Prion-Like Aspects of Beta-Amyloid Aggregation: Seeded Strain-Like Propagation of Beta-Amyloid Morphotypes and Peripheral Transmission of Cerebral Beta-Amyloidosis in APP Transgenic Mice

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Dokumentart: PhDThesis
Date: 2013
Source: erschienen in: Science, Band 330, 2010, S.980-982; EMBO Reports, Volume 14, Issue 11, 2013, S.1017-1022
Language: English
Faculty: 7 Mathematisch-Naturwissenschaftliche Fakultät
Department: Biologie
Advisor: Jucker, Mathias (Prof. Dr. rer. nat.)
Day of Oral Examination: 2014-02-20
DDC Classifikation: 610 - Medicine and health
570 - Life sciences; biology
Keywords: Amyloid , Prion
Other Keywords: Alzheimer
Alzheimer, Amyloid, Protein Aggregation, Prion Strains
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Aggregation of disease-specific proteins occurs in a variety of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and the prionoses. Hence, the term “proteopathies” has been used to refer to these disorders. Among them, the most prevalent is Alzheimer’s diseases with an increasing number of people affected due to the aging of our society. The aggregation of amyloid beta (Aβ) in the brain of patients with Alzheimer’s disease is considered an initial and early event in disease pathogenesis, followed by neurofibrillary tangle formation, neuronal loss, and progressive cognitive decline. Therefore, it is important to understand the underlying mechanisms and impact of early Aβ aggregation that in turn, is a prime target for therapy. The aim of this thesis was to study mechanistic similarities between the induction of Aβ-aggregation and prions, the infectious protein aggregates in prion diseases. In the first project, the transmissibility of β-amyloidosis in an amyloid precursor protein (APP) transgenic (tg) mouse model was studied. The aim was to investigate the possible induction of cerebral Aβ deposition in young APP tg mice after peripheral inoculations with brain extract containing aggregated Aβ (“Aβ seeds”). Previously, it had been shown that intracerebral administration of brain extract containing aggregated Aβ induces the aggregation and deposition of Aβ in brain in a time and concentration dependent manner (Meyer-Luehmann et al., 2006). Results presented in this thesis demonstrate that the intraperitoneal injection of brain extract from aged APP tg mice is sufficient to trigger Aβ deposition in brain in young APP tg mice. However, intraperitoneal injection requires a prolonged incubation time when compared to intracerebral inoculation. This study, to which I contributed and consequently became a co-author, has been published in Science (Eisele et al., 2010). In the second part of the thesis, transmission of conformational variants of β-amyloid deposits with different Aβ42 to Aβ40 ratios was studied. To this end young APP23 or APPPS1 tg mice were intracerebrally inoculated with brain extract containing aggregated Aβ either from aged APP23 or aged APPPS1 tg mice. Biochemical analysis of laser-dissected tissue pieces and histological staining with spectral analysis with luminescent conjugated polythiophenes (LCP) was used to characterise the Aβ aggregates in the donor tissue and in the host. Results revealed that the Aβ40/42 ratio of the induced Aβ deposits and the conformation of the induced Aβ-morphotypes was dependent on the properties of both the brain extract and the inoculated host. This ‘strain-like’ aspect of Aβ-amyloid is reminiscent to findings from studies on prion diseases. This study was done in collaboration with K. P. R. Nilsson from the University of Linköping in Sweden. This study was published in EMBO Reports (Heilbronner et al., 2013). In a third project, the functional impact of induced Aβ deposits in the hippocampus of APP tg mice was investigated. To study the impact of brain extract-induced hippocampal deposition of Aβ on learning and memory, a behavioural laboratory using the Morris water maze was established. Interpretation of the data of this experiment was however difficult and somewhat inconclusive. Overall, however, no severe or obvious cognitive impairment associated with the induced amyloid deposits was found. In summary, the results of this thesis indicate similarities between the experimental transmission of cerebral β-amyloidosis and the transmission of prion diseases regarding (a) the observed induced Aβ aggregation after peripheral application of the Aβ seeds and (b) the transmission and propagation of intrinsic properties of the Aβ seeds. In behavioural experiments we did not find a severe impact of induced hippocampal Aβ deposition on spatial memory in APP tg mice. While our experimental findings contribute to the understanding of the principles underlying the transmission of amyloidogenic proteopathies, it is important to note that evidence for horizontal transmission of cerebral β-amyloidosis in humans is lacking. Nevertheless, identification and further characterisation of subtypes or variants of Aβ aggregates might potentially lead to the identification of new targets for preventive or curative therapies of Alzheimer’s disease.

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