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Neitzel J, Franzmeier N, Rubinski A, Dichgans M, Brendel M, Alzheimer’s Disease Neuroimaging Initiative (ADNI), Malik R, Ewers M. KL-VS heterozygosity is associated with lower amyloid-dependent tau accumulation and memory impairment in Alzheimer's disease. Nat Commun. 2021 Jun 22;12(1):3825. PubMed.
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Cliniques Universitaires Saint-Luc and Massachusetts General Hospital
This paper by Neitzel and colleagues explores the effects of the klotho genetic polymorphism on AD pathophysiology as measured using Florbetapir (amyloid) and Flortaucipir (tau) PET imaging in the ADNI3 cohort. They found the klotho variant to be associated with lower tau burden for a given level of amyloid, consistent with the previous observation that this variant decreases the risk of developing AD. The effect of klotho on tau was mostly observed in the brain regions where klotho mRNA is highly expressed, such as the temporal lobe, suggesting a local effect of klotho on tau pathology and/or on the interaction between amyloid and tau.
This study adds evidence that the association between amyloid and tau pathologies is dependent on genotype. Previous studies (Altmann et al., 2014; Buckley et al., 2019; Hohman et al., 2018) have observed that the E4 genotype increases tau burden for a given level of amyloid, particularly in women. Future studies should investigate how the combination of distinct genetic protective and risk factors impacts the interaction between amyloid and tau, and whether these effects are additive or multiplicative. This will—more than ever—require large samples of well-characterized older adults. Most importantly, we should study the biological pathways underlying this genetic variability and develop new ways of intervening in the risk of developing AD.
References:
Altmann A, Tian L, Henderson VW, Greicius MD, Alzheimer's Disease Neuroimaging Initiative Investigators. Sex modifies the APOE-related risk of developing Alzheimer disease. Ann Neurol. 2014 Apr;75(4):563-73. Epub 2014 Apr 14 PubMed.
Buckley RF, Mormino EC, Chhatwal J, Schultz AP, Rabin JS, Rentz DM, Acar D, Properzi MJ, Dumurgier J, Jacobs H, Gomez-Isla T, Johnson KA, Sperling RA, Hanseeuw BJ, Alzheimer's Disease Neuroimaging Initiative. Associations between baseline amyloid, sex, and APOE on subsequent tau accumulation in cerebrospinal fluid. Neurobiol Aging. 2019 Jun;78:178-185. Epub 2019 Mar 7 PubMed.
View all comments by Bernard HanseeuwADvantage
I read with great satisfaction and interest Neitzel and colleagues’ elegant report on reduced tau accumulation and lower memory impairment, associated with KL-VS heterozygosity in Alzheimer’s disease patients. This work, and the plethora of other recent high-impact published papers (Belloy et al., 2020; Erickson et al., 2019), all highlighting the potential of Klotho as a worthwhile target in the search for Alzheimer’s disease therapeutics, is especially gratifying for me to see, since our lab at Boston University School of Medicine was the first to publish (starting in 2007) that Klotho is neuroprotective (Zeldich et al., 2014), that Klotho protein level in the brain decreases with age (Duce et al., 2008), and that increasing Klotho levels would be beneficial in neurodegenerative diseases (Abraham et al., 2013; King et al., 2012). We have known since 2002 that KL-VS (a Klotho polymorphism that changes two amino acids in the protein) is protective (Arking et al., 2002). Since then, many articles were published on the positive effects of KL-VS heterozygosity on lifespan and health span extension, for a number of age-related diseases, and on human cognition (Dubal et al., 2014). This new work raises a number of important questions for Klothologists and other researchers interested in aging and Alzheimer’s disease:
1. Which KL-VS isoform is involved in the protective effect seen by Neitzel and colleagues?
Klotho is mainly expressed in kidney and brain. It is a type I transmembrane protein which is shed from its membrane by ADAM10 and 17 (Chen et al., 2007). As such, it circulates in blood and CSF and is found in urine as well. A third isoform produced by differential splicing of the Klotho gene generates a shorter, secreted form, found mostly in the brain (Massó et al., 2015). All three isoforms contain the VS sequence in KL-VS carriers, who represent 25 percent of the human population. The functions of the transmembrane and circulating Klotho are different. The circulating isoform may act as a ligand to a receptor to initiate signaling that could affect tau phosphorylation. In the kidney, circulating Klotho inhibits IGF-1, Wnt, and TGF-β signaling. In the kidney, transmembrane Klotho serves as a co-receptor with the FGF receptor for FGF-23 signaling. In the brain, the signaling of all isoforms is still unknown.
