Phosphorylated Aβ peptides in human Down syndrome brain and different Alzheimer's-like mouse models

The deposition of neurotoxic amyloid-beta (A beta) peptides in extracellular plaques in the brain parenchyma is one of the most prominent neuropathological features of Alzheimer's disease (AD), and considered to be closely related to the pathogenesis of this disease. A number of recent studies demonstrate the heterogeneity in the composition of A beta deposits in AD brains, due to the occurrence of elongated, truncated and post-translationally modified A beta peptides that have peculiar characteristics in aggregation behavior and biostability. Importantly, the detection of modified A beta species has been explored to characterize distinct stages of AD, with phosphorylated A beta being present in the clinical phase of AD. People with Down syndrome (DS) develop AD pathology by 40 years of age likely due to the overproduction of A beta caused by the additional copy of the gene encoding the amyloid precursor protein on chromosome 21. In the current study, we analysed the deposition of phosphorylated and non-phosphorylated A beta species in human DS, AD, and control brains. In addition, deposition of these A beta species was analysed in brains of a series of established transgenic AD mouse models using phosphorylation-state specific A beta antibodies. Significant amounts of A beta phosphorylated at serine residue 8 (pSer8A beta) and unmodified A beta were detected in the brains of DS and AD cases. The brains of different transgenic mouse models with either only human mutant amyloid precursor protein (APP), or combinations of human mutant APP, Presenilin (PS), and tau transgenes showed distinct age-dependent and spatiotemporal deposition of pSer8A beta in extracellular plaques and within the vasculature. Together, these results demonstrate the deposition of phosphorylated A beta species in DS brains, further supporting the similarity of A beta deposition in AD and DS. Thus, the detection of phosphorylated and other modified A beta species could contribute to the understanding and dissection of the complexity in the age-related and spatiotemporal deposition of A beta variants in AD and DS as well as in distinct mouse models.