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Abnormal accumulation of extracellular vesicles in hippocampal dystrophic axons and regulation by the primary cilia gene intraflagellar transport homolog 88 in Alzheimer's disease

ABSTRACT: This study identified the specific types of hippocampal neurons whose axons are vulnerable to amyloid-β accumulation. We used the inDropsTM platform to sequence 8 libraries: 5 libraries from the hippocampus of Alzheimer’s disease mice at 12,20, and, 24 weeks of age, and 3 libraries from the hippocampus of normal age-matched mice for the purpose of finding the selectively vulnerable hippocampal neuron type. 22,233 cells with 72,146 transcriptomes were collected after quality control was completed. When the 5,468 neurons that were marked by the expression of Snap25, Syt1, Ndrg4, and Meg3 were examined, we found that three types of neurons, such as somatostatin, chromogranin B, and calbindin-expressing neurons in the hippocampus, were selectively vulnerable to amyloid-β overexpression.

ORGANISM(S): Mus musculus

PROVIDER: GSE230240 | GEO | 2023/09/13

REPOSITORIES: GEO

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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.

Project description:The decline of cognitive function is a feature of normal human aging and is exacerbated in AlzheimerM-bM-^@M-^Ys disease (AD). DNA repair declines in brain cells during normal aging and even more so in AD. Here we show that experimental reduction in levels of the base excision repair enzyme, DNA polymerase M-NM-2 (Polb) renders neurons vulnerable to age-related dysfunction and degeneration in a mouse model of AD. Whereas 3xTgAD mice exhibit age-related extracellular amyloid b-peptide (Ab) accumulation and cognitive deficits, but no neuronal death, 3xTg/Polb+/- mice accumulates intracellular Ab and neurons die in the hippocampus and cerebral cortex. The DNA repair-deficient 3xTgAD mice exhibited increased DNA strand breaks and apoptotic caspase activation with loss of hippocampal volume, and impaired synaptic plasticity and memory retention. Molecular profiling revealed remarkable similarities in gene expression alterations in brain cells of AD patients and 3xTgAD/Polb+/- mice including multiple abnormalities suggestive of impaired cellular bioenergetics. Our findings demonstrate that a modest decrement in oxidative DNA damage processing is sufficient to render neurons vulnerable to AD-related pathogenic molecular and cellular alterations that result in the dysfunction and death of neurons, and associated cognitive deficits. 4 mouse strains were used in these experiments, the 3xTgAD and Pol M-NM-2 (+/-) mice were bred at the National Institute on Aging (Baltimore, Maryland). The original line 3xTgAD line was generated as described previously (Oddo, et. al 2003) and possess APPswe, PS1M146V, and tauP301L mutations. DNA polymerase beta heterozygous mice, Pol M-NM-2 (+/-), were crossed with the 3xTgAD mice to generate a 3xTgAD/Pol M-NM-2 (+/-) mouse. The Wt strain is C57Bl/6. At 20 months of age these mice were euthanized by cervical dislocation, the brain removed from the skull and dissected into regions of interest, the prefrontal cortex was used for the microarray studies.

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Abnormal accumulation of extracellular vesicles in hippocampal dystrophic axons and regulation by the primary cilia gene intraflagellar transport homolog 88 in Alzheimer's disease

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