Resident brain neural precursor cells develop age-dependent loss of therapeutic functions in Alzheimer's mice

Abstract

There is vast knowledge on pathogenic mechanisms in Alzheimer's disease but very little on means by which the brain protects itself from disease. A major candidate in providing neuroprotection is the resident brain neural precursor/stem cell (NPC) pool. Transplanted NPCs possess powerful immune-modulatory and trophic properties in vivo and in vitro, underscoring the question whether resident brain NPCs have any role in regulating disease pathology in Alzheimer's disease, and particularly whether they fail to protect the brain from degeneration. To evaluate brain NPC function in relation to disease pathology, we first characterized the pathological properties of 5xFAD transgenic mouse model of Alzheimer's disease at different ages. We found that age 7 months is a critical time point of heavy amyloid deposition and gliosis but before neurodegeneration and a normal basal rate of NPC turnover in the subventricular zone (SVZ) of 5xFAD mice as compared to wild-type mice. Analysis of NPC functional properties showed that despite preserved rate of turnover, there was substantial SVZ NPC dysfunction as indicated by both ex vivo and in vivo assays. Freshly isolated NPCs from 7-month-old 5xFAD mice exhibited reduced expansion rate and diminished immune-modulatory and trophic properties. Moreover, there was slowed recovery of SVZ NPCs after cytosine-arabinoside insult and markedly reduced migratory response following a lysolecithin-induced lesion in the corpus callosum in vivo. Importantly, these functions were fully preserved in 2-month-old 5xFAD mice, a time point before Alzheimer's disease-specific pathological changes. There was reduced expression of key genes involved in NPC proliferative and migratory response in NPCs derived from 7-month-old 5xFAD mice. The dysfunctional properties and downregulation of gene expression were reversible in NPCs derived from 7-month-old 5xFAD mice following in vitro expansion and were reproduced in wild-type NPC by addition of amyloid beta peptide. Thus, there is age-dependent acquired NPC dysfunction, with loss of immune-modulatory and neurotrophic properties, which is induced by the pathological Alzheimer's brain environment at a critical time point before neurodegeneration. We suggest that failure of resident NPC to provide tissue support may be involved in promoting neurodegeneration.

Keywords: 5xFAD mouse; Alzheimer's disease; Neural stem/precursor cell.