Subcellular trafficking of the amyloid precursor protein gene family and its pathogenic role in Alzheimer's disease.
Changes in the intracellular transport of amyloid precursor protein (APP) affect the extent to which APP is exposed to alpha- or beta-secretase in a common subcellular compartment and therefore directly influence the degree to which APP undergoes the amyloidogenic pathway leading to generation of beta-amyloid. As the presynaptic regions of neurons are thought to be the main source of beta-amyloid in the brain, attention has been focused on axonal APP trafficking. APP is transported along axons by a fast, kinesin-dependent anterograde transport mechanism. Despite the wealth of in vivo and in vitro data that have accumulated regarding the connection of APP to kinesin transport, it is not yet clear if APP is coupled to its specific motor protein via an intracellular interaction partner, such as the c-Jun N-terminal kinase-interacting protein, or by yet another unknown molecular mechanism. The cargo proteins that form a functional complex with APP are also unknown. Due to the long lifespan, and vast extent, of neurons, in particular axons, neurons are highly sensitive to changes in subcellular transport. Recent in vitro and in vivo studies have shown that variations in APP or tau affect mitochondrial and synaptic vesicle transport. Further, it was shown that this axonal dysfunction might lead to impaired synaptic plasticity, which is crucial for neuronal viability and function. Thus, changes in APP and tau expression may cause perturbed axonal transport and changes in APP processing, contributing to cognitive decline and neurodegeneration in Alzheimer's disease.
Kins
Stefan
S
Zentrum für Molekulare Biologie der Universität Heidelberg, Heidelberg, Germany. s.kins@zmbh.uni-heidelberg.de
Lauther
Nadine
N
Szodorai
Anita
A
Beyreuther
Konrad
K
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001370:Axonal Transport / Q000502:physiology*; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D009474:Neurons / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology
D016564:Amyloid beta-Protein Precursor