Alterations of hippocampal neurogenesis during development of Alzheimer's disease-like pathology in OXYS rats

Abstract

Neurogenesis is the key mechanism of neuronal plasticity in the adult mammalian brain. Alterations of neurogenesis happen concurrently with (and contribute to) development and progression of numerous neuropathological conditions including Alzheimer's disease (AD). Being the most common type of dementia, AD is studied extensively; however, the data concerning changes in neurogenesis in the pathogenesis of this disease are inconsistent. Here, using OXYS rats as a suitable model of the most common (sporadic) form of AD, we examined neurogenesis in the hippocampal dentate gyrus in early ontogenesis prior to appearance of any signs of neurodegeneration and during development and progression of AD-like pathology. We demonstrated retardation of hippocampal development in OXYS rats at an early age; this problem may contribute to the emergence of AD signs late in life. Manifestation and progression of AD-like pathology are accompanied by transcriptome changes affecting genes involved in neurogenesis in the hippocampus. These genes are associated with the extracellular matrix and angiogenesis; this observation points to alteration of a cellular microenvironment. This change along with an increased TrkA/p75^NTR ratio of nerve growth factor receptors in the hippocampus may contribute to increased density of immature neurons that we observed at the progressive stage of AD-like pathology in OXYS rats. These changes may be considered a compensatory reaction intended to slow down AD-associated neurodegeneration at the progressive stage of the disease. Collectively, these data suggest that alterations of neurogenesis may not only accompany the course of Alzheimer's disease but also play a causative role in this disorder.

Keywords: Adult neurogenesis; Alzheimer's disease; Hippocampus; OXYS rats; RNA sequencing.