Dataset Information

Hippocampal subfields proteome analysis and comparation in Alzheimer’s disease providing new sight on glia function

ABSTRACT: The hippocampus and entorhinal cortex are the earliest areas affected by AD pathology, which are related to early memory loss in patients. The hippocampus subfields are heterogeneous, with different order and degree affect by AD pathology. Studying the molecular changes may explain the difference, and may provide new therapeutic ideas for AD. In this study, specimens from the Chinese human brain banking were used to compare the proteome changes in the hippocampal subfields and the EC area affected by AD. The region-specific differential expressed proteins (associated with oligodendrocytes and myelin sheath) and co-variant proteins, also considered as constitute proteins (associated with astrocytes) were identified. The IHC results verified the specific loss of myelin in CA1, CA3 and EC areas, and find that protective S100A10-positive astrocytes number was increased in all hippocampal subfields and EC area. Further dual immunofluorescence results find that S100A10-positive astrocytes phagocyte apoptotic neuron debris. A hypothesis was put forward based on this, that S100A10-positive astrocytes protect neurons probably through engulfing apoptotic neurons. This study conducts a comprehensive proteomic analysis on the hippocampus subregion for the first time, highlighting the glia role in AD, and providing more information on the pathogenesis and therapy of AD.

ORGANISM(S): Homo Sapiens

SUBMITTER: Wei Ge

PROVIDER: PXD027380 | iProX | Fri Jul 16 00:00:00 BST 2021

REPOSITORIES: iProX

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Proteomic analysis of human hippocampal subfields provides new insights into the pathogenesis of Alzheimer's disease and the role of glial cells.

Gao Yanpan Y Liu Jiaqi J Wang Jiayu J Liu Yifan Y Zeng Ling-Hui LH Ge Wei W Ma Chao C

Brain pathology (Zurich, Switzerland) 20220111 4

The hippocampus and entorhinal cortex (EC), the earliest affected areas, are considered relative to early memory loss in Alzheimer's disease (AD). The hippocampus is composed of heterogeneous subfields that are affected in a different order and varying degrees during AD pathogenesis. In this study, we conducted a comprehensive proteomic analysis of the hippocampal subfields and EC region in human postmortem specimens obtained from the Chinese human brain bank. Bioinformatics analysis identified ...[more]

PMID: 35016256

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Project description:Alzheimer’s disease (AD) is an unremitting neurodegenerative disorder characterized by cerebral amyloid-β (Aβ) accumulation and gradual decline in cognitive function. Changes in brain energy metabolism arise in the preclinical phase of AD, suggesting an important metabolic component of early AD pathology. Neurons and astrocytes function in close metabolic collaboration, which is essential for the recycling of neurotransmitters in the synapse. However, how this metabolic interplay may be affected during the early stages of AD development has not been sufficiently investigated. Here, we provide an integrative analysis of cellular metabolism during the early stages of Aβ accumulation in the cerebral cortex and hippocampus of the 5xFAD mouse model of AD. Our electrophysiological examination revealed an increase in spontaneous excitatory signaling in hippocampal brain slices of 5xFAD mice. This hyperactive neuronal phenotype coincided with decreased hippocampal TCA cycle metabolism mapped by stable 13C isotope tracing. Particularly, reduced astrocyte TCA cycle activity led to decreased glutamine synthesis, in turn hampering neuronal GABA synthesis in the 5xFAD hippocampus. In contrast, cerebral cortical slices of 5xFAD mice displayed an elevated capacity for oxidative glucose metabolism suggesting a metabolic compensation. When we explored the brain proteome and metabolome of the 5xFAD mice, we found limited changes, supporting that the functional metabolic disturbances between neurons and astrocytes are early events in AD pathology. In addition, we show that synaptic mitochondrial and glycolytic function was impaired selectively in the 5xFAD hippocampus, whereas non-synaptic mitochondrial function was maintained. These findings were supported by ultrastructural analyses demonstrating disruptions in mitochondrial morphology, particularly in the 5xFAD hippocampus. Collectively, our study reveals complex region and cell specific metabolic adaptations, in the early stages of amyloid pathology, which may be fundamental for the progressing synaptic dysfunction in AD.

Dataset Information

Hippocampal subfields proteome analysis and comparation in Alzheimer’s disease providing new sight on glia function

Publications

Proteomic analysis of human hippocampal subfields provides new insights into the pathogenesis of Alzheimer's disease and the role of glial cells.

Similar Datasets

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