Abundance of A[beta] sub(5-x) like immunoreactivity in transgenic 5XFAD, APP/PS1KI and 3xTG mice, sporadic and familial Alzheimer's disease

• Published in: Molecular neurodegeneration Vol. 9; no. 1; p. 13
• Main Authors: Guzman, Erika Avendano, Bouter, Yvonne, Richard, Bernhard C, Lannfelt, Lars, Ingelsson, Martin, Paetau, Anders, Verkkoniemi-Ahola, Auli, Wirths, Oliver, Bayer, Thomas A
• Format: Journal Article
• Language: English
• Published: 01.01.2014
• ISSN: 1750-1326; 1750-1326
• DOI: 10.1186/1750-1326-9-13

Background: According to the modified amyloid hypothesis the main event in the pathogenesis of Alzheimer's disease (AD) is the deposition of neurotoxic amyloid [beta]-peptide (A[beta]) within neurons. Additionally to full-length peptides, a great diversity of N-truncated A[beta] variants is derived from the larger amyloid precursor protein (APP). Vast evidence suggests that A[beta] sub(x-42) isoforms play an important role triggering neurodegeneration due to its high abundance, amyloidogenic propensity and toxicity. Although N-truncated and A[beta] sub(x-42) species have been pointed as crucial players in AD etiology, the A[beta] sub(5-x) isoforms have not received much attention. Results: The present study is the first to show immunohistochemical evidence of A[beta] sub(5-x) in familial cases of AD (FAD) and its distribution in APP/PS1KI, 5XFAD and 3xTG transgenic mouse models. In order to probe A[beta] sub(5-x) peptides we generated the AB5-3 antibody. Positive plaques and congophilic amyloid angiopathy (CAA) were observed among all the FAD cases tested carrying either APP or presenilin 1 (PS1) mutations and most of the sporadic cases of AD (SAD). Different patterns of A[beta] sub(5-x) distribution were found in the mouse models carrying different combinations of autosomal mutations in the APP, PS1 and Tau genes. All of them showed extracellular A[beta] deposits but none CAA. Additionally, they were all affected by a severe amyloid pathology in the hippocampus among other areas. Interestingly, neither 5XFAD nor APP/PS1KI showed any evidence for intraneuronal A[beta] sub(5-x). Conclusions: Different degrees of A[beta] sub(5-x) accumulations can be found in the transgenic AD mouse models and human cases expressing the sporadic or the familial form of the disease. Due to the lack of intracellular A[beta] sub(5-x,) these isoforms might not be contributing to early mechanisms in the cascade of events triggering AD pathology. Brain sections obtained from SAD cases showed higher A[beta] sub(5-x)-immunoreactivity in vascular deposits than in extracellular plaques, while both are equally important in the FAD cases. The difference may rely on alternative mechanisms involving A[beta] sub(5-x) peptides and operating in a divergent way in the late and early onset forms of the disease.