Traffic jam hypothesis: Relationship between endocytic dysfunction and Alzheimer's disease

Membrane trafficking pathways, like the endocytic pathway, carry out fundamental cellular processes that are essential for normal functioning. One such process is regulation of cell surface receptor signaling. A growing body of evidence suggests that beta-amyloid protein (A beta) plays a key role in Alzheimer's disease (AD) pathogenesis. Cleavage of A beta from its precursor, beta-amyloid precursor protein (APP), occurs through the endocytic pathway in neuronal cells. In early-stage AD, intraneuronal accumulation of abnormally enlarged endosomes is common, indicating that endosome trafficking is disrupted. Strikingly, genome-wide association studies reveal that several endocytosis-related genes are associated with AD onset. Also, recent studies demonstrate that alteration in endocytosis induces not only A beta pathology but also the propagation of tau protein pathology, another key pathological feature of AD. Endocytic dysfunction can disrupt neuronal physiological functions, such as synaptic vesicle transport and neurotransmitter release. Thus, traffic jams in the endocytic pathway may be involved in AD pathogenesis and may serve as a novel target for the development of new therapeutics. (C) 2017 Elsevier Ltd. All rights reserved.