Bidirectional regulation of Aβ levels by Presenilin 1

Abstract

Alzheimer's disease (AD) is characterized by accumulation of the β-amyloid peptide (Aβ), which is generated through sequential proteolysis of the amyloid precursor protein (APP), first by the action of β-secretase, generating the β-C-terminal fragment (βCTF), and then by the Presenilin 1 (PS1) enzyme in the γ-secretase complex, generating Aβ. γ-Secretase is an intramembranous protein complex composed of Aph1, Pen2, Nicastrin, and Presenilin 1. Although it has a central role in the pathogenesis of AD, knowledge of the mechanisms that regulate PS1 function is limited. Here, we show that phosphorylation of PS1 at Ser367 does not affect γ-secretase activity, but has a dramatic effect on Aβ levels in vivo. We identified CK1γ2 as the endogenous kinase responsible for the phosphorylation of PS1 at Ser367. Inhibition of CK1γ leads to a decrease in PS1 Ser367 phosphorylation and an increase in Aβ levels in cultured cells. Transgenic mice in which Ser367 of PS1 was mutated to Ala, show dramatic increases in Aβ peptide and in βCTF levels in vivo. Finally, we show that this mutation impairs the autophagic degradation of βCTF, resulting in its accumulation and increased levels of Aβ peptide and plaque load in the brain. Our results demonstrate that PS1 regulates Aβ levels by a unique bifunctional mechanism. In addition to its known role as the catalytic subunit of the γ-secretase complex, selective phosphorylation of PS1 on Ser367 also decreases Aβ levels by increasing βCTF degradation through autophagy. Elucidation of the mechanism by which PS1 regulates βCTF degradation may aid in the development of potential therapies for Alzheimer's disease.Presenilin 1 | phosphorylation | Alzheimer's disease | Aβ | autophagy

Phosphorylated Presenilin 1 decreases β-amyloid by facilitating autophagosome–lysosome fusion

“…In the accompanying paper (22), we show that PS1 phosphorylation at Ser367 induces autophagic flux. To understand the molecular mechanism behind this effect, we examined neurons in the CA1 region of the hippocampus in PS1-S367A mice by transmission electron microscopy.…”

“…3C). We have shown that CK1γ2 phosphorylates PS1 at Ser367 (22). Knock-down of Annexin A2 blocked the increase in Aβ40 induced by the compound 2-((4-(2-hydroxypropan-2-yl)phenyl)amino)-1H-benzo[d]imidazole-6-carbonitrile, a CK1γ inhibitor (Fig.…”

“…The S367D analog of PS1 did not bind to Annexin A2, providing a molecular explanation for the lack of a phosphomimetic effect of PS1-S367D on Aβ accumulation (22). A role for Annexin A2 in the early steps of autophagy has recently been described.…”

Autophagy in periodontal disease: Evidence from a literature review

“…Zheng et al showed that Aβ production was suppressed 3-methyl adenine-dependent autophagy inhibition in vitro (Zheng et al, 2011). Aβ can be synthesized in the autophagosomes, which contain key mediators in its genesis (i.e., amyloid precursor protein and Presenilin-1) (Bustos et al, 2017). Also, tau post-translational modification can disrupt axoplasmic flow via autophagy, specifically through dynein-dynactin motors in vitro (Ikenaka et al, 2013).…”

N-terminal phosphorylation of Huntingtin: A molecular switch for regulating Htt aggregation, helical conformation, internalization and nuclear targeting

“…The discrepancy between these studies could be due to the fact that the use of mutations to mimic or abolish phosphorylation does not allow for assessing the dynamics of phosphorylation and the role of potential cross-talk between the phosphorylation at T3, S13 and S16. Furthermore, increasing evidence shows that the phosphomimicking mutations do not reproduce all aspects of protein phosphorylation (24,(39)(40)(41). We recently showed that the T3D mutation did not fully reproduce the inhibitory effect of T3 phosphorylation on the aggregation of Httex1 (24).…”