19 Dec 2024

Why is age the strongest risk factor for Alzheimer’s disease? In the December 10 Science Signaling, scientists led by Ning Bai, Difei Wang, Yu Di, and Liu Cao at China Medical University in Shenyang, and Hua Liu at Jinzhou Medical University, offer a clue. They report that levels of sirtuin 6, a member of a family of proteins deacetylases, drop with age in human and mouse brain.

The AD connection? SIRT6 deacetylates three adjacent lysines in amyloid precursor protein, and this post-translational modification offers APP up to the ubiquitin-proteasome system for degradation. As SIRT6 peters out, more APP remains to generate Aβ peptides. Indeed, co-first authors Bai and Rong Cheng also found that a SIRT6 activator reined in plaque burden in an APP/PS1 mouse model of AD.

SIRT6 in AD? DNA damage and oxidative stress reduce the level of SIRT6 deacetylase in aging, leading to more acetylated APP. This prevents APP ubiquitination and destruction in the proteasome and allows for production of Aβ. SIRT6 activators reduced Aβ levels in mice. [Courtesy of Cheng et al., 2024]

Sirtuins deacetylate histone and non-histone proteins alike (Grabowska et al., 2017). Previous research has linked the seven proteins in this family to progression of age-related disorders, including AD, Parkinson’s, Huntington’s, and ALS (Herskovits et al., 2013). The enzymes depend on NAD+- and play myriad roles. SIRT3, 4, 5, and 7 regulate mitochondrial metabolism in the brain, while SIRT6 helps prevent toxic responses to oxidative stress (Jęśko et al., 2017). Last year, Bai and colleagues reported that overexpressing SIRT1 in mice neurons tempers Aβ toxicity, while deleting it reduced APP recycling to the cell surface, shunting it to the endosome instead, where amyloidogenic cleavage occurs. They showed that SIRT1 competes with SIRT2, preventing APP from being deacetylated, hence decreasing the production of Aβ (Li et al., 2023). 

Another study reported that, like SIRT1, SIRT6 also was neuroprotective in mice, reducing tau phosphorylation, while in the brains of people who’d had AD, SIRT6 mRNA and protein levels had tanked (Kaluski et al., 2017). Might SIRT6 protect against amyloid pathology?

To find out, Cheng and colleagues measured SIRT6 and APP protein levels in brain extracts of 3- and 24-month-old wild-type mice. The old mice had less SIRT6 and more APP in the cortex and hippocampus than the young ones. In APP/PS1 and 5XFAD  mouse models, SIRT6 levels fell with age while APP levels crept up. DNA damage, hypoxia, and oxidative stress all linked to aging and neurodegenerative diseases including AD, exacerbated these protein shifts. 

The findings suggested a connection between SIRT6 and APP. A clue to what it might be came when Cheng knocked out SIRT6 in liver cells or hippocampal neurons in culture. APP protein levels rose even though its mRNA levels did not change, suggesting the protein was more stable. Lo and behold, SIRT6 removed acetyl groups at three positions in APP: Lysine 649, 650, and 651. This led to ubiquitination of those residues and degradation via the proteasome. When the scientists mutated these lysine residues to arginine, this “tag-and-destroy signal” was reduced.

“We never expected that SIRT6 would destabilize APP,” Bai wrote to Alzforum. “Detecting the elevated acetylation level of APP-Lys649/650/651 could be important for the early diagnosis of AD,” he suggested.

Indeed, a rare mutation to asparagine at position 649, aka 724 according to the Uniprot nomenclature for the longest human APP isoform, was documented in one family with early onset AD (Theuns et al., 2006). Alzforum deems this mutation “likely pathogenic.”

How might the SIRT6-APP interaction affect production of Aβ in aging and AD? The scientists report that as SIRT6 levels go down, APP begins to accumulate in early endosomes, a major site for processing APP into Aβ peptide (Choy et al., 2012). Indeed, the SIRT6 activator MDL-800 halved the density of Aβ plaques in the cortices and hippocampi of 5xFAD mice and protected against memory and spatial navigation losses.

