Alzheimer's disease is a particular form of progressive dementia associated with distinct neuropathological changes [16
]. It is characterized by memory loss and impairment in at least one other area of cognition [18
]. At any time during the disease, patients may also experience changes in behavior or mood. Indeed, several lines of evidence suggest that AD may be a syndrome with overlapping causes that result in identical neuropathological changes, and, if this hypothesis is correct, there will likely be multiple treatment approaches, whose components will vary from patient to patient [21
]. Several lines of investigation have proposed different treatment strategies in AD models, including the induction of neurogenesis.
Various evidence supports the idea that the disease symptoms of AD could partly be due to the impaired formation of new hippocampal neurons from endogenous NSCs in the SGZ, which are believed to contribute to mood regulation, learning and memory [22
]. However, we still do not know what causes the disease.
In AD, different cellular alterations make the induction of neurogenesis more difficult than expected, and an improved understanding of the factors that govern NSC differentiation is needed before the stimulation or introduction of neural precursors into the brain becomes a viable option for the treatment of this disease. AD is extremely complex because the NSCs would have to be pre-differentiated in vitro
into many different types of neuroblasts for subsequent implantation into a large number of brain areas. However, there has been evidence showing that endogenous neuronal precursors can proliferate in response to damage [23
]. Neurogenesis was found to be increased in the brains of patients with AD, compared with the brains of age-matched control subjects [26
], suggesting that compensatory mechanisms are directed to overcome the loss of function [27
]. Currently, it is still unclear how the pathophysiological environment in the AD brain affects neural stem cell biology.
Postmortem analysis of the hippocampus in patients with AD has identified a significant increase in neurogenesis in patients with AD, compared with controls, with the most-severely affected patients displaying the greatest increase [26
]. Other evidence has shown that the expression of proteins that are linked to the activation of cell cycle mechanisms and the regulation of chromosomal replication (MCM2, Ki67, and PCNA) are observed in glial cells and neurons in the hippocampus, entorhinal cortex, and white matter in elderly human brains with different extents of AD-type pathology. These proteins trend toward increased expression levels, which are associated with more-advanced Braak stages [28
Mouse models of AD have provided controversial results. Some studies have demonstrated both increased and decreased hippocampal neurogenesis [29
]. One important factor is the disease severity, with a compensatory increase in progenitor proliferation in the early stages and decreased proliferation and survival with in the advanced stages of the pathology [30