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Early reduction of cerebral lactate in Alzheimer’s disease mouse model: The relationship with Aβ production

Zhang, Mao, Wang, Yanyan, Xu, Xiaofeng, Dai, Limeng, Chen, Xuedan, Wang, Kai, Bai, Yun, Guo, Hong·2022
DOI 10.21203/rs.3.rs-1780387/v1
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Abstract

Lactate arouses an increasing concern in recent studies of Alzheimer’s disease (AD). At late stage of AD, amyloid beta (Aβ) directly promotes lactate level, continuously activating microglial inflammation and aggravating neuronal damage. However, whether lactate fluctuation can effect on Aβ hasn’t been recognized. Especially, it is observed a reduction of lactate in the hippocampus and cortex of early AD mouse model. Hence, this study discusses the relation between decreased lactate and Aβ production at early stage of AD, and its possibly mechanism. As results showed, a specific receptor of lactate, G-protein-coupled receptor 81 (GPR81) and its downstream of phosphatidylinositol 3 kinase /protein kinase B (PI3K/Akt)-cyclic-adenosine-monophosphate response element-binding protein (CREB) is suppressed in the cortex and hippocampus of early AD mouse model. Moreover, deoxyribonucleic acid methyltransferase 1 (DNMT1) is reduced in the presence of increased beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) and Aβ. Previously, it is observed that PI3K/Akt-CREB inhibition leads to DNMT1 downregulation. As an indispensable methyltransferase, DNMT1 reduction can directly inhibit the methylation of specific loci within BACE1 gene promoter, leading to increased BACE1 and Aβ production. Hence, this study proposes a novel insight that lactate reduction contributes to Aβ production at early period of AD. The underlying mechanism is that reduced lactate can hardly activate GPR81-PI3K/Akt-CREB, which results in DNMT1 reduction, and then increasing BACE1 level and Aβ production (Graphic abstract).

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Metadata

Authors
Zhang, M., Wang, Y., Xu, X., Dai, L., Chen, X., Wang, K., Bai, Y., & Guo, H.
Affiliations
Department of Medical Genetics, College of Basic Medical Sciences, Army Medical University
Publisher
Research Square Platform LLC
Published
2022-07-05
DOI
10.21203/rs.3.rs-1780387/v1
Cited by
1
References
1
Type
Preprint
Licence
creativecommons.org/licenses/by/4.0/ (unspecified)

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CoChat. (2026). Citation check: Early reduction of cerebral lactate in Alzheimer’s disease mouse model: The relationship with Aβ production. https://app.cochat.ai/papers/10.21203/rs.3.rs-1780387/v1
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Zhang, M., Wang, Y., Xu, X., Dai, L., Chen, X., Wang, K., Bai, Y., & Guo, H. (2022). Early reduction of cerebral lactate in Alzheimer’s disease mouse model: The relationship with Aβ production. https://doi.org/10.21203/rs.3.rs-1780387/v1

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