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Why Alzheimer’s is a disease of memory: The attack on synapses by Aß oligomers (ADDLs)

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The Journal of Nutrition Health and Aging

Abstract

Individuals with early-stage Alzheimer’s disease (AD) suffer from profound failure to form new memories. A novel molecular mechanism with implications for therapeutics and diagnostics is now emerging in which the specificity of AD for memory derives from disruption of plasticity at synapses targeted by neurologically active Aβ oligomers (1). We have named these oligomers “ADDLs” (for pathogenic Aβ-Derived Diffusible Ligands). ADDLs constitute metastable alternatives to the disease-defining Aβ fibrils deposited in amyloid plaques. In AD brain, ADDLs accumulate primarily as Aβ 12mers (2) (∼54 kDa) and can be found in dot-like clusters distinct from senile plaques (3). Oligomers of equal mass have been reported to occur in tg-mouse AD models where they emerge concomitantly with memory failure (4), consistent with ADDL inhibition of LTP (1). In cell biology studies, ADDLs act as pathogenic gain-of-function ligands that target particular synapses, binding to synaptic spines at or near NMDA receptors (5,6). Binding produces ectopic expression of the memory-linked immediate early gene Arc. Subsequent ADDL-induced abnormalities in spine morphology and synaptic receptor composition (7) are predicted consequences of Arc overexpression, a pathology associated with memory dysfunction in tg-Arc mice. Significantly, the attack on synapses provides a plausible mechanism unifying memory dysfunction with major features of AD neuropathology; recent findings show that ADDL binding instigates synapse loss, oxidative damage, and AD-type tau hyperphosphorylation. Acting as novel neurotoxins that putatively account for memory loss and neuropathology, ADDLs present significant targets for disease-modifying therapeutics in AD.

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Authors and Affiliations

  1. Department of Neurobiology and Physiology, Cognitive Neurology and Alzheimer’s Disease Center, Northwestern University, 60208, Evanston, IL

    K. L. Viola, P. T. Velasco & W. L. Klein

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  1. K. L. Viola
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  2. P. T. Velasco
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  3. W. L. Klein
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Viola, K.L., Velasco, P.T. & Klein, W.L. Why Alzheimer’s is a disease of memory: The attack on synapses by Aß oligomers (ADDLs). J Nutr Health Aging 12 (Suppl 1), S51–S57 (2008). https://doi.org/10.1007/BF02982587

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  • DOI: https://doi.org/10.1007/BF02982587

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