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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.
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Boston University School of Medicine
McGrath et al. report results from a 12-year follow-up of a Framingham Heart Study population, suggesting that a high serum FGF23 level is correlated with dementia. The higher serum FGF23 was associated with an increased risk of incident dementia and AD, but was not associated with structural brain measures predictive of vascular brain injury or with performance on neurocognitive testing.
Klotho is an anti-aging protein that serves as a co-receptor with the FGF receptor to facilitate FGF23 signaling in the kidney resulting in calcium, phosphate, and vitamin D homeostasis. The connection between Klotho and FGF23 was made when it was realized that Klotho-deficient and FGF23-deficient mice share similar, albeit not identical, phenotypes.
In a second article connecting FGF23, Klotho, and cognition, Laszczyk and colleagues show that FGF23 deficiency also leads to hippocampus-dependent cognitive impairment, like that seen in Klotho-deficient mice. However, FGF23-deficient brains had no change in hippocampal synaptic plasticity, no gross structural or developmental defects, and only minor impairment to postnatal hippocampal neurogenesis, in contrast to Klotho-deficient mice.
The authors hypothesize that hippocampal-dependent cognitive impairment could be the result of an increasingly toxic brain micro-environment caused by FGF23 deficiency and a resulting lack of normal ion homeostasis. They conclude that although both Klotho- and FGF23-deficient mice suffer from cognitive decline, in the brain this may occur in parallel pathways and not via Klotho-dependent FGF23 signaling, as demonstrated in the kidney. Interestingly, it was shown by others that patients with severe kidney disease suffer from cognitive decline, suggesting that some peripheral factor may affect the brain.
Nevertheless, Hensel et al. (2016) provided evidence that FGF23 circulates in CSF and that primary hippocampal cells do respond to recombinant FGF23 by signaling that affects neuronal morphology and synaptic density. Thus, FGF23 may serve as a ligand for FGF-R and Klotho in the brain. However, these results need confirmation by other groups.
A recent review in Frontiers in Endocrinology describes Klotho-dependent and independent actions of FGF23. FGF23 also signals directly via the FGF receptor in tissues lacking Klotho, including induction of cardiac hypertrophy and fibrosis, elevation of inflammatory cytokine expression in the liver, and inhibition of neutrophil recruitment (Richter and Faul, 2018).
Hensel N, Schön A, Konen T, Lübben V, Förthmann B, Baron O, Grothe C, Leifheit-Nestler M, Claus P, Haffner D. Fibroblast growth factor 23 signaling in hippocampal cells: impact on neuronal morphology and synaptic density. J Neurochem. 2016 Jun;137(5):756-69. Epub 2016 Mar 7 PubMed.
Richter B, Faul C. FGF23 Actions on Target Tissues-With and Without Klotho. Front Endocrinol (Lausanne). 2018;9:189. Epub 2018 May 2 PubMed.View all comments by Carmela Abraham
University of Southern Denmark
Both Laszczyk et al. and McGrath et al. find that FGF23 is related to cognitive performance, that being in both the mouse and the human. FGF23 is already known to play a role in mineral metabolism, a process acting across multiple organs. Specially, the study implicating serum FGF23 as a risk factor for dementia and Alzheimer’s disease is interesting and fits well with the pathway-related Klotho gene variation that also acts on cognitive performance. However, it is puzzling that FGF23 does not associate with other cognitive measures as it does with dementia. From studies of Klotho, e.g. genetic studies, the KL-VS variant is associated with normal cognitive abilities and is related to synaptic glutamate functions, which is a mechanism for normal learning abilities.
Klotho is associated with a broad range of maladies including cardiovascular diseases, kidney dysfunction, and cognitive disabilities. And klotho is fundamental in several organ functions, also in the brain. But as the associations are dependent on aging, it would be expected also to be the case for the earlier pathway component FGF23. In these studies, timing as well as dosage, i.e. level of FGF23 or Klotho, are important factors to consider, and may be a reason for the inconsistency across cognitive traits as also highlighted in the papers.
For background, appropriate levels of phosphate in the body are maintained by the coordinated regulation of the bone-derived growth factor FGF23 and the membrane-bound protein Klotho. The endocrine actions of FGF23, in association with parathyroid hormone and vitamin D, mobilize sodium–phosphate co-transporters that control renal phosphate transport in proximal tubular epithelial cells. The availability of an adequate amount of Klotho is essential for FGF23 to exert its phosphaturic effects in the kidney.
In the presence of Klotho, FGF23 activates downstream signaling components that influence the homeostasis of phosphate, whereas in the absence of this membrane protein, it is unable to exert such regulatory effects, as demonstrated convincingly in animal models. Several factors, including phosphate and vitamin D, can regulate the production of both FGF23 and Klotho and influence their functions.View all comments by Jonas Mengel-From
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