Mechanisms of Neuronal Death in the Cerebral Cortex during Aging and Development of Alzheimer's Disease-Like Pathology in Rats.

Darya V Telegina,Gleb K Suvorov,Oyuna S Kozhevnikova,Nataliya G Kolosova

doi:10.3390/ijms20225632

Abstract

Alzheimer’s disease (AD) is the commonest type of late-life dementia and damages the cerebral cortex, a vulnerable brain region implicated in memory, emotion, cognition, and decision-making behavior. AD is characterized by progressive neuronal loss, but the mechanisms of cell death at different stages of the disease remain unknown. Here, by means of OXYS rats as an appropriate model of the most common (sporadic) AD form, we studied the main pathways of cell death during development of AD-like pathology, including the preclinical stage. We found that apoptosis is activated at the pre-symptomatic stage (age 20 days) correlating with the retardation of brain development in the OXYS strain early in life. Progression of the AD-like pathology was accompanied by activation of apoptosis and necroptosis resulting from a decline of autophagy-mediated proteostasis. Our results are consistent with the idea that the nature of changes in the pathways of apoptosis, autophagy, and necrosis depends on the stage of AD.

Highlights

Alzheimer’s disease (AD) is the commonest type of age-related dementia and shows increasing prevalence because of aging of the population [1]
Simultaneous immunostaining of NeuN and transferase dUTP nick end labeling (TUNEL) staining were applied for the detection of apoptotic neurons (Figure 1a)
By the age of five months, the numbers of apoptotic total cells and apoptotic neurons decreased in the cortex of OXYS and Wistar rats, but the number of TUNEL + total cells remained greater in OXYS rats

Summary

Introduction

Alzheimer’s disease (AD) is the commonest type of age-related dementia and shows increasing prevalence because of aging of the population [1]. Pathological protein aggregates formation impose stress onto neurons and cause cytotoxic events, which include increased production of reactive oxygen species, synaptic dysfunction, excitotoxicity, endoplasmic-reticulum stress, impaired protein degradation systems, mitochondrial dysfunction, DNA damage, inflammation, as well as cell cycle re-entry [2,3]. These are substantial neuronal challenges, and their pathological alterations eventually cause neurons to die. The clinical signs of AD are thought to correlate with the degree of cerebral neuronal loss that takes place over years and decades, in the hippocampus and cerebral neocortex. AD still lacks an etiology, early prediction, diagnosis, and effective treatment [5]

Objectives

Results

Conclusion