Large Soluble Oligomers of Amyloid β-Protein from Alzheimer Brain Are Far Less Neuroactive Than the Smaller Oligomers to Which They Dissociate

Abstract

Soluble oligomers of amyloid ␤-protein (oA␤) isolated from the brains of Alzheimer's disease (AD) patients have been shown experimentally (in the absence of amyloid plaques) to impair hippocampal synaptic plasticity, decrease synapses, induce tau hyperphosphorylation and neuritic dystrophy, activate microglial inflammation, and impair memory in normal adult rodents. Nevertheless, there has been controversy about what types of oligomers actually confer these AD-like phenotypes. Here, we show that the vast majority of soluble A␤ species obtained from brains of humans who died with confirmed AD elute at high molecular weight (HMW) on nondenaturing size-exclusion chromatography. These species have little or no cytotoxic activity in several bioassays. However, incubation of HMW oA␤ in mildly alkaline buffer led to their quantitative dissociation into low molecular weight oligomers (ϳ8 -70 kDa), and these were now far more bioactive: they impaired hippocampal LTP, decreased neuronal levels of ␤2-adrenergic receptors, and activated microglia in wt mice in vivo. Thus, most soluble A␤ assemblies in AD cortex are large and inactive but under certain circumstances can dissociate into smaller, highly bioactive species. Insoluble amyloid plaques likely sequester soluble HMW oligomers, limiting their potential to dissociate. We conclude that conditions that destabilize HMW oligomers or retard the sequestration of their smaller, more bioactive components are important drivers of A␤ toxicity. Selectively targeting these small, cytotoxic forms should be therapeutically beneficial.

RyR2-Mediated Ca2+ Release and Mitochondrial ROS Generation Partake in the Synaptic Dysfunction Caused by Amyloid β Peptide Oligomers

“…The concentration of AβOs in cerebral cortex brain tissue isolated from controls or from AD patients varies from 50 nM to 2 μM (Yang et al, 2017). We used the sub-lethal AβOs concentration of 500 nM, which is deleterious to neuronal function because it inhibits long term potentiation (Wang et al, 2002; Schlenzig et al, 2012) and produces aberrations in synapse composition, shape and density (Lacor et al, 2007).…”

Microglia in Alzheimer’s disease

“…A recent study showed that under certain circumstances in human AD cortex, highmolecular-weight Aβ species dissociate into small neurotoxic oligomeric Aβ species, and administration of the latter to mice activates microglia in vivo. These activated microglia were characterized by increased microglial CD68 levels and decreased ramification (72). In vitro, Aβ activates microglia by binding to PRRs, including receptors for advanced glycation end products (RAGE) (73), TLRs (74), and scavenger receptors (75,76).…”

BACE inhibition-dependent repair of Alzheimer’s pathophysiology

“…If such soluble forms of Aβ are indeed crucial for the local circuit dysfunctions, then their reintroduction into APP23xPS45 mice that had been successfully treated with NB-360 should lead to a reemergence of neuronal hyperactivity. Plaques are dimer-rich, and dimers (the smallest Aβ oligomers) are thought to be the principal "cytotoxins" in the AD brain (20,21). Therefore, we superfused the cortex of NB-360-treated APP23xPS45 mice with synthetic Aβ dimers (21), after which hyperactivity recurred (Fig.…”