Age-related cognitive decline: can neural stem cells help us?

Abstract

Several studies suggest that an increase in adult neurogenesis has beneficial effects on emotional behavior and cognitive performance including learning and memory. The observation that aging has a negative effect on the proliferation of neural stem cells has prompted several laboratories to investigate new systems to artificially increase neurogenesis in senescent animals as a means to compensate for age-related cognitive decline. In this review we will discuss the systemic, cellular, and molecular changes induced by aging and affecting the neurogenic niche at the level of neural stem cell proliferation, their fate change, neuronal survival, and subsequent integration in the neuronal circuitry. Particular attention will be given to those manipulations that increase neurogenesis in the aged brain as a potential avenue towards therapy.

Figure 1. Potential mechanisms responsible for the age-related decline in neurogenesis

(A-E) Schematic representation of adult neurogenesis in the young (A) or senescent (B-E) hippocampus. Proliferating and quiescent neural stem and progenitors cells (NSCs; pink) are indicated by the presence or lack of mitotic spindles, respectively. Proliferating NSCs divide to generate (arrows) additional NSCs or immature neurons (blue). During maturation, many neurons undergo apoptosis (crosses). A reduced number of neurons in the senescent hippocampus (B-E) can be explained by an increase in quiescence i.e. a lower proportion of proliferating NSCs (B), a change in NSCs fate i.e. an increase in differentiative at the expense of proliferative and/or gliogenic at the expense of neurogenic division (C), depletion of NSCs by cell death (D), or a higher proportion of newborn neurons undergoing apoptosis (E). Continuous or dashed arrows (A-D) indicate a constant or decreases proportion of proliferating NSCs and neurons generated from the total pool of NSCs, respectively. Note that NSCs in E are not colored because neuronal death could potentially occur concomitantly to any of the previous conditions (A-D).

Figure 2. Factors influencing neurogenesis during aging

(From left to right) Factors and stimuli influencing neurogenesis, their physiological increase (yellow arrows) or decrease (blue arrows) during aging, as well as effects on neurogenesis through, primarily, a change in NSCs proliferation (arrows) or neuronal survival (arrowhead) are indicated. Red ticks indicate factors whose manipulation has been shown to correlate with cognitive function. nd=not determined; na=not applicable.