Synaptic Targeting by Alzheimer's-Related Amyloid β Oligomers

By P. Lacor, Maria C. F. Buniel, Lei Chang, Sara J. Fernandez, Yuesong Gong, K. Viola, M. Lambert, P. Velasco, Eileen Bigio, C. Finch and 2 more. Journal of Neuroscience, 2004

861 citations recorded by the source corpus.

The cognitive hallmark of early Alzheimer's disease (AD) is an extraordinary inability to form new memories. For many years, this dementia was attributed to nerve-cell death induced by deposits of fibrillar amyloid β (Aβ). A newer hypothesis has emerged, however, in which early memory loss is considered a synapse failure caused by soluble Aβ oligomers. Such oligomers rapidly block long-term potentiation, a classic experimental paradigm for synaptic plasticity, and they are strikingly elevated in AD brain tissue and transgenic-mouse AD models. The current work characterizes the manner in which Aβ oligomers attack neurons. Antibodies raised against synthetic oligomers applied to AD brain sections were found to give diffuse stain around neuronal cell bodies, suggestive of a dendritic pattern, whereas soluble brain extracts showed robust AD-dependent reactivity in dot immunoblots. Antigens in unfractionated AD extracts attached with specificity to cultured rat hippocampal neurons, binding within dendritic arbors at discrete puncta. Crude fractionation showed ligand size to be between 10 and 100 kDa. Synthetic Aβ oligomers of the same size gave identical punctate binding, which was highly selective for particular neurons. Image analysis by confocal double-label immunofluorescence established that >90% of the punctate oligomer binding sites colocalized with the synaptic marker PSD-95 (postsynaptic density protein 95). Synaptic binding was accompanied by ectopic induction of Arc, a synaptic immediate-early gene, the overexpression of which has been linked to dysfunctional learning. Results suggest the hypothesis that targeting and functional disruption of particular synapses by Aβ oligomers may provide a molecular basis for the specific loss of memory function in early AD.

Subfields: Cellular and Molecular Neuroscience, Neurology, Physiology

View Paper: https://www.semanticscholar.org/paper/25433848289c43a26afd44412edbda9bc408e1d1

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cellular and Molecular Neuroscience

1. D. Holtzman
2. D. Selkoe
3. G. Bu
4. D. Walsh
5. W. Klein
6. K. Viola
7. P. Velasco
8. P. Lacor

In Neurology

1. D. Selkoe
2. G. Bu
3. D. Holtzman
4. E. Niki

In Physiology

1. D. Selkoe
2. D. Holtzman
3. G. Bu
4. J. Herz
5. K. Viola
6. W. Klein
7. D. Walsh
8. P. Velasco

Citations in the corpus

• Aβ Oligomer-Induced Aberrations in Synapse Composition, Shape, and Density Provide a Molecular Basis for Loss of Connectivity in Alzheimer's Disease (2007, methodology): “Because ADDLs are gain-offunction ligands that target synaptic spines (Lacor et al., 2004; Klein et al., 2007) and disrupt synaptic plasticity (Lambert et al., 1998; Wang et al., 2002), their cellular actions may be particularly germane to neuropil damage (Klein et al., 2001; Klein, 2006).”
• Apolipoprotein E and apolipoprotein E receptors: normal biology and roles in Alzheimer disease. (2012, background): “…strong inducers of synaptic suppression, and several mechanisms have been proposed to explain this effect (Lambert et al. 1998; Walsh et al. 2002; Lacor et al. 2004; Snyder et al. 2005; Lesne et al. 2006; Townsend et al. 2006; Haass and Selkoe 2007; Shankar et al. 2007; Berman et al. 2008; Puzzo…”
• A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer’s disease with lecanemab, an anti-Aβ protofibril antibody (2020, background): “Soluble Aβ aggregates have been shown to be more toxic than monomers or insoluble fibrils [4, 6–10], and we hypothesized that reducing these soluble Aβ aggregates could represent an effective treatment approach in early stages of AD [4, 11, 12].”
• 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).”
• Aβ Oligomers – a decade of discovery (2007, background): “Consistent with their synaptotoxic activity, ADDLs have been shown to avidly bind and decorate dendritic arbors of certain cultured neurons (Gong et al. 2003; Lacor et al. 2004).”