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Barucker C, Harmeier A, Weiske J, Fauler B, Albring KF, Prokop S, Hildebrand P, Lurz R, Heppner FL, Huber O, Multhaup G

Nuclear translocation uncovers the amyloid Peptide aβ42 as a regulator of gene transcription

J Biol Chem. 2014 Jul 18;289(29):20182-91. doi: 10.1074/jbc.M114.564690. PubMed Link

Our work addresses the question whether Alzheimer disease amyloid-β peptides (Aβ) may have a physiological function. So far, most reports on Aβ, especially intraneuronal accumulation in brains of patients with Alzheimer disease and in animal models had suggested a pathophysiological role specific for Aβ peptides with 40 and 42 amino acids (Aβ40, Aβ42), respectively. It was not known if Aβ peptides can have a biological activity inside of the cell.

The key finding of our study is that Aβ peptides are internalized by cells and that nuclear Aβ42 is detected in brain tissue of both wild-type and animal models of Alzheimer disease.

We used state-of-the-art technologies to show that Aβ42 specifically interacts as a regulator of gene transcription and that mRNA levels of the examined candidate genes were altered by the potentially neurotoxic Aβ42 peptide. The activity of nuclear Aβ as found by us indicates a novel role for Aβ42 in nuclear signaling. The existing conundrum of non-toxic and toxic amyloidogenic peptides may be explained by the ability of Aβ42 to enter the nucleus and to modulate expression of genes identified by us. Further explorations are needed to characterize their roles in the pathogenesis.

The model illustrates the nuclear uptake of Aβ monomers or oligomers (2x, 4x, low-n) through passing the nuclear membrane pores (1) or its facilitated uptake (2).