Adult Hippocampal Neurogenesis in Alzheimer’s Disease: An Overview of Human and Animal Studies with Implications for Therapeutic Perspectives Aimed at Memory Recovery

Figure 2

Factors that rescue AHN. Top boxes: factors that increase AHN. (1) Physical activity and environmental enrichment increase neurotrophin levels including BDNF, which in turn stimulate NSC proliferation and differentiation. Consistently, pharmacological modulation of neurotrophins (2) through compounds including L-NBP, Osthole, or Prosaposin can initiate NSC proliferation and also promote survival of newborn neurons. (3) Other modulators of proliferation and differentiation of stem cells can act to potentiate the generation of newborn neurons and their neuron fate specification. (4) Microglia can be found in 3 distinct states, each one affecting AHN through different mechanisms. Resting microglia ensure basal neurogenesis by releasing factors that control neuronal differentiation. Active microglia release proinflammatory cytokines that reduce NSC proliferation and differentiation. Congruent with this, microglia inhibitors and anti-inflammatory compounds rescue AHN in AD mice. Alternatively acting state microglia release anti-inflammatory cytokines including IL-4 and IL-10 that favor differentiation, viral-mediated expression of these cytokines reduces astro/microgliosis and enhances AHN. (5) Transplants of stem cells or progenitors as well as enhancing the functional integration of new neurons can potentiate AHN. Enhancing GABA signaling through transplant of GABAergic progenitors favors the maturation of newborn neurons. Transplanted NSCs in the hippocampus can differentiate in neurons or astrocytes. Mesenchymal stem cell transplantation increases neurogenesis by boosting differentiation and proliferation through mechanisms including the stimulation of alternatively activated microglia. Bottom panel: factors that increase AHN are represented along the stages of spatio-temporal transition of neural stem cell to a mature neuron. Numbers refer to the action of factors reported in top boxes. Please note that numbers position is indicative but not definitive as each factor can act through different mechanisms.