Abstract:
As life expectancy increases, the prevalence of age-related health problems is expected to rise. Neurodegeneration and associated cognitive impairments are of particular importance because of their significant impact on health span and quality of life. Although several risk factors are associated with neurodegeneration, aging itself has by far the greatest impact. Alzheimer’s disease (AD) is the most common neurodegenerative disorder associated with aging. Neurofilament light chain (NfL) has gained increasing attention as a potential biomarker for neurodegeneration. Therefore, the aim of this work was to better understand NfL changes in both AD and normal aging. The first part of this thesis aimed at deciphering the mechanism behind NfL increases in AD using APPPS1 transgenic mice, a widely used mouse model of cerebral β-amyloidosis. In these mice, we found increased levels of NfL in the cerebrospinal fluid (CSF) with progressive amyloid-β (Aβ) pathology, overall strikingly similar to the NfL changes in humans with autosomal dominant AD. APPPS1 mice do not develop neurofibrillary Tau tangles, but we could demonstrate increased phosphorylated Tau species (pTau181 and pTau217) in the CSF. To investigate whether Aβ aggregation is sufficient to induce CSF-NfL increases in APPPS1 transgenic mice or whether (p)Tau changes are the driver of the NfL increase in this rodent model, we generated APPPS1 mice with reduced (APPPS1,Tau+/-) or absent (APPPS1,Tau-/-) Tau and compared them to normal (APPPS1,Tau+/+) littermates. Using histological, biochemical and proteomic tools, our results suggest that regardless of Tau reduction or deletion, APPPS1 transgenic mice show an increase in CSF-NfL, indicating that Tau is not required for amyloid-induced neurodegeneration and may even be neuroprotective. In the second part of this thesis, NfL changes in blood were examined in the context of normal aging. We found similar trajectories of plasma-NfL with increasing age in human and mouse (C57BL/6J) cohorts. Further analyses in human centenarians revealed a strong association between plasma-NfL and mortality. In addition, we found an attenuated increase in plasma-NfL in diet-restricted mice, which was accompanied by an increase in lifespan. These observations suggest that age-related mortality may be influenced by declining nervous system function. To investigate the underlying mechanisms and the prognostic value of plasma-NfL as a biomarker of mortality (remaining healthy lifespan), we developed strategies and initiated a comprehensive longitudinal study, assessing plasma-NfL and mortality in aging mice. While the study is still ongoing, preliminary data from 20- and 21-month-old mice revealed a shorter median lifespan of mice with plasma-NfL levels in the highest quartile. This was even more pronounced when the rate of NfL change was used rather than single NfL levels. Furthermore, our preliminary data suggest that frailty and weight loss between 20 and 21 months of age are more strongly associated with mortality than plasma-NfL at this age. Ongoing analyses of later time points and two additional batches of aging mice, as well as comparative analyses of epigenetic changes in blood and faecal microbiome, will increase the validity and complement these initial results. In conclusion, NfL has become a widely used fluid biomarker to assess neurodegeneration in AD and to predict healthy lifespan in humans. The present results add to our mechanistic understanding of NfL changes in AD pathogenesis and NfL as a biomarker of the healthy lifespan in the context of other established biomarkers.
Alzheimer's disease