Alzheimer's disease (AD) is a major cause of dementia, with the number of patients with this condition anticipated to exceed 50 million worldwide in the near future. Despite extensive research efforts, no effective measures are available to facilitate the prevention or treatment of AD, which is due in part to a lack of animal models able to closely replicate a human-like disease state. Here, we describe the generation of three mutant marmoset individuals in which exon 9 of PSEN1 gene product has been deleted (PSEN1-DeltaE9). Such DeltaE9 mutations have been reported to cause early on-set familial AD (references 1-5). We used Transcription Activator-Like Effector Nuclease (TALEN) to destroy the 3' splice site of exon 9 in the marmoset PSEN1 gene. To this end, TALEN exhibits high genome-editing efficacy, generates few off-target effects, and produces minimal mosaicism. Indeed, whole genome sequencing and other analyses illustrated an absence of off-target effects and an apparent absence of mosaicism. Fibroblasts obtained from newborn marmosets exhibited uncleaved full-length presenilin 1 protein (PS1) caused by the perturbation of PS1 endoproteolysis as well as an increased ratio of Abeta42/Abeta40 production, a signature of familial AD pathogenesis. To our knowledge, this is the first non-human primate model of familial AD. We intend to make our marmoset model available to the research community to facilitate the global fight against AD.
The relationship between oral health and the development of Alzheimer’s disease (AD) in the elderly is not yet well understood. In this regard, the association between aging or neurodegeneration of the trigeminal nervous system and the accumulation of amyloid-β(1–42) (Aβ42) oligomers in the pathogenesis of AD is unknown. We focused on selective autophagy in the trigeminal mesencephalic nucleus (Vmes) and the diffusion of Aβ42 oligomers with respect to aging of the trigeminal nervous system and whether the degeneration of Vmes neurons affects the diffusion of Aβ42 oligomers. We used female 2- to 8-mo-old transgenic 3xTg-AD mice and App NL-G-F knock-in mice and immunohistochemically examined aging-related changes in selective autophagy and Aβ42 oligomer processing in the Vmes, which exhibits high amyloid-β (Aβ) expression. We induced degeneration of Vmes neurons by extracting the maxillary molars and examined the changes in Aβ42 oligomer kinetics. Autophagosome-like membranes, which stained positive for Aβ, HO-1, and LC3B, were observed in Vmes neurons of 3xTg-AD mice, while there was weak immunoreactivity of the membranes for intraneuronal Aβ in App NL-G-F mice. By contrast, there was strong immunopositivity for extracellular Aβ42 oligomers with the formation of Aβ42 oligomer clusters in App NL-G-F mice. The expression of Rubicon, which indicates age-related deterioration of autophagy, increased the diffusion of Aβ42 oligomer with the age of Vmes neurons. Tooth extraction increased the extracellular immunopositivity for Aβ42 oligomers in App NL-G-F mice. These results suggest that autophagy maintains homeostasis in Vmes neurons and that deterioration of autophagy due to aging or neurodegeneration leads to the diffusion of Aβ42 oligomers into the extracellular space and possibly the development of AD.
In January 2018, Britain was the first in the world to adopt a Minister of Loneliness. This illustrates the changing view on loneliness: being lonely is not just a feeling of a lack of companionship, but also a serious health problem. For example, we know that loneliness is as bad as smoking 15 cigarettes a day. Moreover, research has shown that lonely people express higher levels of cortical amyloid. Amyloid burden is an important marker of Alzheimer's Disease (AD), a chronic neurodegenerative disease and the main cause of dementia worldwide.Together with other findings a link between loneliness, (perceived) social isolation and AD is now undeniable, but it is hard to tell from human studies whether it is the cause or the effect of AD. We need standardized animal studies to answer this question.In an effort to study how social isolation and AD interact, we used APP KI mice bearing human transgenes known to cause AD, and isolated part of the mice in order to mimic loneliness in latelife while part of them remained group-housed. We next looked at the effects of isolation on the behaviour and symptomatology typically present in AD patients to tap cognition.Our study reveals mixed results. Results indicate that at before isolation, at the age of 16 and 24 months, APP NL/NL and APP NL-G-F/NL-G-F mice do not differ to a significant extent on both the behavioural level. The APP NL-G-F/NL-G-F differentiated slightly worse between the conditioned context and a new context compared to the APP NL/NL mice. However, the difference appeared to be more pronounced after a period of social isolation. Social isolation had distinct effects on the AD-related anxiogenic and dementia-like phenotype. Spatial learning in the MWM task revealed distinct differences between our two models. After isolation APP NL-G-F/NL-G-F mice used less spatial search strategies, compared to control mice, thus reflecting perseveration and less behavioural flexibility due to the isolation period.
We previously developed single App knock-in mouse models of Alzheimer’s disease (AD), harboring the Swedish and Beyreuther/Iberian mutations with or without the Arctic mutation (AppNL-G-F and AppNL-F mice). These models showed amyloid β peptide (Aβ) pathology, neuroinflammation and cognitive impairment in an age-dependent manner. The former line exhibits extensive pathology as early as 6 months but is unsuitable for investigating Aβ metabolism and clearance because the Arctic mutation renders Aβ resistant to proteolytic degradation and prone to aggregation. In particular, it is inapplicable to preclinical immunotherapy studies due to its discrete affinity for anti-Aβ antibodies. The weakness of the latter model is that it may take as long as 18 months for the pathology to become prominent. We have thus generated a new model that exhibits early deposition of wild-type human Aβ by crossbreeding the AppNL-F line with the Psen1P117L/WT line. We show that the effects of the pathogenic mutations in the App and Psen1 genes are additive or synergistic. This new mouse model showed more cored plaque pathology and neuroinflammation than AppNL-G-F mice and will help accelerate the development of disease-modifying therapies to treat preclinical AD.
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