Amyloid Plaques Ameliorate Memory Deficits and Hippocampal Neuron Loss in an Aβ4-42-Driven Alzheimer's Disease Mouse Model.

Extracellular deposition of amyloid-β (Aβ) peptides in the form of plaques is the most prominent pathological hallmark of Alzheimer's disease (AD). The postulated central pathophysiological role of fibrillary Aβ plaques has, however, been questioned, and small, soluble, pre-fibrillar Aβ aggregates (oligomers) have been implicated as the crucial neurotoxic species in AD etiology. While the relationship between insoluble amyloid plaques and soluble Aβ oligomers remains unclear, it has been hypothesized that plaques may serve as reservoirs, sequestering toxic Aβ oligomers in the initial stages of the disease. Next to the canonical "full-length" Aβ1-40 and Aβ1-42 peptides, a variety of N-terminally truncated Aβ variants are present in AD brain tissue, with Aβ4-42 peptides showing high abundance. The detrimental effects of these N-terminally truncated peptides have been previously studied using the Tg4-42hom mouse line, which displays neuron loss and cognitive deficits and accumulates Aβ4-42 peptides in the CA1 region of the hippocampus albeit without amyloid plaque formation. This study aimed to investigate the relationship between soluble Aβ4-42 peptides and insoluble extracellular Aβ deposits by crossing the Tg4-42hom line with the plaque-bearing 5XFAD mouse model. We found that extracellular amyloid deposits in the hippocampus did not aggravate spatial memory deficits in Tg4-42hom mice but rescued recognition memory deficits. Moreover, while proximal CA1 pyramidal neuron loss in the hippocampus of Tg4-42hom mice was not affected by crossing with the 5XFAD line, a reduced loss of distal pyramidal neurons was observed in the filial line. Biochemically, 5XFAD/Tg4-42hom mice showed a trend towards increased levels of insoluble Aβ4-x peptides in the hippocampus. Taken together, these findings support the importance of soluble Aβ oligomers in the pathogenesis of AD and provide evidence for the hypothesis that amyloid plaques provide buffering capacity.