Latest research by Professor Thomas Bayer from University Medicine Center Göttingen carries the promise of developing new treatments.
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by extensive neuronal degeneration and the development of neuritic amyloid plaques and neurofibrillary tangles. Neuronal and synaptic losses in AD are correlated with dementia and occur in specific brain areas involved in memory processing.
Long-standing evidence shows that progressive cerebral deposition of Aß plays a seminal role in the pathogenesis of AD. There is great interest, therefore, in understanding the proteolytic processing of APP, the precursor of Aß, and its proteases responsible for generating Aß. Ragged peptides with a major species beginning with phenylalanine at position 4 of Ab have been reported already in 1985 by Masters et al.1.
In 1992, Mori et al. first described the presence of AßN3(pE) using mass spectrometry of purified Aß protein from AD brains, which explains the difficulties in sequencing the amino-terminus2. They reported that only 10-15% of the total Aß isolated by this method begins at position 3 with AßN3(pE). Later it became clear that AßN3(pE) represents a dominant fraction of Aß peptides in AD and Down’s syndrome brain3-15.
N-terminal deletions in general enhance aggregation of ß-amyloid peptides in vitro16. AßN3(pE) has a higher aggregation propensity17,18, and stability19, and shows an increased toxicity compared to full-length Aß20. In AD only a small proportion of Aß starts at position 1 with L-aspartate in plaques (~10%), and this fraction is higher in vascular amyloid (~65%). In plaques, ~50% of the amyloid starts at position 3 in the form of AßN3(pE), whereas in the vascular amyloid, this form accounts for only 11%5.
A comparison between amyloid peptides of cognitively normal elderly people and AD patients showed that soluble amyloid aggregates are different between these groups. In AD the major Aß species started with N3(pE) and ended at the C-terminus at position 4211.
To identify the molecular mechanisms that lead to AD-typical neuropathological hallmarks transgenic mouse models proved to be a valuable tool. We have been characterizing the APP/PS1KI mouse model that closely mimics the development of AD related neuropathological features including a significant neuronal loss in the hippocampus, a structure involved in learning and memory processes21. Specific neurodegeneration in the hippocampal CA1 subfield and entorhinal cortex is an early event in the AD pathology that correlates directly with the severity of the disease22. As in post-mortem AD brain, it has been demonstrated that the APP/PS1KI mouse model harbours abundant N-modified Aß42 including AßN3(pE). We therefore used this model to study a possible link between accumulation of AßN3(pE) and down-stream AD-typical pathological events. This transgenic mouse model carries M233T/L235P knocked-in mutations in presenilin-1 and overexpresses mutated human ß-amyloid precursor protein. Aßx-42 is the major form of Aß species present in this model with progressive development of a complex pattern of N-truncated variants and dimers, similar to those observed in AD brain.
At the age of six months an age-dependent significant reduced ability to perform working memory and motoric tasks is seen in these mice. The APP/PS1KI mice were smaller and showed development of a thoralumbar kyphosis, together with reduced body weight, and axonal degeneration in brain and spinal cord23. At six months of age already a 33% CA1 neuron loss in the hippocampus, together with a drastic reduction of long-term potentiation was observed24.
CA1 neuron loss in these mice is likely to contribute to the working memory deficits and complete loss of synaptic plasticity (long-term potentiation) after stimulation of the Schaffer collaterals. Intraneuronal Aß and peptides beginning with aspartate at position 1, and pyro-glutamate at position 3 were detected as early as two months of age. Accumulation increased significantly at the age of six months. Of all Aß peptides studied, the peptide that starts with pyro-glutamate (AßN3(pE)) at position 3 showed the highest increase in accumulation in neurons by 435%.
At 10 months of age, an extensive neuronal loss (>50%) is present in the CA1/2 hippocampal pyramidal cell layer that correlates with strong accumulation of intraneuronal Aß and thioflavine-S-positive intracellular material but not with extracellular Aß deposits. A strong reactive astrogliosis develops together with the neuronal loss.
