Full Length ArticleRole of monocarboxylate transporter 4 in Alzheimer disease
Introduction
Alzheimer disease (AD) is a neurodegenerative disease that is clinically characterized by progressive cognitive impairment and personality changes that severely affect the quality of life of patients. Elucidating the pathogenesis of AD and formulating appropriate treatment measures has become an important issue to be solved in AD research. Normal energy metabolism is important for the brain in carrying out its various physiological activities. Energy metabolism disorders affect the normal function of neurons and are associated with memory disorders in AD (Dimitrios and Mattson, 2011). Current research confirms that lactic acid is not only an energy substrate used preferentially by neurons, it also plays an important role in memory formation (Bouzier Sore et al., 2003).
Monocarboxylate transporters (MCTs) are a type of transmembrane transporter of monocarboxylic acids, such as lactic acid. There are three subtypes of MCT in the brain: MCT1, MCT2, and MCT4; these synergistically transport lactic acid between astrocytes and neurons (Machler et al., 2016). In the early stages of this experiment, we noted that MCT4 is elevated in the cerebrospinal fluid (CSF) of patients with mild cognitive impairment. There is currently no report of the correlation between MCT4 and AD. We investigated the potential of MCT4 as an AD drug via in vitro and in vivo experiments. Moreover, we found that its anti-AD mechanism may be mediated by mitochondrial energy metabolism.
Section snippets
Study population
A total of 16 patients with dementia (10 women, 6 men; mean age 71.05 ± 8.13 years), who were admitted to Xuanwu Hospital of Capital Medical University (Beijing, China) between December 2016 and December 2017, were enrolled in the present study. These patients were diagnosed with AD in the stage of mild cognitive impairment (MCI), based on the revised diagnostic criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related
Human protein chip technology for analysis of cerebrospinal fluid
To identify protein changes in patients with early-stage AD, we examined the CSF of 16 patients with MCI using whole-genome chip technology. All enrolled patients developed dementia of Alzheimer type (DAT) after 1 year. Compared with the CSF of healthy controls, 13 proteins were differentially expressed in patients with MCI (Fig. 1A) including SLC16A4 (also known as MCT4), which is a functional protein in energy metabolism. The differential expression of MCT4 in patients with MCI and healthy
Discussion
In this study, we used protein chip technology to analyze the CSF of patients with AD. The expression of MCT4 was significantly increased, i.e., MCT4 was mainly expressed in astrocytes. The expression of MCT2 in neurons was unchanged. After regulating MCT4 overexpression in astrocytes in vitro, neuronal proliferative capacity decreased and apoptosis increased. After knocking down expression of MCT4 in the hippocampus of AD model mice, the apoptosis rate of hippocampal neurons was significantly
Author contribution
Author 1: Ping Hong
Cell and animal experiments
Collected the data
Performed the analysis
Wrote the paper
Author 2: Xiaoyi Zhang
Collected the data
Contributed data or analysis tools
Performed the analysis
Author 3: Shichao Gao
Contributed data or analysis tools
Performed the analysis
Author 4: Peichang Wang
Conceived and designed the analysis
Performed the analysis
Wrote the paper.
Transparency document
Declaration of Competing Interest
The authors declare no conflict of interest.
Acknowledgment
This study was supported by grants from the National Natural Science Foundation of China (No.81501841).
References (17)
- et al.
Dramatic aggregation of Alzheimer abeta by Cu(II) is induced by conditions representing physiological acidosis
J. Biol. Chem.
(1998) - et al.
In vivo evidence for a lactate gradient from astrocytes to neurons
Cell metabolism
(2016) - et al.
Severe cognitive impairment correlates with higher cerebrospinal fluid levels of lactate and pyruvate in a canine model of senile dementia
Prog Neuropsychopharmacol Biol Psychiatry.
(2005) - et al.
Evidence that CD147 modulation of β-Amyloid (Aβ) levels is mediated by extracellular degradation of secreted aβ
J. Biological Chem.
(2008) - et al.
Astrocyte senescence as a component of Alzheimer’s disease
Exp. Gerontol.
(2013) - et al.
Lactate is a preferential oxidative energy substrate over glucose for neurons in culture
J. Cerebral Blood Flow & Metabolism
(2003) - et al.
Passive immunization targeting the N-terminal projection domain of tau decreases tau pathology and improves cognition in a transgenic mouse model of Alzheimer disease and tauopathies
J. Neural Trans.
(2015) - et al.
Disrupted energy metabolism and neuronal circuit dysfunction in cognitive impairment and Alzheimer’s disease
Lancet Neurol.
(2011)
Cited by (14)
Alzheimer's disease: Insights and new prospects in disease pathophysiology, biomarkers and disease-modifying drugs
2023, Biochemical PharmacologyAstrocyte energy and neurotransmitter metabolism in Alzheimer's disease: Integration of the glutamate/GABA-glutamine cycle
2022, Progress in NeurobiologyCitation Excerpt :Such increased acetate metabolism may reflect a metabolic compensation, as acetate can serve as an alternative source of acetylCoA, the pool of which is likely decreased because of the impaired glycolytic activity of AD astrocytes. Hypermetabolism of acetate may be related to increased expression of monocarboxylate transporter 4 (MCT4, SLC16A3) as observed in APP/PS1 mice (Hong et al., 2020). Elevated cerebral MCT expression has also been found in mouse models of diabetes (Pierre et al., 2007) and correlates with increased acetate metabolism in both diabetic mouse models and patients (Andersen et al., 2017b; Mason et al., 2006).
Recent behavioral findings of pathophysiological involvement of lactate in the central nervous system
2022, Biochimica et Biophysica Acta - General SubjectsCitation Excerpt :These reports indicate a negative correlation between AD pathology and lactate metabolism at the mouse and cellular level from human AD patients. However, there are also reports to the contrary: MCT4 expression in the hippocampus is increased in the AD mouse model APP/PS1, and knockdown of MCT4 has been reported to improve memory impairment in the Morris water maze test [95]. Humans have three allelic variants of apolipoprotein E (ApoE), and ApoE4, in particular, is a risk factor for AD [96].
Transport function, regulation, and biology of human monocarboxylate transporter 1 (hMCT1) and 4 (hMCT4)
2021, Pharmacology and TherapeuticsCitation Excerpt :In summary, elucidating the relationship between cancer cell energy metabolism and hMCT1 and hMCT4 expression and function is important for revealing the mechanisms underlying cancer growth, and for improving cancer therapy. MCT1 and MCT4 are distributed brain and reported to be involved in Alzheimer's disease (Hong, Zhang, Gao, & Wang, 2020; Tang, Li, Zhang, & Yao, 2019). Accordingly, MCT1 and MCT4 might be an attractive drug target for treating Alzheimer's disease as well as diabetes and cancer.
- 1
The two authors contributed equally to this work.