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 (A beta) peptide accumulation. Protein aggregates in the cell are cleared by autophagy, a mechanism impaired in AD. To investigate the role of autophagy in A beta 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 A beta plaque burden. This reduction of A beta plaque load was due to inhibition of A beta secretion, which led to aberrant intraneuronal A beta 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 A beta metabolism: autophagy influences secretion of A beta to the extracellular space and thereby directly affects A beta plaque formation, a pathological hallmark of AD.