N-terminally truncated amyloid-b (Ab) peptides are present in early and diffuse plaques of individuals with Alzheimer's disease (AD), are overproduced in early onset familial AD and their amount seems to be directly correlated to the severity and the progression of the disease in AD and Down's syndrome (DS). The pyroglutamate-containing isoforms at position 3 [AbN3(pE))40/42] represent the prominent form among the N-truncated species, and may account for more than 50% of Ab accumulated in plaques. In this study, we compared the toxic properties, fibrillogenic capabilities, and in vitro degradation profile of Ab1-40, Ab1-42, AbN3(pE))40 and AbN3(pE))42. Our data show that fibre morphology of Ab peptides is greatly influenced by the C-terminus while toxicity, interaction with cell membranes and degradation are influenced by the N-terminus. AbN3(pE))40 induced significantly more cell loss than the other species both in neuronal and glial cell cultures. Aggregated AbN3(pE) peptides were heavily distributed on plasma membrane and within the cytoplasm of treated cells. AbN3(pE))40/42 peptides showed a significant resistance to degradation by cultured astrocytes, while fulllength peptides resulted partially degraded. These findings suggest that formation of N-terminally modified peptides may enhance b-amyloid aggregation and toxicity, likely worsening the onset and progression of the disease.
The processing of the amyloid precursor protein (APP) through the formation of C-terminal fragments (CTFs) and the production of beta-amyloid, are events likely to influence the development and the progression of Alzheimer's disease (AD). APP is a transmembrane protein similar to a cell-surface receptor with the intraluminal NPTY motif in the cytosolic C terminus. Although APP holoprotein can be bound to intracellular proteins like Fe65, X11, and mDab, the ultimate function and the mechanisms through which this putative receptor transfers its message are unclear. Here it is shown that in human brain, a subset of tyrosine-phosphorylated CTFs represent docking sites for the adaptor protein ShcA. ShcA immunoreactivity is greatly enhanced in Alzheimer's patients; it is mainly localized to glial cells and occurs at reactive astrocytes surrounding cerebral vessels and amyloid plaques. Grb2 also is involved in complexes with ShcA and tyrosine-phosphorylated CTFs, and in AD brain the interaction between Grb2-ShcA and CTFs is enhanced. Also, a higher amount of phospho-ERK1,2 is present in AD brain in comparison with control cases, likely as a result of the ShcA activation. In vitro experiments show that the ShcA-CTFs interaction is strictly confined to glial cells when treated with thrombin, which is a well-known ShcA and ERK1,2 activator, mitogen, and regulator of APP cleavage. In untreated cells ShcA does not interact with either APP or CTFs, although they are normally produced. Altogether these data suggest that CTFs are implicated in cell signaling via Shc transduction machinery, likely influencing MAPK activity and glial reaction in AD patients.
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