Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
Cell Rep. 2013 Oct 17;5(1):61-9. doi: 10.1016/j.celrep.2013.08.042. Epub 2013 Oct 3.
Alzheimer's disease (AD) is a neurodegenerative disease biochemically characterized by aberrant protein aggregation, including amyloid beta (Aβ) peptide accumulation. Protein aggregates in the cell are cleared by autophagy, a mechanism impaired in AD. To investigate the role of autophagy in Aβ pathology in vivo, we crossed amyloid precursor protein (APP) transgenic mice with mice lacking autophagy in excitatory forebrain neurons obtained by conditional knockout of autophagy-related protein 7. Remarkably, autophagy deficiency drastically reduced extracellular Aβ plaque burden. This reduction of Aβ plaque load was due to inhibition of Aβ secretion, which led to aberrant intraneuronal Aβ accumulation in the perinuclear region. Moreover, autophagy-deficiency-induced neurodegeneration was exacerbated by amyloidosis, which together severely impaired memory. Our results establish a function for autophagy in Aβ metabolism: autophagy influences secretion of Aβ to the extracellular space and thereby directly affects Aβ plaque formation, a pathological hallmark of AD.
阿尔茨海默病（AD）是一种神经退行性疾病，其生物化学特征为异常蛋白聚集，包括淀粉样β（Aβ）肽积累。细胞内的蛋白聚集体通过自噬清除，AD 中自噬机制受损。为了研究自噬在体内 Aβ病理学中的作用，我们将淀粉样前体蛋白（APP）转基因小鼠与通过条件性敲除自噬相关蛋白 7 缺失兴奋性前脑神经元中的自噬的小鼠进行杂交。值得注意的是，自噬缺陷大大减少了细胞外 Aβ斑块负担。这种 Aβ 斑块负荷的减少是由于 Aβ 分泌的抑制，导致核周区域异常的神经元内 Aβ 积累。此外，淀粉样变性加剧了自噬缺陷诱导的神经退行性变，从而严重损害了记忆。我们的研究结果确立了自噬在 Aβ 代谢中的作用：自噬影响 Aβ 向细胞外空间的分泌，从而直接影响 Aβ 斑块的形成，这是 AD 的病理标志。
