Adult Hippocampal Neurogenesis in Aging and Alzheimer's Disease

Abstract

Cognitive deficits associated with Alzheimer's disease (AD) severely impact daily life for the millions of affected individuals. Progressive memory impairment in AD patients is associated with degeneration of the hippocampus. The dentate gyrus of the hippocampus, a region critical for learning and memory functions, is a site of adult neurogenesis in mammals. Recent evidence in humans indicates that hippocampal neurogenesis likely persists throughout life, but declines with age and is strikingly impaired in AD. Our understanding of how neurogenesis supports learning and memory in healthy adults is only beginning to emerge. The extent to which decreased neurogenesis contributes to cognitive decline in aging and AD remains poorly understood. However, studies in rodent models of AD and other neurodegenerative diseases raise the possibility that targeting neurogenesis may ameliorate cognitive dysfunction in AD. Here, we review recent progress in understanding how adult neurogenesis is impacted in the context of aging and AD.

Keywords: Alzheimer's disease; adult neurogenesis; aging; cognitive decline; neural stem cell.

Figure 1

Adult Hippocampal Neurogenesis in Mice (A) Schematic representation of the mouse hippocampus. The panel on the left illustrates a coronal cut through the dorsal hippocampus of a mouse brain. The panel on the right is a coronal section through the dorsal hippocampus. (B) Schematic representation of adult hippocampal neurogenesis in the mouse. Quiescent NSCs become activated to generate daughter cells that either return to quiescence for self-renewal of the NSC pool or differentiate into neurons. Neural progenitors that survive beyond the early survival stage mature into granule neurons and integrate into hippocampal circuitry. Markers expressed throughout the phases of neurogenesis are shown.

Figure 2

The Impact of AD on Adult Hippocampal Neurogenesis Several mechanisms contribute to the AD-associated decline in neurogenesis. Blue text indicates an increase associated with AD and red text indicates a decrease associated with AD. Phosphorylated tau buildup in interneurons contributes to reduced activation of NSCs and the presence of lipid droplets inhibits proliferation of activated NSCs. An increase in inflammation inhibits proliferation and maturation, while reduced FGF inhibits differentiation. Increased GSK3β, the kinase responsible for phosphorylating tau, inhibits both proliferation and maturation. Finally, an imbalance of GABAergic and glutamatergic input inhibits granule cell integration and disrupts granule cell morphology.