“The aim of this study was to provide a theoretical basis for further understanding of the pathogenesis of AD and seeking effective therapeutic targets,” Bai wrote

The interplay between various sirtuins and APP biology in the human brain needs more study. Why would deacetylation by SIRT6 abrogate Aβ pathology while deacetylation by SIRT2 enhances it, as the same group reported previously (Bai et al., 2022)? The answer may lie in which lysines a given SIRT modifies. SIRT2 deacetylates lysines 132 and 134, which ushers APP into endosomes, while SIRT6 has the opposite effect.—Kristel Tjandra

Kristel Tjandra is a freelance writer in Springfield, Virginia

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References

Research Models Citations

1. APPPS1
2. 5xFAD (B6SJL)

Mutations Citations

1. APP K724M

Paper Citations

2. Herskovits AZ, Guarente L. Sirtuin deacetylases in neurodegenerative diseases of aging. Cell Res. 2013 Jun;23(6):746-58. Epub 2013 May 21 PubMed.
3. Jęśko H, Wencel P, Strosznajder RP, Strosznajder JB. Sirtuins and Their Roles in Brain Aging and Neurodegenerative Disorders. Neurochem Res. 2017 Mar;42(3):876-890. Epub 2016 Nov 24 PubMed.
4. Li N, Bai N, Zhao X, Cheng R, Wu X, Jiang B, Li X, Xue M, Xu H, Guo Q, Guo W, Ma M, Cao S, Feng Y, Song X, Wang Z, Zhang X, Zou Y, Wang D, Liu H, Cao L. Cooperative effects of SIRT1 and SIRT2 on APP acetylation. Aging Cell. 2023 Oct;22(10):e13967. Epub 2023 Aug 21 PubMed.
5. Kaluski S, Portillo M, Besnard A, Stein D, Einav M, Zhong L, Ueberham U, Arendt T, Mostoslavsky R, Sahay A, Toiber D. Neuroprotective Functions for the Histone Deacetylase SIRT6. Cell Rep. 2017 Mar 28;18(13):3052-3062. PubMed.
6. Theuns J, Marjaux E, Vandenbulcke M, Van Laere K, Kumar-Singh S, Bormans G, Brouwers N, Van den Broeck M, Vennekens K, Corsmit E, Cruts M, De Strooper B, Van Broeckhoven C, Vandenberghe R. Alzheimer dementia caused by a novel mutation located in the APP C-terminal intracytosolic fragment. Hum Mutat. 2006 Sep;27(9):888-96. PubMed.
7. Choy RW, Cheng Z, Schekman R. Amyloid precursor protein (APP) traffics from the cell surface via endosomes for amyloid β (Aβ) production in the trans-Golgi network. Proc Natl Acad Sci U S A. 2012 Jul 24;109(30):E2077-82. PubMed.
8. Bai N, Li N, Cheng R, Guan Y, Zhao X, Song Z, Xu H, Yi F, Jiang B, Li X, Wu X, Jiang C, Zhou T, Guo Q, Guo W, Feng Y, Wang Z, Ma M, Yu Y, Wang Z, Zhang S, Wang C, Zhao W, Liu S, Song X, Liu H, Cao L. Inhibition of SIRT2 promotes APP acetylation and ameliorates cognitive impairment in APP/PS1 transgenic mice. Cell Rep. 2022 Jul 12;40(2):111062. PubMed.

Further Reading

News

1. Brain-Specific Sirtuin Expression Delays Aging in Mice 6 Sep 2013
2. Sirtuins’ Status Less Certain as Study Questions Longevity Effect 26 Sep 2011
3. Sirtuins Link Stress, Autophagy 22 Feb 2008
4. Research Brief: SIRTs Keep Brain Minty Fresh 25 Jul 2010