Amyloid-beta oligomers: possible roles as key neurotoxins in Alzheimer's Disease

Abstract

Alzheimer's disease is the most common form of senile dementia. Although the amyloid-beta peptide was identified in 1984 as the major constituent of the senile plaques that characterize the disease, accumulating evidence indicates that the plaque density does not correspond well to the concurrent disease state. In order to resolve this disconnect, a number of recent studies have shifted away from the senile plaque and classical fibrillar forms of amyloid toward a less well structured species as the proximate neurotoxic factor underlying cognitive failure in Alzheimer's disease: soluble amyloid-beta peptide oligomer (also known as the amyloid-beta peptide-derived diffusible ligand). Paradoxically, several studies in the last 2 years have shown that picomolar levels of amyloid-beta peptide have neutral activity or perhaps even an essential role in learning and memory. Here we highlight some of the key observations underlying the growing focus on the amyloid-beta peptide oligomer.

Fig 1

APP processing and Aβ accumulation. Mature APP (center and inside the dashed box) is metabolized by 2 competing pathways: the α-secretase pathway, which generates sAPPα and C83 (also known as C-terminal fragment α; left), and the β-secretase pathway, which generates sAPPβ and C99 (right). Some β-secretase cleavage is displaced by 10–amino acid residues and generates sAPPβ′ and C89. All carboxy-terminal fragments (C83, C99, and C89) are substrates for γ-secretase, which generates AICD, and the secreted peptides p3 (not shown), Aβ (right), and Glu11 Aβ. Aβ aggregates into small multimers (dimers, trimers, etc.) known as oligomers. Oligomers appear to be the most potent neurotoxins, whereas the end-stage senile plaque is relatively inert. Abbreviations: Aβ, amyloid-β peptide; AICD, amyloid precursor protein intracellular domain; APP, amyloid precursor protein; sAPP, soluble amyloid precursor protein. Reprinted with permission from Journal of Clinical Investigation. Copyright 2005, American Society for Clinical Investigation.

Fig 2

Memory impairment produced by the depletion of endogenous Aβ(1–42) is rescued by exogenous oligomeric human Aβ(1–42). (A) An oligomeric/monomeric preparation of Aβ42 was examined via 4% to 12% tris-tricine nondenaturing polyacrylamide gel electrophoresis/western blotting with the anti-Aβ monoclonal antibody 6E10 (Covance Research; 1:1000). Bands corresponding to tetramers, trimers, and monomers were detected. (B) Acq and retention, expressed as the mean latency ± SEM (seconds), of rats that received intrahippocampal injections of either anti-Aβ or a control monoclonal antibody combined with either sc peptide or Aβ(1–42) 15 minutes before IA training. *P < 0.05, **P < 0.01, and ***P < 0.001. Test 1 occurred 24 hours after training; test 2 occurred 5 days after training. (C) Acq and retention, expressed as the mean latency ± SEM (seconds), of rats that received intrahippocampal injections of PBS, sc peptide, or Aβ(1–42) immediately after IA training. The administration of Aβ(1–42) immediately after IA training enhanced memory retention 24 hours after training. *P < 0.05 and **P < 0.01. Abbreviations: Aβ, amyloid-β peptide; Acq, memory acquisition; IA, inhibitory avoidance; PBS, phosphate-buffered saline; sc, scrambled; SEM, standard error of the mean. Reprinted with permission from Learning & Memory. Copyright 2009, Cold Spring Harbor Press.

Fig 3

Relationship linking the Aβ peptide species to the oligomerization state and neurotoxicity. Abbreviation: Aβ, amyloid-β peptide. Reprinted with permission from Nature Chemistry. Copyright 2009, Nature Publishing Group.