Aβ Oligomer-Induced Aberrations in Synapse Composition, Shape, and Density Provide a Molecular Basis for Loss of Connectivity in Alzheimer's Disease

By P. Lacor, Maria C. F. Buniel, Paul W. Furlow, Antonio Sanz Clemente, P. Velasco, M. Wood, K. Viola, W. Klein. Journal of Neuroscience, 2007

1,061 citations recorded by the source corpus.

The basis for memory loss in early Alzheimer's disease (AD) seems likely to involve synaptic damage caused by soluble Aβ-derived oligomers (ADDLs). ADDLs have been shown to build up in the brain and CSF of AD patients and are known to interfere with mechanisms of synaptic plasticity, acting as gain-of-function ligands that attach to synapses. Because of the correlation between AD dementia and synaptic degeneration, we investigated here the ability of ADDLs to affect synapse composition, structure, and abundance. Using highly differentiated cultures of hippocampal neurons, a preferred model for studies of synapse cell biology, we found that ADDLs bound to neurons with specificity, attaching to presumed excitatory pyramidal neurons but not GABAergic neurons. Fractionation of ADDLs bound to forebrain synaptosomes showed association with postsynaptic density complexes containing NMDA receptors, consistent with observed attachment of ADDLs to dendritic spines. During binding to hippocampal neurons, ADDLs promoted a rapid decrease in membrane expression of memory-related receptors (NMDA and EphB2). Continued exposure resulted in abnormal spine morphology, with induction of long thin spines reminiscent of the morphology found in mental retardation, deafferentation, and prionoses. Ultimately, ADDLs caused a significant decrease in spine density. Synaptic deterioration, which was accompanied by decreased levels of the spine cytoskeletal protein drebrin, was blocked by the Alzheimer's therapeutic drug Namenda. The observed disruption of dendritic spines links ADDLs to a major facet of AD pathology, providing strong evidence that ADDLs in AD brain cause neuropil damage believed to underlie dementia.

Subfields: Cellular and Molecular Neuroscience, Pharmacology, Physiology

View Paper: https://www.semanticscholar.org/paper/d1b18cd7c7e055eea96a8edc0f1bf77ef2f720db

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Citations in the corpus

Memantine: a NMDA receptor antagonist that improves memory by restoration of homeostasis in the glutamatergic system--too little activation is bad, too much is even worse. (2007, background): “Subsequent consequences of this such as synaptic deterioration including loss of the spine cytoskeletal protein debrin were completely prevented by memantine at a concentration of 5 mM (Lacor et al., 2007).”
Linking Lipids to Alzheimer’s Disease: Cholesterol and Beyond (2011, background): “Furthermore, oligomeric assemblies of amyloid-β appear to have high affinity for synaptic membranes, particularly dendritic spine”
Biosensing with plasmonic nanosensors. (2008, methodology): “For example, an LSPR-shift assay was used to measure concentrations of amyloid-derived diffusible ligands (ADDLs), a neurotoxin that is thought to be important in the pathology of Alzheimer's diseas”
Impaired Balance of Mitochondria Fission and Fusion in Alzheimer Disease (2009, background): “Along these lines, A overexpression decreases spine density (Hsieh et al., 2006) and ADDLs directly bind to dendritic spines (Lacor et al., 2004) and induce abnormalities in spine composition, shape, and abundance (Lacor et al., 2007).”
Eph-ephrin bidirectional signaling in physiology and disease. (2008, background): “It will be interesting to investigate whether Eph/ephrin dysfunction may cause some forms of mental retardation and the accompanying dendritic spine abnormalities, and whether downregulation of EphB2 cell-surface clusters by soluble amyloid β protein has a role in the synapse/spine degeneration and ”