Alzheimer's Disease and Hippocampal Adult Neurogenesis; Exploring Shared Mechanisms

Abstract

New neurons incorporate into the granular cell layer of the dentate gyrus throughout life. Neurogenesis is modulated by behavior and plays a major role in hippocampal plasticity. Along with older mature neurons, new neurons structure the dentate gyrus, and determine its function. Recent data suggest that the level of hippocampal neurogenesis is substantial in the human brain, suggesting that neurogenesis may have important implications for human cognition. In support of that, impaired neurogenesis compromises hippocampal function and plays a role in cognitive deficits in Alzheimer's disease mouse models. We review current work suggesting that neuronal differentiation is defective in Alzheimer's disease, leading to dysfunction of the dentate gyrus. Additionally, alterations in critical signals regulating neurogenesis, such as presenilin-1, Notch 1, soluble amyloid precursor protein, CREB, and β-catenin underlie dysfunctional neurogenesis in Alzheimer's disease. Lastly, we discuss the detectability of neurogenesis in the live mouse and human brain, as well as the therapeutic implications of enhancing neurogenesis for the treatment of cognitive deficits and Alzheimer's disease.

Keywords: Alzheimer's disease; cognition; hippocampus; learning and memory; neurogenesis.

Figure 1

Common mechanisms of neurogenesis and Alzheimer's disease and the implications for learning. (A) Signals that play a role in neurogenesis, such as Notch-1, Wnt/β-catenin, CREB, sAPP, tau, and presenilin-1 are implicated in Alzheimer's disease. (B) Following learning, changes in the neurogenic niche include alterations in Notch and sAPP, increased expression of neurotrophins such as VEGF, BDNF, and IGF which enhance angiogenesis and provide support for the neurogenic niche and lead to increased neurogenesis. Upregulation of CREB signaling by neural progenitor cells and neurons may promote survival and maturation of NPCs. Increased dendritic branching of mature neurons and synaptic plasticity may be mediated by presenilin-1 and APP. The factors mediating these processes are dysfunctional or compromised in Alzheimer's disease, suggesting that defective neurogenesis may affect hippocampal function in Alzheimer's disease.

Figure 2

Therapeutic and translational potential of neurogenesis. Examples of current and prospective methods for the modulation and detection of neurogenesis. Means of enhancing neurogenesis include noninvasive, environmental modulations like cognitively complex activities and exercise, as well as molecular interventions like anti-depressants, pro-neurogenic small molecules, hormones or neurotransmitters, or other manipulations of the neurogenic pathways. While readouts of human neurogenesis are typically done in postmortem tissue using radioactive isotopes or analysis of neurogeneic cell markers, imaging techniques such as fMRI, or blood biomarkers will offer non-invasive avenues to determine neurogenesis during life.