Aβ Secretion and Plaque Formation Depend on Autophagy

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. [Display omitted] •Aβ secretion is dependent on autophagy•Autophagy defect decreases extracellular Aβ deposition•Aβ accumulates intracellularly upon autophagy deficiency, causing neurodegeneration•Autophagy defect causes cognitive dysfunction in a mouse model of Alzheimer’s disease In this study, Nilsson, Saido, and colleagues show that autophagy influences secretion of Alzheimer’s disease (AD) amyloid beta (Aβ) peptide. Autophagy deficiency, achieved by genetic deletion of autophagy-related gene 7 in excitatory neurons in mouse brain, reduced Aβ plaque load and caused intracellular Aβ accumulation. In addition, amyloidosis exacerbated autophagy-deficiency-induced neurodegeneration and caused severe memory impairment. Thus, autophagy has a key role in the two main characteristics of AD: intracellular Aβ accumulation and extracellular Aβ plaque formation.