2. Is KL-VS enzymatic activity part of the mechanism?
Klotho may also act as a glucuronidase/sialidase to modify receptors or ion channels that would indirectly affect tau phosphorylation positively, for example, less phosphorylation at positions 217 and 181 that were just recently found to be specific for AD tau (Barthélemy et al., 2020; Palmqvist et al., 2020). Interestingly, p-tau217 appears to be the most robust plasma biomarker for Alzheimer’s disease yet. As an enzyme, Klotho activates the calcium channels TRPV5 and 6 and the potassium channel, ROMK1, which could also participate in intracellular signaling. We reported that Klotho activates AKT in primary neurons and oligodendrocyte progenitor cells (Chen et al., 2013; Zeldich et al., 2014). A recent article reports that sulfhydration of AKT triggers tau phosphorylation by activating glycogen synthase kinase 3β in Alzheimer's disease (Sen et al., 2020).
3. Does Klotho act via β-amyloid or directly on tau?
Since in patients with lots of amyloid KL-VS is protective via tau, we may conclude that KL-VS is bypassing amyloid to influence tau post-translational modifications such as phosphorylation.
4. Is KL-VS more protective because there is more of it, or because KL-VS possesses a protective gain of function due to the two amino acid substitutions?
KL-VS levels in conditioned medium of transfected cells and in human blood are slightly higher than those of wild-type Klotho, likely due to more shedding. We have reported that, in vitro, KL-VS exhibits stronger binding to FGFR and FGF23, which leads to an increased ERK phosphorylation (Tucker Zhou et al., 2013). Moreover, when comparing the glucuronidase activity of recombinant KL-VS with that of recombinant wild-type Klotho, we found that they differ (unpublished data). The aberrant enzymatic activity of KL-VS could also affect tau phosphorylation.
5. Is KL-VS more anti-inflammatory than wild-type Klotho?
We and others showed that Klotho has anti-inflammatory properties (Zeldich et al., 2019). If Klotho inhibits microglia activation, it may affect the propagation of tau from neuron to neuron (Asai et al., 2015). However, we don’t have evidence that KL-VS is more anti-inflammatory than wild-type Klotho.
Neitzel et al. are the first to publish a beneficial Klotho-tau-cognition relationship. While there is so much more we need to learn before we fully understand the mysterious mechanisms of this neuroprotective pleiotropic protein, we do know that increasing its levels will be beneficial in neurodegenerative and other diseases of aging.
References:
Abraham C, Zeldich E, Chen C. The anti-aging protein Klotho as a therapeutic target for neurodegenerative diseases. Paper presented at: Journal of neurochemistry, 2013.
Arking DE, Krebsova A, Macek M Sr, Macek M Jr, Arking A, Mian IS, Fried L, Hamosh A, Dey S, McIntosh I, Dietz HC. Association of human aging with a functional variant of klotho. Proc Natl Acad Sci U S A. 2002 Jan 22;99(2):856-61. Epub 2002 Jan 15 PubMed.
Asai H, Ikezu S, Tsunoda S, Medalla M, Luebke J, Haydar T, Wolozin B, Butovsky O, Kügler S, Ikezu T. Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat Neurosci. 2015 Nov;18(11):1584-93. Epub 2015 Oct 5 PubMed.
Barthélemy NR, Horie K, Sato C, Bateman RJ. Blood plasma phosphorylated-tau isoforms track CNS change in Alzheimer's disease. J Exp Med. 2020 Nov 2;217(11) PubMed.
Belloy ME, Napolioni V, Han SS, Le Guen Y, Greicius MD, Alzheimer’s Disease Neuroimaging Initiative. Association of Klotho-VS Heterozygosity With Risk of Alzheimer Disease in Individuals Who Carry APOE4. JAMA Neurol. 2020 Jul 1;77(7):849-862. PubMed.
Chen CD, Podvin S, Gillespie E, Leeman SE, Abraham CR. Insulin stimulates the cleavage and release of the extracellular domain of Klotho by ADAM10 and ADAM17. Proc Natl Acad Sci U S A. 2007 Dec 11;104(50):19796-801. PubMed.
