Alzheimer's disease (AD) is caused by a pronounced accumulation and aggregation of amyloid beta (Ab) and tau in the brain which induce a severe neurodegeneration and onset of clinical symptoms. Autophagy is a key cellular mechanism that degrades protein aggregates and which is impaired in AD. To elucidate the role of autophagy in neurodegeneration and its interplay with Ab, we generated autophagy-deficient amyloid precursor protein (APP) knock-in AD mice. Interestingly, deletion of autophagy leads to intracellular accumulation of Ab, which assembles into fibril structures that cause onset of neurodegeneration and impaired memory, while extracellular Aβ plaque deposition is decreased. This is due to a decreased autophagy-mediated secretion of Aβ through exosomes. Another enzymatic activity involved in Aβ metabolism is neprilysin, the major Aβ-degrading enzyme. In an attempt to find a way to activate neprilysin as a therapeutical approach to lower Aβ levels, we have identified subtype-specific somatostatin receptors that activate neprilysin, which are currently being targeted in high-throughput screening to identify blood-brain barrier permeable agonists.