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Coming dissertations at MedFak

  • Characterization of the novel “Uppsala mutation” causing a familial form of early onset Alzheimer’s disease Author: María Pagnon de la Vega Link: Publication date: 2021-08-18 14:30

    The Alzheimer’s disease (AD) brain displays extracellular plaques of amyloid-β (Aβ), neurofibrillary tangles of tau and neuronal loss. The 40-42 amino acid Aβ peptide is formed from the amyloid precursor protein (APP) by β-secretase and γ-secretase, while α-secretase prevents Aβ generation. According to the amyloid cascade hypothesis, AD is initiated by increased brain levels of toxic Aβ species. Our laboratory has previously identified two APP mutations, causing early onset AD. Whereas the Swedish mutation results in increased β-secretase cleavage leading to higher Aβ levels, the Arctic mutation leads to a conformational Aβ change that promotes formation of toxic Aβ protofibrils.

    In this thesis, we have performed a screen for novel disease-causing mutations in 102 patients with early onset dementia disorders, who underwent investigation at the Memory clinic at Uppsala University Hospital. Mainly, we found a new APP mutation, which causes familial dominantly inherited AD with age at symptom onset in the early forties. This Uppsala APP mutation, consists of an intra-Aβ deletion of six consecutive amino acids, which results in Aβ with 34-36 amino acids (AβUppΔ19-24).

    Affected mutation-carriers develop symptoms typical of AD. As for biomarkers, the patients display expected changes although brain Aβ imaging by [11C]PIB-PET is only slightly pathological and Aβ42-analysis of cerebrospinal fluid yields normal results. By investigating neuropathological, biochemical and structural properties of AβUppΔ19-24 in patient samples, on synthetic peptides and in cell culture models we found evidence that Uppsala APP is pathogenic via three mechanisms: increased β-secretase cleavage, altered α-secretase cleavage and rapid formation of Aβ fibrils into unique polymorphs.

    To allow for in vivo studies of molecular mechanisms related to the Uppsala APP mutation we generated transgenic mice, expressing human APP with this mutation together with Swedish APP (to increase Aβ levels). In the brain of tg-UppSwe mice, we observed diffuse aggregates of mainly AβUpp42Δ19-24, which, given their normal γ-secretase activity, distinguishes these mice from most transgenic mouse models. In order to study if AβUppΔ19-24 co-aggregates with wild-type Aβ (Aβwt), we crossed tg-UppSwe with tg-Swe. Analyses of brains from such mice indicated that AβUppΔ19-24 may act as seeds for Aβwt by changing its aggregation behavior and thereby increasing its deposition in brain.

    Taken together, our studies of the Uppsala APP mutation have provided new knowledge of pathogenic molecular mechanisms in AD and of basic Aβ biology. Such insights may in a longer perspective help us to develop new diagnostics and therapeutics for this disorder. 

  • Sleep disturbances : Consequences and comorbidities Author: Shadi Amid Hägg Link: Publication date: 2021-08-17 10:28

    Background: Sleep disorders are common in the general population, with insomnia and sleep-related breathing disorders being the most common disorders. Since sleep has many important functions, such as a role in consolidation of memories and learning, energy conservation, cardiovascular and immune system regulation, it is not surprising that the disruption of normal sleep may lead to negative health effects and various comorbidities.  

    Aim: The overall aim of this thesis was to investigate the impact of disturbed sleep on various consequences and comorbidities. 

    Methods and results: Papers I and II were based on the Sleep and Health in Women (SHE), a population-based prospective study of women, where a questionnaire was sent to women in 2000 and 2010. 

    In paper I, the study cohort comprised 4,320 women <67 years of age who answered both questionnaires and had worked during the follow-up period. In women, having a long history of insomnia symptoms was associated with an increased risk of self-reported occupational accidents.

    In paper II, the 4,882 participants who answered the questions regarding nocturnal gastroesophageal reflux and snoring in both questionnaires were included in the study cohort. Women with nocturnal gastroesophageal reflux and snoring were at an increased risk of developing daytime sleepiness and to involuntarily fall asleep during the day. 

    Paper III was based on the RHINE-cohort with participants from seven Northern European centers. The study cohort in paper III comprised the 2,568 smokers in the baseline study that also reported being smokers or former smokers in the follow-up study. It was found that having insomnia symptoms or excessive daytime sleepiness decreases the chance of long-term smoking cessation, and that smoking increases the risk of incident difficulties inducing sleep. 

    Paper IV was the population-based, cross-sectional GA2LEN-survey which was conducted in four major Swedish cities. Paper IV included the 25,901 participants who answered questions regarding both snoring and insomnia symptoms. The combination of snoring and insomnia symptoms was associated with an increased risk of hypertension, asthma, chronic obstructive pulmonary disease, and daytime sleepiness. 

    Conclusions: Disturbed sleep, due to varying causes, influences the risk of occupational accidents, on the chance of successful smoking cessation, on the risk of daytime sleepiness, hypertension, and obstructive lung disease. In clinical consultation, it is important to always inquire about disturbed sleep as it can have an impact on many aspects of health.