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

Ekaterina A Rudnitskaya,Natalia A Stefanova,Nataliya G Kolosova,Tatiana A Kozlova,Alena O Burnyasheva

doi:10.3390/biomedicines9070823

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.

Highlights

The most common type of Alzheimer’s disease (AD) (∼95% of cases) is sporadicAD, which is a progressive neurodegenerative disorder of middle-aged-to-old individuals.The pathological changes associated with AD are thought to begin many years before the emergence of clinical symptoms
We investigated the features of development of the hippocampus and prefrontal cortex (PFC) in senescence-accelerated OXYS rats during the first postnatal week
We demonstrated a disturbance in astroglial support of these structures as well as a microglial deficiency and higher intensity of apoptosis concurrently with a relatively unchanged neuronal population and hippocampal neurogenesis during a critical period for the formation of a network between these brain structures

Summary

Introduction

The most common type of Alzheimer’s disease (AD) (∼95% of cases) is sporadicAD, which is a progressive neurodegenerative disorder of middle-aged-to-old individuals.The pathological changes associated with AD are thought to begin many years before the emergence of clinical symptoms. AD, which is a progressive neurodegenerative disorder of middle-aged-to-old individuals. Accumulating data indicate that middle age is a critical period for the relevant pathological processes. The third trimester of pregnancy in humans is a crucial period when proper cytoarchitecture of the brain and functional connections among neurons are formed. Disturbances of brain development in the third trimester of pregnancy may cause cognitive and behavioral disorders, e.g., encephalopathy, or fetal alcohol syndrome [9,10]. To date, little is known about the long-lasting effects of developmental alterations on adult brain function and about a possible contribution and role of these alterations in the development of the neurodegenerative processes that lead to such conditions as AD, Parkinson’s disease, or others. The first step in the investigation of these effects may be made by studying the early phenotype of model organisms of neurodegenerative disorders

Methods

Results

Conclusion