Studies on the Involvement of the Immune system in Alzheimer's disease

Abstract

The main subject of this doctoral work is the role of the immune system in Alzheimer's disease (AD), and how its understanding may help to develop novel diagnostic and therapeutic options for the disease.This study is structured in 2 parts, the first centred on mouse models of AD and in particular on the relationship between pathological features and inflammation in the brain of APPPS1/KI mice, while in the second part the focus is shifted on immune system involvement in human in vivo. The APP/PS1KI mouse model for AD has been previously shown to harbour severe pathological alterations, including behavioural deficits, axonal degeneration and hippocampal neuron loss starting at the age of 6 months. We observed early activation of the inflammatory marker GFAP already at 2 months, followed at 6 months by reduced levels of pre- and post-synaptic markers. Inflammatory processes are considered to play an important role in the progression of neurodegenerative changes in AD, and these data add further evidence to their association with axonal degeneration and neuron loss.It has previously been shown that immune complexes (IC) of a given biomarker with class M immunoglobulins (IgM) provide better performances compared to the unbound biomarker in a number of cancer entities. In the present work, we investigated IC of IgM-Aβ as a potential biomarker for Alzheimer s disease (AD). Aβ IgM concentration has been measured in 75 plasma samples from patients with AD, individuals with mild cognitive impairment (MCI), and healthy age- and sex-matched controls (HC). Using an ELISA assay detecting Aβ IgM complexes, we observed that high levels of Aβ IgMs were detectable in HC and MCI patients; however, there was no significant difference to the AD group. To overcome the impossibility to discriminate IC of specific Aβ forms, we measured in the same plasma samples the level of IgM autoantibodies directed against different Aβ epitopes as potential diagnostic biomarkers for Alzheimer s disease (AD). The mean level of anti-Aβ3(pE)-IgM was significantly decreased in AD patients compared to HC. In the group of MCI patients there was a significant positive correlation between anti-Aβ3(pE)-IgM and cognitive decline expressed as MMSE (rho = 0.58, df = 13, p = 0.022). These observations indicate that the level of IgM autoantibodies against Aβ3(pE) represents a promising plasma biomarker for AD and correlates with the cognitive status of individuals at risk of developing AD.These data are in line with the idea of a possible pivotal role of Aβ3(pE) in AD development, as shown by a novel mouse model expressing only truncated Aβ3(pE)-42 demonstrating high neurotoxicity of this peptide. To better analyze pyroglutamate-positive plaque load in the brain, a novel monoclonal antibody highly specific for Aβ3(pE) has been developed.Niedersächsische Staats- und Universitätsbibliothek Göttingen 37070 GöttingenUrheberrechtCopyright