Department of Genetics, Evolution and Environment, Institute of Healthy Ageing, University College London, London WC1E 6BT, UK.
UK Dementia Research Institute at UCL, London WC1E 6BT, UK.
Hum Mol Genet. 2020 Aug 11;29(14):2420-2434. doi: 10.1093/hmg/ddaa125.
Alzheimer's disease (AD) is the most common form of dementia and the most prevalent neurodegenerative disease. Genome-wide association studies have linked PICALM to AD risk. PICALM has been implicated in Aβ42 production and turnover, but whether it plays a direct role in modulating Aβ42 toxicity remains unclear. We found that increased expression of the Drosophila PICALM orthologue lap could rescue Aβ42 toxicity in an adult-onset model of AD, without affecting Aβ42 level. Imbalances in the glutamatergic system, leading to excessive, toxic stimulation, have been associated with AD. We found that Aβ42 caused the accumulation of presynaptic vesicular glutamate transporter (VGlut) and increased spontaneous glutamate release. Increased lap expression reversed these phenotypes back to control levels, suggesting that lap may modulate glutamatergic transmission. We also found that lap modulated the localization of amphiphysin (Amph), the homologue of another AD risk factor BIN1, and that Amph itself modulated postsynaptic glutamate receptor (GluRII) localization. We propose a model where PICALM modulates glutamatergic transmission, together with BIN1, to ameliorate synaptic dysfunction and disease progression.
阿尔茨海默病（AD）是最常见的痴呆症形式，也是最普遍的神经退行性疾病。全基因组关联研究将 PICALM 与 AD 风险联系起来。PICALM 被认为与 Aβ42 的产生和周转有关，但它是否在调节 Aβ42 毒性方面发挥直接作用仍不清楚。我们发现，增加果蝇 PICALM 同源物 lap 的表达可以挽救 AD 成人发病模型中的 Aβ42 毒性，而不影响 Aβ42 水平。谷氨酸能系统的失衡导致过度、毒性刺激，与 AD 有关。我们发现 Aβ42 导致突触前囊泡谷氨酸转运体（VGlut）的积累和自发谷氨酸释放增加。增加 lap 的表达将这些表型逆转回对照水平，表明 lap 可能调节谷氨酸能传递。我们还发现 lap 调节了另一个 AD 风险因子 BIN1 的同源物 amphiphysin（Amph）的定位，而 Amph 本身调节突触后谷氨酸受体（GluRII）的定位。我们提出了一个模型，其中 PICALM 与 BIN1 一起调节谷氨酸能传递，以改善突触功能障碍和疾病进展。
