Role of monocarboxylate transporter 4 in Alzheimer disease

doi:10.1016/j.neuro.2019.11.006

NeuroToxicology

Volume 76, January 2020, Pages 191-199

https://doi.org/10.1016/j.neuro.2019.11.006 Get rights and content

Highlights

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MCT4 MCT4 expression was elevated in the cerebrospinal fluid of patients with mild cognitive impairment.
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The APP/PS1 mice began to show cognitive decline at 3 months of age and MCT4 in the hippocampus of 2- and 3-month old APP/PS1 mice was higher than that of C57 mice.
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This change is similar to that in people with mild cognitive impairment.
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Overexpression of cytoplasmic MCT4 increased the expression of Aβ42, γ-secretase, and CD147 in the co-culture system; in addition, the growth ability of primary neurons decreased significantly, extracellular lactic acid increased, and neuronal apoptosis increased.
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In AD model mice, siMCT4 injection improved cognitive ability, reduced neuronal apoptosis, and reduced γ-secretase expression.

Abstract

The pathological process of Alzheimer disease (AD) is closely related to energy metabolism disorders. In the nervous system, monocarboxylate transporter 4 (MCT4) is expressed in the glial cell membrane and is responsible for transporting intracellular lactic acid. In this study, we found that MCT4 expression was elevated in the cerebrospinal fluid of patients with mild cognitive impairment. Two- and three-month-old APPswe/PS1dE9 (APP/PS1) mice and C57 mice were studied. The APP/PS1 mice began to show cognitive decline at 3 months of age and MCT4 in the hippocampus of 2- and 3-month old APP/PS1 mice was higher than that of C57 mice. This change is similar to that in people with mild cognitive impairment. Subsequently, MCT4 overexpression/siRNA lentiviral particles were used to establish stable primary astrocytes. Overexpression and knockdown of MCT4 had no significant effect on glial cell apoptosis. Transfected astrocytes were co-cultured with neurons. Overexpression of cytoplasmic MCT4 increased the expression of Aβ42, γ-secretase, and CD147 in the co-culture system; in addition, the growth ability of primary neurons decreased significantly, extracellular lactic acid increased, and neuronal apoptosis increased. In AD model mice, siMCT4 injection improved cognitive ability, reduced neuronal apoptosis, and reduced γ-secretase expression. Taken together, these results suggest that MCT4 is involved in energy metabolism during early pathological processes in AD, and suppression of MCT4 represents a new potential neuroprotective factor for AD.

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).

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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).
Astrocytes contribute to the complex cellular pathology of Alzheimer’s disease (AD). Neurons and astrocytes function in close collaboration through neurotransmitter recycling, collectively known as the glutamate/GABA-glutamine cycle, which is essential to sustain neurotransmission. Neurotransmitter recycling is intimately linked to astrocyte energy metabolism. In the course of AD, astrocytes undergo extensive metabolic remodeling, which may profoundly affect the glutamate/GABA-glutamine cycle. The consequences of altered astrocyte function and metabolism in relation to neurotransmitter recycling are yet to be comprehended. Metabolic alterations of astrocytes in AD deprive neurons of metabolic support, thereby contributing to synaptic dysfunction and neurodegeneration. In addition, several astrocyte-specific components of the glutamate/GABA-glutamine cycle, including glutamine synthesis and synaptic neurotransmitter uptake, are perturbed in AD. Integration of the complex astrocyte biology within the context of AD is essential for understanding the fundamental mechanisms of the disease, while restoring astrocyte metabolism may serve as an approach to arrest or even revert clinical progression of AD.
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¹: The two authors contributed equally to this work.

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Full Length ArticleRole of monocarboxylate transporter 4 in Alzheimer disease

Highlights

Abstract

Introduction

Section snippets

Study population

Human protein chip technology for analysis of cerebrospinal fluid

Discussion

Author contribution

Transparency document

Declaration of Competing Interest

Acknowledgment

J. Biol. Chem.

Cell metabolism

Prog Neuropsychopharmacol Biol Psychiatry.

J. Biological Chem.

Astrocyte senescence as a component of Alzheimer’s disease

Exp. Gerontol.

Lactate is a preferential oxidative energy substrate over glucose for neurons in culture

J. Cerebral Blood Flow & Metabolism

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.

Disrupted energy metabolism and neuronal circuit dysfunction in cognitive impairment and Alzheimer’s disease

Lancet Neurol.

Full Length Article
Role of monocarboxylate transporter 4 in Alzheimer disease