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

Despite amyloid plaques, consisting of insoluble, aggregated amyloid-beta 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-beta oligomers, consisting of multiple amyloid-beta monomers, as precursors of insoluble amyloid-beta plaques. Dissecting the biological effects of single amyloid-beta oligomers, for example of amyloid-beta dimers, an abundant amyloid-beta oligomer associated with clinical progression of Alzheimer's disease, has been difficult due to the inability to control the kinetics of amyloid-beta multimerization. For investigating the biological effects of amyloid-beta dimers, we stabilized amyloid-beta dimers by an intermolecular disulphide bridge via a cysteine mutation in the amyloid-beta peptide (A beta-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-beta dimers, but not monomers, amyloid-beta plaques or insoluble amyloid-beta 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-beta dimers were unable to initiate the formation of insoluble amyloid-beta aggregates in tgDimer mice, after crossbreeding tgDimer mice with the CRND8 mouse, an amyloid-beta plaque generating mouse model, A beta-S8C dimers were sequestered into amyloid-beta plaques, suggesting that amyloid-beta plaques incorporate neurotoxic amyloid-beta dimers that by themselves are unable to self-assemble. Our results suggest that within the fine interplay between different amyloid-beta species, amyloid-beta dimer neurotoxic signalling, in the absence of amyloid-beta plaque pathology, may be involved in causing early deficits in synaptic plasticity, learning and memory that accompany Alzheimer's disease.