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 A beta plays a seminal role in the pathogenesis of AD. There is great interest, therefore, in understanding the proteolytic processing of APP, the precursor of A beta, and its proteases responsible for generating A beta. 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 A beta N3(pE) using mass spectrometry of purified A protein from AD brains, which explains the difficulties in sequencing the amino-terminus2. They reported that only 10-15% of the total A isolated by this method begins at position 3 with A beta N3(pE). Later it became clear that A beta N3(pE) represents a dominant fraction of A peptides in AD and Down's syndrome brain3-15.
N-terminal deletions in general enhance aggregation of "-amyloid peptides in vitro16. A beta N3(pE) has a higher aggregation propensity17,18, and stability19, and shows an increased toxicity compared to full-length A beta20. In AD only a small proportion of A beta 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 A beta N3(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 A beta species started with N3(pE) and ended at the C-terminus at position 4211.
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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 A beta 42 including A beta N3(pE). We therefore used this model to study a possible link between accumulation of A beta N3(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 "-amyloid precursor protein. A x-42 is the major form of A beta 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 A 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 A peptides studied, the peptide that starts with pyro-glutamate (A beta N3(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 A and thioflavine-S-positive intracellular material but not with extracellular A 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 A X-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 A beta aggregation. No intracellular A 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 A X-42 accumulation.
From these observations we conclude that intraneuronal A X-42 accumulation is the major neurotoxic factor in AD etiology.
Of special interest is that pyro-glutamate-A 42 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 A aggregation is therefore an important mechanism and therapeutic target.
Materials provided by European College of Neuropsychopharmacology. Note: Content may be edited for style and length.
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