Klotho an Autophagy Stimulator as a Potential Therapeutic Target for Alzheimer's Disease: A Review

Abstract

Alzheimer's disease (AD) is an age-associated neurodegenerative disease; it is the most common cause of senile dementia. Klotho, a single-pass transmembrane protein primarily generated in the brain and kidney, is active in a variety of metabolic pathways involved in controlling neurodegeneration and ageing. Recently, many studies have found that the upregulation of Klotho can improve pathological cognitive deficits in an AD mice model and have demonstrated that Klotho plays a role in the induction of autophagy, a major contributing factor for AD. Despite the close association between Klotho and neurodegenerative diseases, such as AD, the underlying mechanism by which Klotho contributes to AD remains poorly understood. In this paper, we will introduce the expression, location and structure of Klotho and its biological functions. Specifically, this review is devoted to the correlation of Klotho protein and the AD phenotype, such as the effect of Klotho in upregulating the amyloid-beta clearance and in inducing autophagy for the clearance of toxic proteins, by regulating the autophagy lysosomal pathway (ALP). In summary, the results of multiple studies point out that targeting Klotho would be a potential therapeutic strategy in AD treatment.

Keywords: Alzheimer’s disease; Klotho; autophagy; autophagy lysosomal pathway (ALP); neurodegenerative disease.

Figure 1

Multifactorial effects of Klotho in the pathology of AD.

Figure 2

Effects of Klotho on the NLRP3/caspase-1 signaling pathway in AD. Klotho inhibits the accumulation of amyloid β peptide which can affect microglia directly and stimulate the NLRP3/caspase-1 signaling in the brain. The black arrow represents the consequence of Aβ stimulation. NLRP3: Nucleotide-binding oligomerization domain leucine-rich repeat and pyrin domain-containing protein 3; ASC: Apoptosis-associated speck-like protein containing a caspase recruitment domain; pro IL-1β: inactive interleukin-1β precursor; IL-1β: interleukin-1β.

Figure 3

Transformation of microglia with the overexpression of Klotho. Microglia are usually in a resting state in the brain. Once activated, they show either M1 or M2 phenotypes. In the activated M1 phenotype, the expression of caspase-1 and IL-1β is enhanced, which stimulate a pro-inflammatory response and cause neurotoxicity. In contrast, when Klotho is overexpressed, M1 microglia are differentiated into M2 microglia. The secretion of caspase-1 and IL-1β is decreased, thereby facilitating Aβ clearance, preserving neurons and protecting against cognitive dysfunction.

Figure 4

Role of Klotho protein in ULK1-induced autophagy. Left: Klotho overexpression. AMPK is active and mTOR is inhibited by AMPK and Klotho protein. ULK1 is subsequently phosphorylated by active AMPK at sites Ser 317 and 777. The complex of ULK1/ATG13/FIP200 is formed and autophagy is promoted. Right: Klotho deficiency. AMPK becomes inactive while mTOR becomes active. Activated mTOR phosphorylates ULK1 on Ser757, preventing ULK1 from interacting with AMPK, suppressing the formation of the ULK1 complex, and inhibiting autophagy.

Figure 5

Mechanism of Klotho activity in autophagy induction through TFEB nuclear translocation. Soluble Klotho (sKlotho) or recombinant mouse Klotho (rKlotho) inhibits mTOR (S211) activity, thereby preventing TFEB phosphorylation resulting in nuclear translocation and activation of the transcription factor EB (TFEB). sKlotho or rKlotho also represses glycogen synthase kinase 3β (GSK3β) (S9) phosphorylation to trigger TFEB nuclear translocation. Improved TFEB-mediated lysosomal gene transcription by sKlotho increases lysosomal biogenesis and eventually enhances autophagy flux.