mice compared to wild-type (APP/PS1; Clu) littermate controls, with a concomitant increase in neuritic dystrophy and gliosis.
Thus, both physiologic ~ 30% overexpression or ~ 50% reduction in CLU have substantial impacts on amyloid load and associated pathologies. Our results demonstrate that CLU plays a major role in Aβ accumulation in the brain and suggest that efforts aimed at CLU upregulation via pharmacological or gene delivery approaches offer a promising therapeutic strategy to regulate amyloid pathology.
脑内淀粉样β（Aβ）肽的积累是阿尔茨海默病（AD）的病理标志。 簇集蛋白（CLU）基因赋予 AD 的风险，AD 患者 CLU 高度上调，常见的非编码、保护性 CLU 变体与表达增加相关。尽管有强有力的证据表明 CLU 参与淀粉样代谢，但 CLU 参与 AD 的具体机制尚未完全阐明，或者脑内 CLU 水平的生理变化是否具有保护作用。
我们使用基因传递方法在星形胶质细胞中过表达 CLU，星形胶质细胞是脑内 CLU 表达的主要来源。我们发现，CLU 过表达可显著减少 APP/PS1 小鼠 AD 淀粉样变性模型中皮质和海马区的总淀粉样和纤维状淀粉样。CLU 过表达还改善了淀粉样相关神经毒性和神经胶质增生。为了补充这些过表达研究，我们还使用杂合子（Clu）小鼠和 APP/PS1 模型中的对照同窝仔鼠分析了 Clu 单倍不足的影响。与野生型（APP/PS1；Clu）同窝仔鼠对照相比，CLU 减少导致 APP/PS1 中皮质和海马区的淀粉样斑块负荷显著增加，伴有神经突营养不良和神经胶质增生增加。
因此，CLU 的生理表达增加约 30%或减少约 50%对淀粉样负荷和相关病理学都有重大影响。我们的结果表明 CLU 在脑内 Aβ 积累中起主要作用，并表明通过药理学或基因传递方法上调 CLU 以调节淀粉样蛋白病理学的努力提供了有希望的治疗策略。
