AICD Nuclear Signaling and Its Possible Contribution to Alzheimer's Disease

作者：Konietzko Uwe^*

来源：Current Alzheimer Research, 2012, 9(2): 200-216.

DOI：10.2174/156720512799361673

• Alzheimer's disease
• amyloid precursor protein
• APP
• AICD
• nuclear signaling
• Fe65
• regulated intramembrane proteolysis
• RIP
• synapse
• endosome

Altered proteolytic processing of the beta-amyloid precursor protein (APP) is a central event in familial and sporadic Alzheimer's disease (AD). In a process termed regulated intramembrane proteolysis (RIP), APP first undergoes ectodomain shedding executed either by alpha- secretases at the plasma membrane or by beta-secretase in the endosomal compartment. The remaining membrane-anchored stubs are cleaved within the membrane plane by the gamma-secretase complex, releasing the APP intracellular domain (AICD) into the cytosol and leading to the generation of the A beta peptide in the amyloidogenic pathway that is initiated by beta-secretase. The A beta peptides aggregate to form soluble oligomers and finally deposit into amyloid plaques that are a hallmark of AD. Recent evidence indicates a role for A beta oligomers in regulating synaptic plasticity with excess amounts of oligomers disrupting synaptic function. The amyloid cascade hypothesis of AD is centered on the A beta peptide, the APP fragment that has been most intensely studied, while other cleavage products have been largely neglected. The secreted ectodomain generated after alpha-cleavage in the non-amyloidogenic pathway has neurotrophic and neuroproliferative activities, thus opposing the neurotoxicity observed with high concentrations of A beta. Further, in analogy to many other membrane proteins that are subject to RIP, AICD can translocate to the nucleus to regulate transcription. Many RIP substrates are localized to the synapse and thus could convey a direct signal from the synapse to the nucleus upon cleavage. Evidence indicates that only the amyloidogenic pathway generates AICD capable of nuclear signaling, due to the subcellular compartmentalization of APP processing. In aging and sporadic AD there is an increase in beta-secretase levels and activity generating more A beta peptides and concomitantly leading to an increase in AICD nuclear signaling. In this review, I summarize the current knowledge on AICD nuclear signaling and propose mechanisms to explain how this physiological function of APP might impact the pathology seen in AD.

• 出版日期2012-2