Adult hippocampal neurogenesis and its role in Alzheimer's disease

Abstract

The hippocampus, a brain area critical for learning and memory, is especially vulnerable to damage at early stages of Alzheimer's disease (AD). Emerging evidence has indicated that altered neurogenesis in the adult hippocampus represents an early critical event in the course of AD. Although causal links have not been established, a variety of key molecules involved in AD pathogenesis have been shown to impact new neuron generation, either positively or negatively. From a functional point of view, hippocampal neurogenesis plays an important role in structural plasticity and network maintenance. Therefore, dysfunctional neurogenesis resulting from early subtle disease manifestations may in turn exacerbate neuronal vulnerability to AD and contribute to memory impairment, whereas enhanced neurogenesis may be a compensatory response and represent an endogenous brain repair mechanism. Here we review recent findings on alterations of neurogenesis associated with pathogenesis of AD, and we discuss the potential of neurogenesis-based diagnostics and therapeutic strategies for AD.

Figure 1

Neurogenesis in the adult hippocampus. A population of radial cells in the SGZ corresponds to quiescent NSCs (type 1 cells). They coexist with actively proliferating nonradial NSCs (type 2 cells) that generate both astrocytes and neuroblasts. Neuroblasts migrate into the granule cell layer (GCL) and differentiate into dentate granule cells (DGCs). Newborn DGCs gradually develop elaborate dendritic trees in the molecular layer (Mol) to receive inputs from the EC and project to CA3 pyramidal neurons (red) as well as hilar interneurons (blue).

Figure 2

Molecular basis for AD and interaction with neurogenesis in the adult hippocampus. In the non-amyloidogenic pathway, APP is processed by α-secretase that cleaves within the Aβ domain. sAPPα and a membrane-bound carboxyl-terminal fragment are generated. In the amyloidogenic pathway, APP is sequentially cleaved by β- and γ-secretases to release the neurotoxic Aβ peptide. β-secretase cleavage of APP forms a secreted ectodomain sAPPβ and a membrane-bound fragment. Cleavage of the latter product generates AICD and Aβ. Suggested functions of relevant signal molecules in adult hippocampal neurogenesis are summarized.