Could α-Klotho Unlock the Key Between Depression and Dementia in the Elderly: from Animal to Human Studies

Abstract

α-Klotho is known for its aging-related functions and is associated with neurodegenerative diseases, accelerated aging, premature morbidity, and mortality. Recent literature suggests that α-Klotho is also involved in the regulation of mental functions, such as cognition and psychosis. While most of studies of α-Klotho are focusing on its anti-aging functions and protective role in dementia, increasing evidence showed many shared symptoms between depression and dementia, while depression has been proposed as the preclinical stage of dementia such as Alzheimer’s disease (AD). To see whether and how α-Klotho can be a key biological link between depression and dementia, in this review, we first gathered the evidence on biological distribution and function of α-Klotho in psychiatric functions from animal studies to human clinical investigations with a focus on the regulation of cognition and mood. Then, we discussed and highlighted the potential common underlying mechanisms of α-Klotho between psychiatric diseases and cognitive impairment. Finally, we hypothesized that α-Klotho might serve as a neurobiological link between depression and dementia through the regulation of oxidative stress and inflammation.

Full text

Could α-Klotho Unlock the Key Between Depression and Dementia
in the Elderly: from Animal to Human Studies
Xiang Gao
1
&Yuhong Li
1
&Zuoli Sun
2
&Hong Xu
2
&Guangwei Ma
1
&Qi Deng
1
&Claire X. Zhang
1
&Rena Li
1,2
Received: 12 June 2020 / Accepted: 25 January 2021
#The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature 2021
Abstract
α-Klotho is known for its aging-related functions and isassociatedwith neurodegenerative diseases, accelerated aging, premature
morbidity, and mortality. Recent literature suggests that α-Klotho is also involved in the regulation of mental functions, such as
cognition and psychosis. While most of studies of α-Klotho are focusing on its anti-aging functions and protective role in
dementia, increasing evidence showed many shared symptoms between depression and dementia, while depression has been
proposed as the preclinical stage of dementia such as Alzheimer’s disease (AD). To see whether and how α-Klotho can be a key
biological link between depression and dementia, in this review, we first gathered the evidence on biological distribution and
function of α-Klotho in psychiatric functions from animal studies to human clinical investigations with a focus on the regulation
of cognition and mood. Then, we discussed and highlighted the potential common underlying mechanisms of α-Klotho between
psychiatric diseases and cognitive impairment. Finally, we hypothesized that α-Klotho might serve as a neurobiological link
between depression and dementia through the regulation of oxidative stress and inflammation.
Keywords α-Klotho .Aging .Dementia .Depression
Introduction
The α-Klotho gene is located on human chromosome 13 and
contains five exons [1,2] and encodes a single-pass type I
transmembrane protein with three domains: a short intracellu-
lar domain (~60 amino acids), a transmembrane domain, and a
large extracellular domain (~950 amino acids). As an anti-
aging protein, α-Klotho is widely expressed throughout the
human tissues, and the brain is one of the organs with highest
expression [3]. A full-length α-Klotho protein (~140 kD) can
be substrates for several enzymes [4,5], and the cleaved ex-
tracellular domain (~130 kD) gets into the blood, urine, and
cerebrospinal fluid as a soluble α-Klotho protein [6,7]. While
the full-length membrane-bound α-Klotho is known as a co-
receptor for fibroblast growth factor-23 (FGF23) and plays a
role in regulating the excretion of phosphate and synthesis of
active vitamin D [8–10], the soluble α-Klotho acts as a hor-
monal factor as well as an enzyme in regulating growth factor
signaling [11–13], oxidative stress [14], and ion channels and
transporters [15–18].
α-Klotho plays a well-recognized anti-aging function in
both animal models and human studies. Mice with lower ex-
pression of α-Klotho gene show shortened life span and pre-
mature onset of age-related phenotypes [1], while overexpres-
sion of α-Klotho gene prolongs the life span [19].
Furthermore, human studies reveal that allelic variations in
α-Klotho gene are closely associated with longevity, as well
as the risk of aging-related health conditions, such as cardio-
vascular disease [20], glucose metabolism [21], bone mineral
density [22], renal stones [23], breast cancer [24], and cogni-
tive impairment [25–27]. α-Klotho is also well studied in
Alzheimer’s disease (AD), the most common dementia in
the elderly [28], while few studies also proposed the potential
role of α-Klotho in the mood disorders [29–31].
With strong clinical evidence showing that depression and
dementia often share common symptoms, depression might
be a preclinical stage of dementia. For example, 5–11% of
AD patients also suffer from depression [32], and individuals
with depression had higher risk of dementia [33–36]. Studies
also reported a reduction of hippocampal volume in both
*Rena Li
renali@ccmu.edu.cn
1
Beijing Institute of Brain Disorders, Laboratory of Brain Disorders,
Ministry of Science and Technology, Collaborative Innovation
Center for Brain Disorders, Capital Medical University,
Beijing 100069, China
2
Beijing Key Laboratory of Mental Disorders, Beijing Anding
Hospital, Beijing 100088, China
https://doi.org/10.1007/s12035-021-02313-0
/ Published online: 1 February 2021
Molecular Neurobiology (2021) 58:2874–2885
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