Paradigm shift in Alzheimers's research: new ...( Alzheimers disease (AD) is a progres...)

Alzheimers 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" 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", and its proteases responsible for generating A". 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"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"N3(pE). Later it became clear that A"N3(pE) represents a dominant fraction of A" peptides in AD and Downs syndrome brain3-15.

N-terminal deletions in general enhance aggregation of "-amyloid peptides in vitro16. A"N3(pE) has a higher aggregation propensity17,18, and stability19, and shows an increased toxicity compared to full-length A"20. In AD only a small proportion of A" 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"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" species started with N3(pE) and ended at the C-terminus at position 4211.