Local Klotho Enhances Neuronal Progenitor Proliferation in the Adult Hippocampus

Abstract

Klotho is an aging-related protein associated with hippocampal cognitive performance in mammals. Klotho regulates progenitor cell proliferation in non-neuronal tissues, but its role in adult hippocampal neurogenesis (AHN) has not been explored. Klotho expression in the adult mouse hippocampus was examined by immunofluorescence and PCR. AHN was evaluated in the hippocampus of klotho knock-out mice (KO), klotho KO/vitamin D-receptor mutant mice, and in a model of local klotho hippocampal knockdown. The recombinant Klotho effect on proliferation was measured in mouse-derived hippocampal neural progenitor cells. Hippocampal-dependent memory was assessed by a dry-land version of the Morris water maze. Klotho was expressed in the granular cell layer of the adult Dentate Gyrus. AHN was increased in klotho KO mice, but not in klotho KO/vitamin D-receptor mutant mice. Inversely, local downregulation of hippocampal Klotho diminished AHN. Recombinant Klotho increased the proliferation rate of neural progenitors. Downregulation of hippocampal Klotho correlated with a decreased performance in hippocampal dependent memory. These results suggest that Klotho directly participates in regulating AHN. Our observations indicate that Klotho promotes proliferation, AHN and hippocampal dependent cognition. Increased neurogenesis in klotho KO mice may be secondary to the activation of other pathways altered in the model, such as vitamin D.

Intermittent fasting enhances long-term memory consolidation, adult hippocampal neurogenesis, and expression of longevity gene Klotho

“…Notably, this finding was only observed in the DH, the axis most implicated in cognitive processing and spatial memory [77]. Although previous studies have demonstrated that Kl is important for AHN [32,33], to our knowledge this is the first time that a gene has been proposed to regulate AHN specifically in one axis of the hippocampus. This finding is aligned with previous reports that showed Kl knockout mice exhibit impaired long-term memory recall without changes in emotionality [25,78].…”

“…We demonstrate that, with an overall 10% matched-energy intake, IF in the form of every-other-day feeding is superior to daily CR in enhancing long-term memory performance in mice, and we provide evidence that this enhancement is associated with increased AHN and expression of the longevity gene Kl. Previous studies have already implicated Kl in the regulation of the hippocampal neurogenic process to different extent depending on the age of the mice [32,33]. The human hippocampal progenitor cell line HPC0A07/03A was transduced with a lentivirus to generate a cell line named Klover that conditionally overexpressed the secreted form of KL in response to doxycycline withdrawal.…”

Klotho Deficiency Accelerates Stem Cells Aging by Impairing Telomerase Activity

“…Prior studies have shown that KL regulates life-extension, and derives much of its antiaging capacities from regulation of the telomerase activity in stem cells (11,12). For example, one study demonstrated that mice enjoyed extended life spans when KL was overexpressed (12,13). Conversely, KL deficiency has been shown to induce premature aging (12).…”

Enhanced Expression of Secreted α-Klotho in the Hippocampus Alters Nesting Behavior and Memory Formation in Mice

“…Since it has been shown previously that overexpression of full-length α-Klotho affects neurogenesis (Zhou et al, 2018), we tested whether human secreted Klotho expressed in CA1 neurons enhances pluripotency in the SGZ (Laszczyk et al, 2017). Several transcription factors have been described that can be utilized to evaluate the state of newly developed cells (Salech et al, 2017). We used the transcription factor sex determining region Y-box 2 (SOX2) as a marker protein for pluripotent cells.…”