Autophagy, amyloidogenesis and Alzheimer disease

Autophagy is the sole pathway for organelle turnover in cells and is a vital pathway for degrading normal and aggregated proteins, particularly under stress or injury conditions. Recent evidence has shown that the amyloid beta peptide is generated from amyloid beta precursor protein (APP) during autophagic turnover of APP-rich organelles supplied by both autophagy and endocytosis. A beta generated during normal autophagy is subsequently degraded by lysosomes. Within neurons, autophagosomes and endosomes actively form in synapses and along neuritic processes but efficient clearance of these compartments requires their retrograde transport towards the neuronal cell body, where lysosomes are most concentrated. In Alzheimer disease, the maturation of autophagolysosomes and their retrograde transport are impeded, which leads to a massive accumulation of 'autophagy intermediates' (autophagic vacuoles) within large swellings along dystrophic and degenerating neurites. The combination of increased autophagy induction and defective clearance of A beta-generating autophagic vacuoles creates conditions favorable for A beta accumulation in Alzheimer disease.