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Glia Not Neurons: Uncovering Brain Dysmaturation in a Rat Model of Alzheimer's Disease.

ABSTRACT: Sporadic Alzheimer's disease (AD) is a severe disorder of unknown etiology with no definite time frame of onset. Recent studies suggest that middle age is a critical period for the relevant pathological processes of AD. Nonetheless, sufficient data have accumulated supporting the hypothesis of "neurodevelopmental origin of neurodegenerative disorders": prerequisites for neurodegeneration may occur during early brain development. Therefore, we investigated the development of the most AD-affected brain structures (hippocampus and prefrontal cortex) using an immunohistochemical approach in senescence-accelerated OXYS rats, which are considered a suitable model of the most common-sporadic-type of AD. We noticed an additional peak of neurogenesis, which coincides in time with the peak of apoptosis in the hippocampus of OXYS rats on postnatal day three. Besides, we showed signs of delayed migration of neurons to the prefrontal cortex as well as disturbances in astrocytic and microglial support of the hippocampus and prefrontal cortex during the first postnatal week. Altogether, our results point to dysmaturation during early development of the brain-especially insufficient glial support-as a possible "first hit" leading to neurodegenerative processes and AD pathology manifestation later in life.

SUBMITTER: Rudnitskaya EA

PROVIDER: S-EPMC8301397 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Glia Not Neurons: Uncovering Brain Dysmaturation in a Rat Model of Alzheimer's Disease.

Rudnitskaya Ekaterina A EA Kozlova Tatiana A TA Burnyasheva Alena O AO Stefanova Natalia A NA Kolosova Nataliya G NG

Biomedicines 20210715 7

Sporadic Alzheimer's disease (AD) is a severe disorder of unknown etiology with no definite time frame of onset. Recent studies suggest that middle age is a critical period for the relevant pathological processes of AD. Nonetheless, sufficient data have accumulated supporting the hypothesis of "neurodevelopmental origin of neurodegenerative disorders": prerequisites for neurodegeneration may occur during early brain development. Therefore, we investigated the development of the most AD-affected ...[more]

PMID: 34356887

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Project description:Brain damage associated with Alzheimer's disease (AD) occurs even decades before the symptomatic onset, raising the need to investigate its progression from prodromal stages. In this context, animal models that progressively display AD pathological hallmarks (e.g. TgF344-AD) become crucial. Translational technologies, such as magnetic resonance spectroscopy (MRS), enable the longitudinal metabolic characterization of this disease. However, an integrative approach is required to unravel the complex metabolic changes underlying AD progression, from early to advanced stages. TgF344-AD and wild-type (WT) rats were studied in vivo on a 7 Tesla MRI scanner, for longitudinal quantitative assessment of brain metabolic profile changes using MRS. Disease progression was investigated at 4 time points, from 9 to 18 months of age, and in 4 regions: cortex, hippocampus, striatum, and thalamus. Compared to WT, TgF344-AD rats replicated common findings in AD patients, including decreased N-acetylaspartate in the cortex, hippocampus and thalamus, and decreased glutamate in the thalamus and striatum. Different longitudinal evolution of metabolic concentration was observed between TgF344-AD and WT groups. Namely, age-dependent trajectories differed between groups for creatine in the cortex and thalamus and for taurine in cortex, with significant decreases in Tg344-AD animals; whereas myo-inositol in the thalamus and striatum showed greater increase along time in the WT group. Additional analysis revealed divergent intra- and inter-regional metabolic coupling in each group. Thus, in cortex, strong couplings of N-acetylaspartate and creatine with myo-inositol in WT, but with taurine in TgF344-AD rats were observed; whereas in the hippocampus, myo-inositol, taurine and choline compounds levels were highly correlated in WT but not in TgF344-AD animals. Furthermore, specific cortex-hippocampus-striatum metabolic crosstalks were found for taurine levels in the WT group but for myo-inositol levels in the TgF344-AD rats. With a systems biology perspective of metabolic changes in AD pathology, our results shed light into the complex spatio-temporal metabolic rewiring in this disease, reported here for the first time. Age- and tissue-dependent imbalances between myo-inositol, taurine and other metabolites, such as creatine, unveil their role in disease progression, while pointing to the inadequacy of the latter as an internal reference for quantification.

Project description:BackgroundVagal afferent neurons represent the key neurosensory branch of the gut-brain axis, which describes the bidirectional communication between the gastrointestinal system and the brain. These neurons are important for detecting and relaying sensory information from the periphery to the central nervous system to modulate feeding behavior, metabolism, and inflammation. Confounding variables complicate the process of isolating the role of the vagal afferents in mediating these physiological processes. Therefore, we developed a microfluidic model of the sensory branch of the gut-brain axis. We show that this microfluidic model successfully compartmentalizes the cell body and neurite terminals of the neurons, thereby simulates the anatomical layout of these neurons to more accurately study physiologically-relevant processes.MethodsWe implemented a primary rat vagal afferent neuron culture into a microfluidic platform consisting of two concentric chambers interconnected with radial microchannels. The microfluidic platform separated cell bodies from neurite terminals of vagal afferent neurons. We then introduced physiologically-relevant gastrointestinal effector molecules at the nerve terminals and assessed their retrograde transport along the neurite or capacity to elicit an electrophysiological response using live cell calcium imaging.ResultsThe angle of microchannel outlets dictated the probability of neurites growing into a chamber versus tracking along chamber walls. When the neurite terminals were exposed to fluorescently-labeled cholera toxin subunit B, the proteins were taken up and retrogradely transported along the neurites over the course of 24 h. Additionally, mechanical perturbation (e.g., rinsing) of the neurite terminals significantly increased intracellular calcium concentration in the distal soma. Finally, membrane-displayed receptor for capsaicin was expressed and trafficked along newly projected neurites, as revealed by confocal microscopy.ConclusionsIn this work, we developed a microfluidic device that can recapitulate the anatomical layout of vagal afferent neurons in vitro. We demonstrated two physiologically-relevant applications of the platforms: retrograde transport and electrophysiological response. We expect this tool to enable controlled studies on the role of vagal afferent neurons in the gut-brain axis.

Dataset Information

Glia Not Neurons: Uncovering Brain Dysmaturation in a Rat Model of Alzheimer's Disease.

Publications

Glia Not Neurons: Uncovering Brain Dysmaturation in a Rat Model of Alzheimer's Disease.

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