Forschungsinformationssystem Universität Greifswald

Bouter Y*, Kacprowski T*, Weißmann R¹, Dietrich K, Borgers H, Brauß A, Sperling C¹, Wirths O, Albrecht M, Jensen L¹, Kuß A¹, Bayer T

1 - Institut für Humangenetik

Interfakultäres Institut für Genetik und Funktionelle Genomforschung / Abt. Funktionelle Genomforschung

One of the central research questions on the etiology of Alzheimer’s disease (AD) is the elucidation of the molecular signatures triggered by the amyloid cascade of pathological events. Next generation sequencing allows the identification of genes involved in disease processes in an unbiased manner. We have combined this technique with the analysis of two AD mouse models. (1) The 5XFAD model develops early plaque formation, intraneuronal A? aggregation, neuron loss and behavioral deficits. (2) The Tg4-42 model expresses N-truncated A?4-42 and develops neuron loss and behavioral deficits albeit without plaque formation. Our results show that learning and memory deficits in the Morris water maze and fear conditioning tasks in Tg4-42 mice at 12 months of age are similar to the deficits in 5XFAD animals. This suggested that comparative gene expression analysis between the models would allow the dissection of plaque-related and -unrelated disease relevant factors. Using deep sequencing differentially expressed genes (DEG) were identified and subsequently verified by qRT-PCR. 19 DEGs were identified in presymptomatic young 5XFAD mice, and none in young Tg4-42 mice. In the aged cohort, 131 DEGs were found in 5XFAD and 56 DEGs in Tg4-42 mice. Interestingly, 36 DEGs were identified in both mouse models indicating common disease pathways associated with behavioral deficits and neuron loss. Many of the DEGs specific to the 5XFAD model belong to neuroinflammatory processes typically associated with plaques. As Tg4-42 mice do not develop any plaques, but still show massive neuron loss, we conclude that only the DEGs common to both models together with those specific to Tg4-42 are defining the molecular signature underlying memory decline in AD.