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bioRxiv · 10.1101/438630

The unique nested gene ALZAS as a potential source of Aβ-peptides in Alzheimer’s disease

Gano, C.·Reichmann, H.·Janetzky, B.
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Abstract

Amyloid-beta (A{beta}) peptides are considered to be the cause of neuronal and synaptic cell death in Alzheimers disease (AD) since approximately 100 years. To date, it is assumed that A{beta}-peptides arise from the proteolytic cleavage of the amyloid precursor protein (APP). However, within the APP gene, a nested gene called ALZheimer ASsociated (ALZAS) exists, which includes the entire A{beta}42-sequence and thus may also be the origin of various A{beta}-species. Here, we firstly confirmed expression and the postulated amino acid sequence of ALZAS and revealed the binding of selected monoclonal A{beta}-antibodies to A{beta}- and ALZAS protein. We confirmed the specificity of the anti-ALZAS antibody to ALZAS by protein sequence analysis. This anti-ALZAS antibody detects the same amino acid sequence as the autoantibody found in human blood of AD patients. Since no detailed data are currently available concerning ALZAS expression and the amount, localization and function of ALZAS protein in human cells and tissue, we performed gene (over)expression experiments on transcriptional and translational level. We verified a considerably lower mRNA amount of ALZAS compared to the host gene APP. Nevertheless, ALZAS transcription and translation seems to be heavily regulated in different human tissues and cells. Artificially increased mRNA levels of ALZAS did not led to an enhanced protein amount or considerable increase in cell death. Notably, cell localization of the ALZAS protein showed accordance to endosomes indicating that ALZAS, which contains the whole transmembrane domain of APP, might be a peripheral membrane protein. Since endosome dysfunctions are a characteristic event in early stages of AD and the highest ALZAS-autoantibody levels were already detected in early AD stages, ALZAS might play a crucial role in AD pathology and could possibly be a further diagnostic marker.

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Gano, C., Reichmann, H., Janetzky, B.. 2018-10-09. The unique nested gene ALZAS as a potential source of Aβ-peptides in Alzheimer’s disease. https://doi.org/10.1101/438630

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