Amyloid-β dimers in the absence of plaque pathology impair learning and synaptic plasticity

Abstract

Despite amyloid plaques, consisting of insoluble, aggregated amyloid-β peptides, being a defining feature of Alzheimer's disease, their significance has been challenged due to controversial findings regarding the correlation of cognitive impairment in Alzheimer's disease with plaque load. The amyloid cascade hypothesis defines soluble amyloid-β oligomers, consisting of multiple amyloid-β monomers, as precursors of insoluble amyloid-β plaques. Dissecting the biological effects of single amyloid-β oligomers, for example of amyloid-β dimers, an abundant amyloid-β oligomer associated with clinical progression of Alzheimer's disease, has been difficult due to the inability to control the kinetics of amyloid-β multimerization. For investigating the biological effects of amyloid-β dimers, we stabilized amyloid-β dimers by an intermolecular disulphide bridge via a cysteine mutation in the amyloid-β peptide (Aβ-S8C) of the amyloid precursor protein. This construct was expressed as a recombinant protein in cells and in a novel transgenic mouse, termed tgDimer mouse. This mouse formed constant levels of highly synaptotoxic soluble amyloid-β dimers, but not monomers, amyloid-β plaques or insoluble amyloid-β during its lifespan. Accordingly, neither signs of neuroinflammation, tau hyperphosphorylation or cell death were observed. Nevertheless, these tgDimer mice did exhibit deficits in hippocampal long-term potentiation and age-related impairments in learning and memory, similar to what was observed in classical Alzheimer's disease mouse models. Although the amyloid-β dimers were unable to initiate the formation of insoluble amyloid-β aggregates in tgDimer mice, after crossbreeding tgDimer mice with the CRND8 mouse, an amyloid-β plaque generating mouse model, Aβ-S8C dimers were sequestered into amyloid-β plaques, suggesting that amyloid-β plaques incorporate neurotoxic amyloid-β dimers that by themselves are unable to self-assemble. Our results suggest that within the fine interplay between different amyloid-β species, amyloid-β dimer neurotoxic signalling, in the absence of amyloid-β plaque pathology, may be involved in causing early deficits in synaptic plasticity, learning and memory that accompany Alzheimer's disease.

Impaired AMPA signaling and cytoskeletal alterations induce early synaptic dysfunction in a mouse model of Alzheimer's disease

“…Although plaques and tangles have traditionally been regarded as the main histopathological hallmarks of AD, a large body of evidence accumulated over the past decade suggests that soluble forms of these proteins are sufficient to trigger the development of the neurotoxicity process in AD (Berger et al., 2007; Bittner et al., 2010; Chabrier, Cheng, Castello, Green & LaFerla, 2014; Forner et al., 2017; Guerrero‐Munoz, Gerson & Castillo‐Carranza, 2015; Muller‐Schiffmann et al., 2016; Shankar et al., 2008; Spires‐Jones & Hyman, 2014; Tu, Okamoto, Lipton & Xu, 2014). These studies have clearly shown that soluble Aβ and tau oligomers are toxic to synapses and that the accumulation of these soluble isoforms correlates significantly with synaptic and memory impairments (Berger et al., 2007; Bittner et al., 2010; Chabrier et al., 2014; Forner et al., 2017; Guerrero‐Munoz et al., 2015; Muller‐Schiffmann et al., 2016; Shankar et al., 2008; Spires‐Jones & Hyman, 2014; Tu et al., 2014).…”

“…These studies have clearly shown that soluble Aβ and tau oligomers are toxic to synapses and that the accumulation of these soluble isoforms correlates significantly with synaptic and memory impairments (Berger et al., 2007; Bittner et al., 2010; Chabrier et al., 2014; Forner et al., 2017; Guerrero‐Munoz et al., 2015; Muller‐Schiffmann et al., 2016; Shankar et al., 2008; Spires‐Jones & Hyman, 2014; Tu et al., 2014). In addition, we have also demonstrated that Aβ oligomers modulate the development of tau pathology and accelerate cognitive and synaptic impairments (Chabrier et al., 2014).…”

Revisiting rodent models: Octodon degus as Alzheimer’s disease model?

“…Quantitative measurements underpinned the absence of considerable amounts of insoluble Aβ (Fig. 4) and revealed Aβ-levels that are in the same range as those in wild-type mice [29] and below those of wild-type naked mole rats [34]. …”

“…The brain was immediately snap-frozen in liquid nitrogen and stored at −80 °C. Fractionation of brain tissue was performed by preparative ultracentrifugation as described previously [29]. In brief, brain tissue was homogenated in 9 volumes of TBS buffer (150 mM sodium chloride, 50 mM Tris, pH 7, supplemented with protease inhibitor, Complete EDTA-free, Roche, Basel, Switzerland) and subsequently centrifuged (100,000 g, 4 °C, 1 h).…”

Soluble Amyloid-β42 Stimulates Glutamate Release through Activation of the α7 Nicotinic Acetylcholine Receptor

“…In AD brains, A␤ 40 and A␤ 42 are the predominant peptide isoforms, the latter of which is believed to aggregate faster and thusly considered more neurotoxic [3]. For example, recent evidence supports soluble A␤ 42 dimers as the neurotoxic isoform precipitating AD pathology [4][5][6].…”