Willumsen, Nanet; (2020) Deciphering pathological heterogeneity in familial Alzheimer’s disease. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Introduction: Alzheimer’s disease (AD) is the most common neurodegenerative dementia and its cause is unknown. In rare cases AD can be caused by mutations in the PSEN1, PSEN2 or APP gene and this form of AD is termed familial Alzheimer’s disease (FAD). While the genetic cause is determined, there is considerable heterogeneity in terms of clinical presentation and pathological appearance at post-mortem. Previously it has been suggested pathological features of FAD may influence clinical features. It has also been suggested that FAD mutations may influence both pathological and clinical features. Common features of AD may also play a role in FAD, such as microglial activation and the influence of genetic modifiers of disease, such as APOE. The aims of this thesis were to investigate the associations of Aβ pathology (including CAA) and microglial load to age at onset and disease duration. Investigate histological profiles of Aβ pathologies (including CAA) and microglial load and the associations between these pathologies in genetic causes of FAD and APOE genotypes. Observe the contribution of specific Aβ peptide species to the histological profiles of Aβ pathology, and the association of these peptide with FAD and APOE genotypes. Generate and differentiate FAD patient derived iPSC to neuronal cultures to assess the association of FAD mutation with Aβ peptide profiles and PSEN1 maturity in a neuronal model of FAD. We hypothesise that histological features and Aβ peptide profiles will segregate with FAD mutation location, while microglial phenotype will associate with specific Aβ pathologies. Additionally, we predict the Aβ profiles observed in FAD cell lines will reflect histological profiles of Aβ aggregation. Materials and Methods: Nissl staining was performed on the frontal cortex of 20 FAD cases from the Queen Square Brain Bank (QSBB) (PSEN1 mutation carriers n=16, 10 pre-codon 200, 6 post-codon 200 and APP mutation carriers n=4). Cortical layers were delineated and serial sections immunohistochemically stained with antibodies against Aβ, Iba1, CD68 and CR3/43 and a subset were also stained for Tau. Aβ plaque type, load (% area stained), proportion of Aβ positive cerebral amyloid angiopathy (CAA), and microglial load were analysed per cortical layer. Additionally, in frontal and occipital cortex tissue from the 20 QSBB cases and an additional 21 FAD cases from the Institute of Psychiatry, Psychology and Neuroscience (combined total n=41, PSEN1 mutation carriers n=31, 20 pre-codon 200, 11 post-codon 200 and APP mutation carriers n=10) the proportion and severity of cortical and leptomeningeal CAA were investigated via vessel counts. In the temporal and occipital cortex of the 20 QSBB cases, IHC with Aβ isoform specific antibodies was conducted to investigate genetic contribution to isoform specific pathology. Finally, 5 induced pluripotent stem cell (iPSC) lines from FAD patients were generated. Four FAD lines and two control lines were differentiated into cortical neurons to investigate Aβ isoform production via ELISA and PSEN1 protein levels and maturity were assessed. Results: Clinical features in this FAD cohort were influenced by both FAD mutation and APOE status. Pathological Aβ deposits showed variability across cortical layers, and specific features were more associated with distinct mutations. Microglial phenotype did not differ by FAD mutation group or APOE status however associations with Aβ pathologies were observed. CAA differed between mutations groups, while APOE4 genotype had a non-significant effect of CAA pathology in FAD. Analysis of Aβ production from FAD iPSC derived cortical neurons showed that Aβ production differed not only compared to control cell lines but compared to other independent PSEN1 mutations. This could be the result of changes to PSEN1 maturation. Conclusions: It was shown that there is pathological heterogeneity in FAD of which some aspects associate with specific FAD mutation subgroup. For instance, greater Aβ and CWP frequency in the lower layers in the PSEN1 post-codon 200 group as well as greater proportion and severity of CAA. Correlations between plaques, CAA and microglia indicate contribution of clearance mechanisms to histological features observed in FAD, which can differ by mutation group. Specifically, CD68 was generally associated with greater CAA and reduced Aβ pathology. In the cellular models, specific FAD mutations, particularly those post-codon 200, affect Aβ peptide ratios, which associates with observed pathological heterogeneity and suggests that differences in the aggregation and clearance of these peptides modifies the histological appearance of Aβ pathology. Combined with the observed effect of APOE genotype on disease duration, peptide profiles and CAA severity, this may contribute to the differences in clinical aspects of FAD.

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