Background Alzheimer’s disease (AD) is characterized by the extracellular accumulation of amyloid-β (Aβ). Brain glucose hypometabolism, an early feature of AD, reflects neuronal metabolic dysfunction before the onset of clinical symptoms. While Aβ plaques are central to AD pathogenesis, the mechanisms by which different Aβ species, such as plaques and soluble oligomers, drive cell-type-specific neurometabolic dysfunction during disease progression remain poorly understood. This study evaluated the roles of different Aβ species in the neurometabolic trajectory across the presymptomatic, symptomatic, and advanced stages of AD. Methods 5xFAD and wild-type (WT) mice were investigated for cognitive performance, quantitative Aβ levels, and glial activation markers at 3, 6, and 12 months of age. Neuronal and astroglial metabolic activities were evaluated ex vivo using state-of-the-art 1H-[13C]-NMR spectroscopy in conjunction with administration of [1,6-13C2]glucose and [2-13C]acetate, respectively. Results The 5xFAD mice exhibited cognitive decline from 6 months that further deteriorated by 12 months. There was a marked increase in Aβ-plaque burden and soluble oligomers from 3 to 12 months of age. These mice showed a significant reduction in hippocampal glutamatergic (0.145 ± 0.031 vs. 0.172 ± 0.016 µmol/g/min, p = 0.035) and GABAergic neuronal metabolic activity (0.027 ± 0.006 vs 0.033 ± 0.003 µmol/g/min, p = 0.028) as early as 3 months of age, with similar reductions observed in the cerebral cortex. The neurometabolic impairments further aggravated with age. Astrocytic metabolic activity was not significantly changed till 6 months but was increased at 12 months in 5xFAD mice in both the cerebral cortex (0.101 ± 0.014 vs. 0.084 ± 0.006 µmol/g/min, p = 0.011) and hippocampus (0.103 ± 0.006 vs. 0.089 ± 0.012 µmol/g/min, p = 0.011). The increase in astrocytic metabolic activity paralleled reactive gliosis, suggesting a shift from early neuronal metabolic impairment to heightened astroglial metabolic activity and inflammatory glial responses during the advanced AD stage. Notably, Aβ40 oligomers exhibited a greater sensitivity to impairment in neuronal glucose oxidation and cognitive function than Aβ42 oligomers or fibrillar plaques. Conclusions These findings delineate a sequential neurometabolic cascade during AD progression, characterized by early neuronal glucose hypometabolism, subsequent cognitive decline linked to soluble Aβ40 oligomers, and late-stage astroglial metabolic activation. Collectively, these results suggest that soluble Aβ40 oligomers exhibit the greatest sensitivity to neurometabolic and cognitive impairment during AD.

In vivo evidence for soluble Aβ oligomer-driven neuronal metabolic dysfunction in 5xFAD mice

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2026年7月11日

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Chaynita Dashora,
Anant Bahadur Patel

摘要

Background

Alzheimer’s disease (AD) is characterized by the extracellular accumulation of amyloid-β (Aβ). Brain glucose hypometabolism, an early feature of AD, reflects neuronal metabolic dysfunction before the onset of clinical symptoms. While Aβ plaques are central to AD pathogenesis, the mechanisms by which different Aβ species, such as plaques and soluble oligomers, drive cell-type-specific neurometabolic dysfunction during disease progression remain poorly understood. This study evaluated the roles of different Aβ species in the neurometabolic trajectory across the presymptomatic, symptomatic, and advanced stages of AD.

Methods

5xFAD and wild-type (WT) mice were investigated for cognitive performance, quantitative Aβ levels, and glial activation markers at 3, 6, and 12 months of age. Neuronal and astroglial metabolic activities were evaluated ex vivo using state-of-the-art ¹H-[¹³C]-NMR spectroscopy in conjunction with administration of [1,6-¹³C₂]glucose and [2-¹³C]acetate, respectively.

Results

The 5xFAD mice exhibited cognitive decline from 6 months that further deteriorated by 12 months. There was a marked increase in Aβ-plaque burden and soluble oligomers from 3 to 12 months of age. These mice showed a significant reduction in hippocampal glutamatergic (0.145 ± 0.031 vs. 0.172 ± 0.016 µmol/g/min, p = 0.035) and GABAergic neuronal metabolic activity (0.027 ± 0.006 vs 0.033 ± 0.003 µmol/g/min, p = 0.028) as early as 3 months of age, with similar reductions observed in the cerebral cortex. The neurometabolic impairments further aggravated with age. Astrocytic metabolic activity was not significantly changed till 6 months but was increased at 12 months in 5xFAD mice in both the cerebral cortex (0.101 ± 0.014 vs. 0.084 ± 0.006 µmol/g/min, p = 0.011) and hippocampus (0.103 ± 0.006 vs. 0.089 ± 0.012 µmol/g/min, p = 0.011). The increase in astrocytic metabolic activity paralleled reactive gliosis, suggesting a shift from early neuronal metabolic impairment to heightened astroglial metabolic activity and inflammatory glial responses during the advanced AD stage. Notably, Aβ₄₀ oligomers exhibited a greater sensitivity to impairment in neuronal glucose oxidation and cognitive function than Aβ₄₂ oligomers or fibrillar plaques.

Conclusions

These findings delineate a sequential neurometabolic cascade during AD progression, characterized by early neuronal glucose hypometabolism, subsequent cognitive decline linked to soluble Aβ₄₀ oligomers, and late-stage astroglial metabolic activation. Collectively, these results suggest that soluble Aβ₄₀ oligomers exhibit the greatest sensitivity to neurometabolic and cognitive impairment during AD.