RETRACTED: SIRT1 Suppresses β-Amyloid Production by Activating the α-Secretase Gene ADAM10

Abstract

Summary A hallmark of Alzheimer's disease (AD) is the accumulation of plaques of Aβ 1-40 and 1-42 peptides, which result from the sequential cleavage of APP by the β and γ-secretases. The production of Aβ peptides is avoided by alternate cleavage of APP by the α and γ-secretases. Here we show that production of β-amyloid and plaques in a mouse model of AD are reduced by overexpressing the NAD-dependent deacetylase SIRT1 in brain, and are increased by knocking out SIRT1 in brain. SIRT1 directly activates the transcription of the gene encoding the α-secretase, ADAM10. SIRT1 deacetylates and coactivates the retinoic acid receptor β, a known regulator of ADAM10 transcription. ADAM10 activation by SIRT1 also induces the Notch pathway, which is known to repair neuronal damage in the brain. Our findings indicate SIRT1 activation is a viable strategy to combat AD, and perhaps other neurodegenerative diseases.

Testing the Therapeutic Potential of Doxycycline in a Drosophila melanogaster Model of Alzheimer Disease

“…Recent studies have shown that inhibitors of ␤ and blockers of ␥ secretase are very hard to prepare and may cause side effects, respectively, because they are important for the cleavage of other molecules (41). Alternatively, stimulation of the non-amyloidogenic amyloid precursor protein processing is being developed (8). The peptide and its precursor are normal products of the cells, and although their physiological roles in neuronal function are still unknown, the implication in neuronal and synaptic activity has been suggested (4).…”

“…In health, the shorter and less aggregation-prone A␤40 peptide predominates, whereas in disease, the more hydrophobic A␤42 is overproduced (5). Data from familial AD cases indicate that the production of aggregation-prone isoforms of A␤ is sufficient to cause disease (6), and so therapeutic strategies have focused mainly on the prevention of the peptide generation (7)(8)(9). Unfortunately, the development of ␥ secretase inhibitors in particular has been hampered by a range of serious unwanted effects.…”

ADAM10 as a Biomarker for Alzheimer’s Disease: A Study with Brazilian Elderly

“…In the last few years, the scientific literature has discussed the ADAM10 activity as a possible AD biomarker [11,13,21,22,23]. ADAM10 has a leading role in the physiological APP metabolism, working as the main α-secretase in the nonamyloidogenic pathway [10].…”

Translational Repression of the Disintegrin and Metalloprotease ADAM10 by a Stable G-quadruplex Secondary Structure in Its 5′-Untranslated Region

“…The prodomain is important for folding of ADAM10 and acts as a potent inhibitor of ADAM10 activity (14,15). Recently, it was demonstrated that ADAM10 transcription is stimulated by all-trans retinoic acid and by the deacetylase Sirtuin1 (16,17). Moreover, we demonstrated previously that ADAM10 expression could be suppressed at the translational level by its unusual long GC-rich 5Ј-UTR (18).…”