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The role of amyloid beta 4-42 in the etiology of Alzheimer's disease

dc.contributor.advisorBayer, Thomas A. Prof. Dr.
dc.contributor.authorBouter, Yvonne
dc.titleThe role of amyloid beta 4-42 in the etiology of Alzheimer's diseasede
dc.contributor.refereeBayer, Thomas A. Prof. Dr.
dc.description.abstractengN-truncated Aβ4-42 has been identified as a particular abundant Aβ species in the hippocampus and cortex of Alzheimer's patients. However, relatively little is known about the contribution of Aβ4-42 to the development and progression of AD. In order to study the effects of chronic exposure of Aβ4-42 the transgenic mouse model Tg4-42 was generated. The Tg4-42 mouse model, expressing exclusively human Aβ4-42, allows to investigate the neurotoxic effects of Aβ4-42 in vivo. In the present work, it could be shown that Tg4-42 mice show region-specific intraneuronal accumulation of Aβ accompanied by gliosis. Tg4-42 mice showed strong intraneuronal Aβ immunoreactivity predominantly in the CA1 pyramidal cell layer of the hippocampus. Strikingly, transgenic mice expressing Aβ4-42 develop a massive CA1 neuron loss. The progressive neuron loss in the hippocampus of Tg4-42 mice correlates strongly with intraneuronal Aβ4-42. The behavior analysis of Tg4-42 mice revealed hippocampus-dependant memory deficits similar to AD patients. Importantly, the observed memory deficits in Tg4-42 mice are not confounded by motor impairments or abnormal anxiety. Mice are profoundly impaired in their spatial reference memory assessed in the Morris water maze. Moreover, aged Tg4-42 showed a decline in contextual fear memory. The over-expression of Aβ4-42 in this mouse model induces severe age-dependant memory deficits that can be attributed to the massive neuron loss in the hippocampus. The transgenic mouse model Tg4–42 is unique as it harbors no mutations in the Aβ sequence. In summary, Tg4-42 is a valid AD mouse model showing key features of sporadic AD. One of the central research questions on the etiology of 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. The gene expression profiles of Tg4-42 mice were compared to the widely used 5XFAD mouse model using next-generation sequencing. The comparison with 5XFAD, an established plaque-developing AD mouse model, revealed a remarkable overlap in the molecular signature. The jointly differentially expressed genes might indicate common pathways that are involved in the comparable learning and memory decline apparent at twelve months of age in both transgenic models. The pool of genes that showed differential expression exclusively in Tg4-42 is likely associated to soluble Aβ as no extracellular plaques are found in this model. In addition, the robust CA1 neuron loss could also contribute to the differential expression profile. As most of the genes with expression levels exclusively altered in 5XFAD mice belong to inflammation-associated pathways, it can be concluded that the majority of these genes are regulated in connection with plaque formation in this model and are not associated with neuron loss and memory decline. Furthermore, the deep sequencing approach identified a plethora of genes that have so far not been linked to AD and therefore open up new avenues of research into the etiology of this devastating neurodegenerative disorder. In summary, the results of this thesis demonstrate Aβ4-42 as a toxic Aβ variant that likely plays an important role in triggering AD
dc.contributor.coRefereeHanisch, Uwe-Karsten Prof. Dr.
dc.contributor.thirdRefereeEhrenreich, Hannelore Prof. Dr. Dr.
dc.subject.engAlzheimer's diseasede
dc.subject.engtruncated abetade
dc.subject.engabeta 4-42de
dc.subject.engtransgenic mouse modelde
dc.subject.engneuron lossde
dc.subject.engmemory deficitsde
dc.subject.engintraneuronal abetade
dc.subject.engnext generation sequencingde
dc.subject.engdeep sequencingde
dc.subject.engdifferentially expressed genesde
dc.affiliation.instituteMedizinische Fakultät
dc.subject.gokfullMedizin (PPN619874732)

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