Department of Brain Sciences, Imperial College London, Hammersmith Hospital, London, UK.
Glia. 2020 May;68(5):1017-1030. doi: 10.1002/glia.23759. Epub 2019 Dec 4.
The role of astrocytes in the progression of Alzheimer's disease (AD) remains poorly understood. We assessed the consequences of ablating astrocytic proliferation in 9 months old double transgenic APP23/GFAP-TK mice. Treatment of these mice with the antiviral agent ganciclovir conditionally ablates proliferating reactive astrocytes. The loss of proliferating astrocytes resulted in significantly increased levels of monomeric amyloid-β (Aβ) in brain homogenates, associated with reduced enzymatic degradation and clearance mechanisms. In addition, our data revealed exacerbated memory deficits in mice lacking proliferating astrocytes concomitant with decreased levels of synaptic markers and higher expression of pro-inflammatory cytokines. Our data suggest that loss of reactive astrocytes in AD aggravates amyloid pathology and memory loss, possibly via disruption of amyloid clearance and enhanced neuroinflammation.
星形胶质细胞在阿尔茨海默病（AD）进展中的作用仍知之甚少。我们评估了在 9 个月大的双转基因 APP23/GFAP-TK 小鼠中消除星形胶质细胞增殖的后果。用抗病毒药物更昔洛韦处理这些小鼠可条件性消除增殖性反应性星形胶质细胞。增殖性星形胶质细胞的丧失导致脑匀浆中单体淀粉样β（Aβ）水平显著增加，同时降低了酶降解和清除机制。此外，我们的数据显示，缺乏增殖性星形胶质细胞的小鼠记忆缺陷加剧，同时突触标志物水平降低，促炎细胞因子表达增加。我们的数据表明，AD 中反应性星形胶质细胞的丧失加剧了淀粉样蛋白病理和记忆丧失，可能是通过破坏淀粉样蛋白清除和增强神经炎症。