Moreover, we have studied the neuron loss in different cholinergic nuclei and found that cholinergic neurons degenerate as a function of intraneuronal AßX-42 accumulation. This finding may explain cholinergic deficits in AD patients and indicates that cholinergic dysfunction is a down-stream event in AD pathology.
In addition, complete loss of neurogenesis in the dentate gyrus in APP/PS1KI mice points to a degenerative mechanism, which is independent from intracellular Aß aggregation. No intracellular Aß was detected in these neurons. The reduced number of dentate gyrus neurons (-30% at six months of age) may be at least partly a function of loss of neurogenesis.
•Overall, this mouse model develops a robust neuronal dysfunction and degeneration, which triggers AD-typical changes on different levels including synaptic plasticity and working memory.
•The neuron loss in different brain areas mostly follows the pattern of intraneuronal AßX-42 accumulation.
•From these observations we conclude that intraneuronal AßX-42 accumulation is the major neurotoxic factor in AD etiology.
•Of special interest is that pyro-glutamate-Aß42 is the variant, which aggregates fastest in degenerating neurons. This is likely due to its enhanced stability and propensity to aggregate.
•Therefore, this peptide most likely seems to be responsible for the observed neuronal toxicity.
The prevention of pyro-glutamate Aß aggregation is therefore an important mechanism and therapeutic target.
References1.Masters, C.L., et al. Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci U S A 82, 4245-4249 (1985).
24.Wirths, O., Weis, J., Kayed, R., Saido, T.C. & Bayer, T.A. Age-dependent axonal degeneration in an Alzheimer mouse model. Neurobiol Aging 8, online version (2006). doi:10.1016/j.neurobiolaging.2006.07.021.
Maria Vrijmoed-de Vries | alfa
The end of pneumonia? New vaccine offers hope
23.10.2017 | University at Buffalo
Scientists track ovarian cancers to site of origin: Fallopian tubes
23.10.2017 | Johns Hopkins Medicine
Salmonellae are dangerous pathogens that enter the body via contaminated food and can cause severe infections. But these bacteria are also known to target...
University of Maryland researchers contribute to historic detection of gravitational waves and light created by event
On August 17, 2017, at 12:41:04 UTC, scientists made the first direct observation of a merger between two neutron stars--the dense, collapsed cores that remain...
Seven new papers describe the first-ever detection of light from a gravitational wave source. The event, caused by two neutron stars colliding and merging together, was dubbed GW170817 because it sent ripples through space-time that reached Earth on 2017 August 17. Around the world, hundreds of excited astronomers mobilized quickly and were able to observe the event using numerous telescopes, providing a wealth of new data.
Previous detections of gravitational waves have all involved the merger of two black holes, a feat that won the 2017 Nobel Prize in Physics earlier this month....
Material defects in end products can quickly result in failures in many areas of industry, and have a massive impact on the safe use of their products. This is why, in the field of quality assurance, intelligent, nondestructive sensor systems play a key role. They allow testing components and parts in a rapid and cost-efficient manner without destroying the actual product or changing its surface. Experts from the Fraunhofer IZFP in Saarbrücken will be presenting two exhibits at the Blechexpo in Stuttgart from 7–10 November 2017 that allow fast, reliable, and automated characterization of materials and detection of defects (Hall 5, Booth 5306).
When quality testing uses time-consuming destructive test methods, it can result in enormous costs due to damaging or destroying the products. And given that...
Using a new cooling technique MPQ scientists succeed at observing collisions in a dense beam of cold and slow dipolar molecules.
How do chemical reactions proceed at extremely low temperatures? The answer requires the investigation of molecular samples that are cold, dense, and slow at...
23.10.2017 | Event News
17.10.2017 | Event News
10.10.2017 | Event News
23.10.2017 | Life Sciences
23.10.2017 | Physics and Astronomy
23.10.2017 | Health and Medicine