GALM Alleviates Aβ Pathology and Cognitive Deficit Through Increasing ADAM10 Maturation in a Mouse Model of Alzheimer's Disease.
10.1007/s12264-025-01386-4
- Author:
Na TIAN
1
;
Junjie LI
1
;
Xiuyu SHI
1
;
Mingliang XU
1
;
Qian XIAO
1
;
Qiuyun TIAN
1
;
Mulan CHEN
1
;
Weihong SONG
2
;
Yehong DU
3
,
4
;
Zhifang DONG
5
Author Information
1. Growth, Development, and Mental Health of Children and Adolescence Center, Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China.
2. Townsend Family Laboratories, Department of Psychiatry, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada.
3. Growth, Development, and Mental Health of Children and Adolescence Center, Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China. dudu0000807@
4. com.
5. Growth, Development, and Mental Health of Children and Adolescence Center, Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China. zfdong@cqmu.edu.cn.
- Publication Type:Journal Article
- Keywords:
ADAM10;
Alzheimer’s disease;
GALM;
Learning and memory;
Long-term potentiation;
α-D-galactose
- MeSH:
Animals;
ADAM10 Protein/metabolism*;
Alzheimer Disease/pathology*;
Amyloid Precursor Protein Secretases/metabolism*;
Disease Models, Animal;
Humans;
Mice;
Amyloid beta-Peptides/metabolism*;
Male;
Mice, Transgenic;
Membrane Proteins/metabolism*;
Cognitive Dysfunction/pathology*;
Mice, Inbred C57BL;
Amyloid beta-Protein Precursor/metabolism*;
Female;
Hippocampus/metabolism*;
Long-Term Potentiation/physiology*
- From:
Neuroscience Bulletin
2025;41(8):1377-1389
- CountryChina
- Language:English
-
Abstract:
Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder worldwide, causing dementia and affecting millions of individuals. One prominent characteristic in the brains of AD patients is glucose hypometabolism. In the context of galactose metabolism, intracellular glucose levels are heightened. Galactose mutarotase (GALM) plays a crucial role in maintaining normal galactose metabolism by catalyzing the conversion of β-D-galactose into α-D-galactose (α-D-G). The latter is then converted into glucose-6-phosphate, improving glucose metabolism levels. However, the involvement of GALM in AD progression is still unclear. In the present study, we found that the expression of GALM was significantly increased in AD patients and model mice. Genetic knockdown of GALM using adeno-associated virus did not change the expression of amyloid precursor protein (APP) and APP-cleaving enzymes including a disintegrin and metalloprotease 10 (ADAM10), β-site APP-cleaving enzyme 1 (BACE1), and presenilin-1 (PS1). Interestingly, genetic overexpression of GALM reduced APP and Aβ deposition by increasing the maturation of ADAM10, although it did not alter the expression of BACE1 and PS1. Further electrophysiological and behavioral experiments showed that GALM overexpression significantly ameliorated the deficits in hippocampal CA1 long-term potentiation (LTP) and spatial learning and memory in AD model mice. Importantly, direct α-D-G (20 mg/kg, i.p.) also inhibited Aβ deposition by increasing the maturation of ADAM10, thereby improving hippocampal CA1 LTP and spatial learning and memory in AD model mice. Taken together, our results indicate that GALM shifts APP processing towards α-cleavage, preventing Aβ generation by increasing the level of mature ADAM10. These findings indicate that GALM may be a potential therapeutic target for AD, and α-D-G has the potential to be used as a dietary supplement for the prevention and treatment of AD.
