The presence of Ab pE3 (N-terminal truncated Ab starting with pyroglutamate) in Alzheimer's disease (AD) has received considerable attention since the discovery that this peptide represents a dominant fraction of Ab peptides in senile plaques of AD brains. This was later confirmed by other reports investigating AD and Down's syndrome postmortem brain tissue. Importantly, Ab pE3 has a higher aggregation propensity, and stability, and shows an increased toxicity compared to full-length Ab. We have recently shown that intraneuronal accumulation of Ab pE3 peptides induces a severe neuron loss and an associated neurological phenotype in the TBA2 mouse model for AD. Given the increasing interest in Ab pE3 , we have generated two novel monoclonal antibodies which were characterized as highly specific for Ab pE3 peptides and herein used to analyze plaque deposition in APP/PS1KI mice, an AD model with severe neuron loss and learning deficits. This was compared with the plaque pattern present in brain tissue from sporadic and familial AD cases. Abundant plaques positive for Ab pE3 were present in patients with sporadic AD and familial AD including those carrying mutations in APP (arctic and Swedish) and PS1. Interestingly, in APP/PS1KI mice we observed a continuous increase in Ab pE3 plaque load with increasing age, while the density for Ab 1-x plaques declined with aging. We therefore assume that, in particular, the peptides starting with position 1 of Ab are N-truncated as disease progresses, and that, Ab pE3 positive plaques are resistant to age-dependent degradation likely due to their high stability and propensity to aggregate.

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Abeta accumulation has an important function in the etiology of Alzheimer's disease (AD) with its typical clinical symptoms, like memory impairment and changes in personality. However, the mode of this toxic activity is still a matter of scientific debate. We used the APP/PS1KI mouse model for AD, because it is the only model so far which develops 50% hippocampal CA1 neuron loss at the age of 1 year. Previously, we have shown that this model develops severe learning deficits occurring much earlier at the age of 6 months. This observation prompted us to study the anatomical and cellular basis at this time point in more detail. In the current report, we observed that at 6 months of age there is already a 33% CA1 neuron loss and an 18% atrophy of the hippocampus, together with a drastic reduction of long-term potentiation and disrupted paired pulse facilitation. Interestingly, at 4 months of age, there was no long-term potentiation deficit in CA1. This was accompanied by reduced levels of pre-and post-synaptic markers. We also observed that intraneuronal and total amount of different Abeta peptides including N-modified, fibrillar and oligomeric Abeta species increased and coincided well with CA1 neuron loss. Overall, these data provide the basis for the observed robust working memory deficits in this mouse model for AD at 6 months of age.

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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-Ab as a potential biomarker for Alzheimer's disease (AD). Ab-IgM concentration has been measured in 75 plasma samples from patients with AD, individuals with mild cognitive impairment (MCI), and healthy age-and sexmatched controls (HC). To characterize the fractions associated with Ab, pooled plasma samples were subjected to gel-filtration analysis. Size-separated fractions were analyzed for the presence of Ab using a sandwich ELISA assay. A strong reactivity was observed in the high molecular weight IgM ([500 kDa) and 150 kDa (IgG) fractions indicating that blood Ab is strongly associated with antibodies. Using an ELISA assay detecting Ab-IgM complexes, we observed that high levels of Ab-IgMs were detectable in HC and MCI patients; however, there was no significant difference to the AD group.

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