Title:Pathogenesis of Abeta Oligomers in Synaptic Failure
VOLUME: 10 ISSUE: 3
Author(s):Senthilkumar Sivanesan, Aaron Tan and Jayakumar Rajadas
Affiliation:Biomaterials and Advanced Drug Delivery Laboratory, Stanford University School of Medicine, Stanford, CA, USA.
Keywords:Abeta, membrane, memory, oligomers, receptors, spine, synapse
Abstract:The soluble Abeta oligomers in brain are highly correlated with memory related synaptic dysfunctions in Alzheimer’s
disease (AD). However, more recent studies implicate the involvement of Abeta dimers and trimers in memory
related AD pathology. Apparently, Abeta oligomers can bind with cellular prion protein at the membrane receptors, forming
annular amyloid pores and membrane ion channels to induce aberrant spine cytoskeletal changes. Hence synapse targeting
of Abeta oligomers involves activation of many receptors such as N-Methyl-D-aspartate (NMDA), alpha-amino-3-
hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), nicotinic acetylcholine (nAChRs), p75 neurotrophin (p75NTR)
following aberrant clustering of metabotropic glutamate receptors (mGluR5) leading to neuronal loss and LTP failure. In
particular, NMDA and AMPA receptor activation by soluble amyloid oligomers involves calcium mediated mitochondrial
dysfunction, decreased Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) levels at the synapses accompanying
dramatic loss of synaptic proteins such as postsynaptic density-95 (PSD-95), dynamin-1 and synaptophysin. This kind of
receptor-Abeta oligomer interaction might eventually affect the neuronal membrane integrity by altering dielectric barrier,
various synaptic proteins, spine morphology and density and P/Q calcium currents that might provoke a cascade of events
leading to neuronal loss and memory failure. In this review, we try to explain in detail the various possible mechanisms
that connect Abeta oligomers with synapse damage and memory failure.
