Hippocampal Disruptions of Synaptic and Astrocyte Metabolism are Primary Events of Early Amyloid Pathology in the 5xFAD Mouse Model of Alzheimer's Disease

Andersen, Jens V.; Skotte, Niels H.; Christensen, Sofie K.; Polli, Filip S.; Shabani, Mohammad; Markussen, Kia H.; Haukedal, Henriette; Westi, Emil W.; Castillo, Marta; Sun, Runyuan; Kohlmeier, Kristi A.; Schousboe, Arne; Gentry, Matthew S.; Tanila, Heikki; Freude, Kristine; Aldana, Blanca I.; Mann, Matthias; Waagepetersen, Helle S.

doi:10.2139/ssrn.3838989

Cited by 3 publications

(2 citation statements)

References 77 publications

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“…This disparity in astrocytic composition may also impact their connectivity, as we revealed significant differences in the number of primary connected astrocytes in the hippocampus and SSC of control mice. Interestingly, a recent study comparing biochemical changes in astrocytes from the cortex and hippocampus identified significant alteration of biochemical processes in astrocytes from the hippocampus but not in the cortex of 5xFAD mice (72).…”

Section: Discussionmentioning

confidence: 96%

Potassium homeostasis during disease progression of Alzheimer’s Disease

Samokhina,

Mangat,

Malladi

et al. 2024

Preprint

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Alzheimers disease (AD) is an age-dependent neurodegenerative disorder characterized by neuronal loss leading to dementia and ultimately death. Whilst the loss of neurons is central to the disease, it is becoming clear that glia, specifically astrocytes, contribute to the onset and progression of neurodegeneration. Astrocytic role in retaining ion homeostasis in the extracellular milieu is fundamental for multiple brain functions, including synaptic plasticity and neuronal excitability, which are compromised during AD and affect neuronal signalling. In this study, we have measured the astrocytic K+ clearance rate in the hippocampus and somatosensory cortex of a mouse model for AD during disease progression. Our results establish that astrocytic [K+]o clearance in the hippocampus is reduced in symptomatic 5xFAD mice, and this decrease is region-specific. The decrease in the [K+]o clearance rate correlated with a significant reduction in the expression and conductivity of Kir4.1 channels and a decline in the number of primary connected astrocytes. Moreover, astrocytes in the hippocampus of symptomatic 5xFAD mice demonstrated increased reactivity which was accompanied by an increased excitability and altered spiking profile of nearby neurons. These findings indicate that the supportive function astrocytes typically provide to nearby neurons is diminished during disease progression, which affects the neuronal circuit signalling in this area and provides a potential explanation for the increased vulnerability of neurons in AD.

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Section: Discussionmentioning

confidence: 96%

Potassium homeostasis during disease progression of Alzheimer’s Disease

Samokhina,

Mangat,

Malladi

et al. 2024

Preprint

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“…Jens V. Andersen et al 102 found that before Aβ formation, APPswe/PSEN1dE9 mice had altered glucose metabolism, and hampered glutamine processing and mitochondrial. Jens V. Andersen et al 103 found that before Aβ formation in 5XFAD mice, reduced astrocyte TCA cycle activity and decreased glutamine synthesis led to hampered neuronal GABA synthesis in the 5xFAD hippocampus. Claudia Salcedo et al 104 found that human‐induced pluripotent stem cells (hiPSCs) with APP and PSEN‐1 mutations show reduced leucine‐derived synthesis of glutamate, glutamine, and aspartic acid.…”

Section: Dysmetabolism Of Astrocytes In Neurodegenerative Diseasesmentioning

confidence: 99%

Brain Energy Metabolism: Astrocytes in Neurodegenerative Diseases

et al. 2022

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Astrocytes are the greatest number and special ramified cell-type in CNS. They have several functions: their processes and cerebral vessels form the blood-brain barrier (BBB); their synapses represent the third element of the tripartite synapse; they provide a certain degree of metabolic supplement for neurons.Astrocytes provide essential metabolic support for neighboring neurons and other cell types, and protect their neighboring cells by ingesting excessive glutamate and K + and releasing growth

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The neural basis of neuropsychiatric symptoms in Alzheimer’s disease

Zhang,

Zhang

et al. 2024

Front. Aging Neurosci.

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Neuropsychiatric symptoms (NPS) such as depression, anxiety, apathy and aggression affect up to 90% of Alzheimer’s disease (AD) patients. These symptoms significantly increase caregiver stress and institutionalization rates, and more importantly they are correlated with faster cognitive decline. However, the neuronal basis of NPS in AD remains largely unknown. Here, we review current understanding of NPS and related pathology in studies of AD patients and AD mouse models. Clinical studies indicate that NPS prevalence and severity vary across different AD stages and types. Neuroimaging and postmortem studies have suggested that pathological changes in the anterior cingulate cortex, hippocampus, prefrontal cortex, and amygdala are linked to NPS, although the precise mechanisms remain unclear. Studies of AD mouse models have indicated that amyloid-beta and tau-related neurodegeneration in the hippocampus, prefrontal cortex, and anterior cingulate cortex are correlated with NPS-like behavioral deficits. A better understanding of the NPS phenotypes and related pathological changes will pave the way for developing a better management strategy for NPS in AD patients.

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Hippocampal Disruptions of Synaptic and Astrocyte Metabolism are Primary Events of Early Amyloid Pathology in the 5xFAD Mouse Model of Alzheimer's Disease

Cited by 3 publications

References 77 publications

Potassium homeostasis during disease progression of Alzheimer’s Disease

Potassium homeostasis during disease progression of Alzheimer’s Disease

Brain Energy Metabolism: Astrocytes in Neurodegenerative Diseases

The neural basis of neuropsychiatric symptoms in Alzheimer’s disease

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