Neurogenesis in the Adult Brain: Implications for Alzheimers Disease

Veronica      Galvan; Dale   E.   Bredesen

Abstract

The function of neurogenesis in the adult brain is still unknown. Interventions such as environmental enrichment and exercise impinge on neurogenesis, suggesting that the process is regulated by experience. Conversely, a role for neurogenesis in learning has been proposed through ‘cellular plasticity’, a process akin to synaptic plasticity but operating at the network level. Although neurogenesis is stimulated by acute injury, and possibly by neurodegenerative processes such as Alzheimers disease (AD), it does not suffice to restore function. While the role and direction of change in the neurogenic response at different stages of AD is still a matter of debate, it is possible that a deficit in neurogenesis may contribute to AD pathogenesis since at least one of the two regions ostensibly neurogenic in the adult human brain (the subgranular zone of the dentage gyrus and the ventriculo-olfactory neurogenic system) support high-level functions affected in early AD (associative memory and olfaction respectively). The age of onset and the rate of progression of sporadic forms of AD are highly variable. Sporadic AD may have a component of insufficient neurogenic replacement or insufficient neurogenic stimulation that is correlated with traits of personal history; the rate of neurogenesis and the survival of replicating progenitors is strongly modified by behavioral interventions known to impinge on the rate of neurogenesis and the probability of survival of newly born neurons - exercise, enriched experience, and learning. This view is consistent with epidemiological data suggesting that higher education and increased participation in intellectual, social and physical aspects of daily life are associated with slower cognitive decline in healthy elderly (“cognitive reserve”) and may reduce the risk of AD. Although neurogenesis can be modulated exogenously by growth factors, stimulation of neurogenesis as a mean to treat neurodegeneration is still for the most part speculative. Moreover, it is possible that different roles of neurogenesis during the course of AD are dictated by the degree of permissibility of the environment in which the process is taking place. A unique opportunity may exist in which the therapeutic stimulation of neurogenesis might contribute to functional ‘repair’ of the adult diseased brain, before damage to whole neuronal networks has ensued. In spite of the considerable gaps in our knowledge of neurogenesis, and of the considerable limitations that will need to be overcome before we can intervene in the process, that new neurons are added continuously to the adult mammalian brain is a discovery that has already changed the way we think about neurobiology, and may soon change the way we understand and approach neurodegenerative diseases such as AD.

Keywords: Amyloid precursor protein, ventriculo-olfactory neurogenic system, dentate gyrus, hippocampal circuits, Minimal cognitive impairment

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