| dc.description.abstracteng | A heterogeneou s mixture of amyloid beta
(Aβ) isoforms exists in the brains of Alzheimer's disease (AD)
patients. Despite decades of research, relatively little is known
about the precise contribution of these variousAβ species to the
development and progression of AD. Recent work has identified
pyroglutamate-modified amyloid beta (Aβ pE) as a
particularly abundant and toxic peptide. Transgenic mice designed
to specifically overproduceAβ pE exhibit neuron loss and
behavioral deficits. Unfortunately, general breeding issues and the
severe pathology found in these models restrict their use for
additional transgenic studies. In the first project of this thesis,
the TBA42 mouse model was generated to overcome these problems and
further explore the consequences ofAβ pE accumulation
in vivo. Using immunohistochemistry, it was shown that TBA42
mice develop region-specific intraneuronal and extracellularAβ /Aβ
pE deposits accompanied by progressive gliosis.
Decreased anxiety and altered rearing behavior were the earliest
and most persistent behavioral changes identified in this model.
TBA42 mice also displayed age-dependent deficits in motor
performance and working memory. The phenotype observed in the TBA42
model is comparable to otherAβ pE -generating transgenic
mouse lines. However, the moderate pathology and behavioral
impairments of TBA42 mice make them suitable for further transgenic
experiments. Numerous studies have explored the therapeutic
benefits of reducingAβ pE in AD mouse models. However,
few have addressed whether elevatingAβ pE levels is
sufficient to aggravate ongoing disease processes. Earlier attempts
to answer this question relied on the ectopic overexpression of
human glutaminyl cyclase (hQC) in an established AD mouse model. QC
is the primary enzyme responsible for catalyzing the formation ofAβ
pE. Since QC has multiple targets, it cannot be excluded
that ectopic QC overexpression affected these other substrates,
thereby influencing the results of previous experiments. To study
how an exclusive increase inAβ pE affects AD pathology,
the TBA42 and 5XFAD mouse models were crossed to produce FAD42 mice
for the second project of this thesis. The 5XFAD mouse model is a
well-characterized AD transgenic model with aggressive amyloid
deposition. FAD42 mice exhibited aggravated behavioral deficits
compared to 5XFAD and TBA42 mice. ELISA and plaque load
measurements also revealed elevatedAβ pE in FAD42 mice.
These results were accompanied by an increase in endogenous QC
activity in FAD42 mouse brain. However, FAD42 mice displayed no
changes inAβ x-42 or otherAβ isoforms, as determined by
ELISA and mass spectrometry. In total, these observations support a
key pathogenic role forAβ pE in AD and argue for its
ability to seedAβ deposition. Aβ 4-42 is another majorAβ
species in AD brain. Sedimentation studies suggested thatAβ
4-42 displays rapid aggregation kinetics, but nothing is
known about the in vivo toxicity of this peptide. Most
transgenic AD mouse models rely on artificial combinations of
mutations to study amyloid pathology. However, the majority of AD
patients do not possess mutations. Direct, moderate expression of a
particularAβ species in vivo may therefore create a more
physiologically relevant AD model. Given these considerations, the
third project of this thesis focused on the creation of TBA83 mice,
a transgenic model which exclusively expressesAβ 4-42.
TBA83 mice exhibited sparse, region-specific intraneuronal and
extracellularAβ deposits and mild gliosis. In addition, TBA83 mice
displayed deficits in motor function and hippocampal-dependent
memory. The lack of severeAβ deposition in TBA83 mice ultimately
suggests a pathological function for solubleAβ 4-42.
Taken together, the results of this thesis confirm the relevance
ofAβ pE to AD progression. The pathogenic properties
ofAβ 4-42 were also identified for the first time in
vivo, warranting further studies of thisAβ isoform. | de |