Chen CD, Sloane JA, Li H, Aytan N, Giannaris EL, Zeldich E, Hinman JD, Dedeoglu A, Rosene DL, Bansal R, Luebke JI, Kuro-o M, Abraham CR. The antiaging protein Klotho enhances oligodendrocyte maturation and myelination of the CNS. J Neurosci. 2013 Jan 30;33(5):1927-39. PubMed.
Dubal DB, Yokoyama JS, Zhu L, Broestl L, Worden K, Wang D, Sturm VE, Kim D, Klein E, Yu GQ, Ho K, Eilertson KE, Yu L, Kuro-o M, De Jager PL, Coppola G, Small GW, Bennett DA, Kramer JH, Abraham CR, Miller BL, Mucke L. Life extension factor klotho enhances cognition. Cell Rep. 2014 May 22;7(4):1065-76. Epub 2014 May 10 PubMed.
Duce JA, Podvin S, Hollander W, Kipling D, Rosene DL, Abraham CR. Gene profile analysis implicates Klotho as an important contributor to aging changes in brain white matter of the rhesus monkey. Glia. 2008 Jan 1;56(1):106-17. PubMed.
Erickson CM, Schultz SA, Oh JM, Darst BF, Ma Y, Norton D, Betthauser T, Gallagher CL, Carlsson CM, Bendlin BB, Asthana S, Hermann BP, Sager MA, Blennow K, Zetterberg H, Engelman CD, Christian BT, Johnson SC, Dubal DB, Okonkwo OC. KLOTHO heterozygosity attenuates APOE4-related amyloid burden in preclinical AD. Neurology. 2019 Apr 16;92(16):e1878-e1889. Epub 2019 Mar 13 PubMed.
King GD, Chen C, Huang MM, Zeldich E, Brazee PL, Schuman ER, Robin M, Cuny GD, Glicksman MA, Abraham CR. Identification of novel small molecules that elevate Klotho expression. Biochem J. 2012 Jan 1;441(1):453-61. PubMed.
Massó A, Sánchez A, Gimenez-Llort L, Lizcano JM, Cañete M, García B, Torres-Lista V, Puig M, Bosch A, Chillon M. Secreted and Transmembrane αKlotho Isoforms Have Different Spatio-Temporal Profiles in the Brain during Aging and Alzheimer's Disease Progression. PLoS One. 2015;10(11):e0143623. Epub 2015 Nov 24 PubMed.
Palmqvist S, Janelidze S, Quiroz YT, Zetterberg H, Lopera F, Stomrud E, Su Y, Chen Y, Serrano GE, Leuzy A, Mattsson-Carlgren N, Strandberg O, Smith R, Villegas A, Sepulveda-Falla D, Chai X, Proctor NK, Beach TG, Blennow K, Dage JL, Reiman EM, Hansson O. Discriminative Accuracy of Plasma Phospho-tau217 for Alzheimer Disease vs Other Neurodegenerative Disorders. JAMA. 2020 Aug 25;324(8):772-781. PubMed.
Sen T, Saha P, Jiang T, Sen N. Sulfhydration of AKT triggers Tau-phosphorylation by activating glycogen synthase kinase 3β in Alzheimer's disease. Proc Natl Acad Sci U S A. 2020 Feb 25;117(8):4418-4427. Epub 2020 Feb 12 PubMed. Correction.
Tucker Zhou TB, King GD, Chen C, Abraham CR. Biochemical and functional characterization of the klotho-VS polymorphism implicated in aging and disease risk. J Biol Chem. 2013 Dec 20;288(51):36302-11. Epub 2013 Nov 11 PubMed.
Zeldich E, Chen CD, Boden E, Howat B, Nasse JS, Zeldich D, Lambert AG, Yuste A, Cherry JD, Mathias RM, Ma Q, Lau NC, McKee AC, Hatzipetros T, Abraham CR. Klotho Is Neuroprotective in the Superoxide Dismutase (SOD1G93A) Mouse Model of ALS. J Mol Neurosci. 2019 Oct;69(2):264-285. Epub 2019 Jun 27 PubMed.
Zeldich E, Chen CD, Colvin TA, Bove-Fenderson EA, Liang J, Tucker Zhou TB, Harris DA, Abraham CR. The neuroprotective effect of Klotho is mediated via regulation of members of the redox system. J Biol Chem. 2014 Aug 29;289(35):24700-15. Epub 2014 Jul 18 PubMed.
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