| dc.description.abstracteng | Amyloid pathology in Alzheimer’s disease (AD) is characterized by a heterogeneity of amyloid-β peptides (Aβ) variants. The N-terminally truncated Aβ4-42 peptides are among the most abundant species and were reported having an enhanced aggregation propensity and comparable toxicity to full-length Aβ peptides. Employing transgenic mouse models of AD, we aim to address the importance of this particular Aβ isoform in AD pathology. We questioned if an alteration of their degradation or generation affects the course of the pathology and how Aβ4-42 peptides and the two main neuropathological hallmarks of AD, extracellular amyloid deposits and tau pathology, are interrelated in-vivo.
We showed that Aβ4-42 is a substrate of the enzyme Neprilysin (NEP) in-vitro, and that in-vivo, the absence of endogenous NEP in the Tg4-42het mouse model of AD, exclusively expressing Aβ4-42 peptides preferentially in the CA1 region of the hippocampus, led to an increased deposition of this isoform in hippocampal CA1 pyramidal neurons. The removal of ADAMTS4, a metalloprotease able to generate Aβ4-x peptides in oligodendrocytes, from the 5xFAD mouse model of familial AD, caused an improvement in the motor deficits characterizing this transgenic line, concomitant to reduced Aβ4-x levels in the spinal cord.
To investigate the relationship between Aβ4-42 peptides and extracellular amyloid pathology, the FAD/Tg4-42hom line was generated crossing the Tg4-42hom transgenic model, characterized by the sole expression of the Aβ4-42 isoform and time-dependent behavioral deficits and neurodegeneration, with the plaque-bearing 5xFAD mouse model of AD, demonstrating no impairment or hippocampal loss of neurons at the age employed here. While an aggravation of deficits in motor performance and an increased loss of spinal α-motoneurons was detected in the filial line, cognitive performance was unaltered. Surprisingly, a rescue of recognition memory could even be observed in FAD/Tg4-42hom mice, accompanied by an increased number of pyramidal neurons in the distal portion of the CA1 region of the hippocampus compared to Tg4-42hom controls. Together with increased levels of insoluble Aβ4-x peptides in the hippocampus of FAD/Tg4-42hom mice, these results support the hypothesis of extracellular amyloid plaques possessing buffering properties towards soluble Aβ4-42 peptides.
In the classical amyloid cascade hypothesis, Aβ is considered to act upstream of tau pathology. This hypothesis is supported by several studies on APP-overexpressing lines that have been crossed with mouse models of tauopathy. We crossed the Tg4-42hom line with the MAPT (PS19) transgenic tau model to investigate whether soluble N-truncated Aβ4-42 variants affect the phosphorylation and aggregation of tau. Although the co-expression of Aβ4-42 and transgenic human tau caused an aggravation of spatial memory deficits, neurodegeneration, and tau hyperphosphorylation remained unaltered in MAPT/Tg4-42hom mice compared to the transgenic parental lines. | de |