Adult neurogenesis and neurodegenerative diseases: A systems biology perspective

Abstract

New neurons are generated throughout adulthood in two regions of the brain, the olfactory bulb and dentate gyrus of the hippocampus, and are incorporated into the hippocampal network circuitry; disruption of this process has been postulated to contribute to neurodegenerative diseases including Alzheimer’s disease and Parkinson’s disease. Known modulators of adult neurogenesis include signal transduction pathways, the vascular and immune systems, metabolic factors, and epigenetic regulation. Multiple intrinsic and extrinsic factors such as neurotrophic factors, transcription factors, and cell cycle regulators control neural stem cell proliferation, maintenance in the adult neurogenic niche, and differentiation into mature neurons; these factors act in networks of signaling molecules that influence each other during construction and maintenance of neural circuits, and in turn contribute to learning and memory. The immune system and vascular system are necessary for neuronal formation and neural stem cell fate determination. Inflammatory cytokines regulate adult neurogenesis in response to immune system activation, whereas the vasculature regulates the neural stem cell niche. Vasculature, immune/support cell populations (microglia/astrocytes), adhesion molecules, growth factors, and the extracellular matrix also provide a homing environment for neural stem cells. Epigenetic changes during hippocampal neurogenesis also impact memory and learning. Some genetic variations in neurogenesis related genes may play important roles in the alteration of neural stem cells differentiation into new born neurons during adult neurogenesis, with important therapeutic implications. In this review, we discuss mechanisms of and interactions between these modulators of adult neurogenesis, as well as implications for neurodegenerative disease and current therapeutic research.

Targeted neurogenesis pathway-based gene analysis identifies ADORA2A associated with hippocampal volume in mild cognitive impairment and Alzheimer's disease

“…The new neurons generated during adult neurogenesis are incorporated into hippocampal network circuitry during construction and maintenance of neural circuits and contribute to learning and memory (Aimone, Li et al 2014, Winner and Winkler 2015). The progenitor cells in DG divide periodically, and DG experiences stability in neurogenesis throughout life (Scharfman and Bernstein 2015, Horgusluoglu, Nudelman et al 2016). In rodents, neural stem cells (NSCs) in the DG make approximately 8,000 to 10,000 new neurons per day.…”

“…Many molecular mechanisms and pathways play a role in the hippocampal neurogenesis process, including the proliferation of neural progenitor cells, the differentiation, migration, and maturation of adult neurons (Urban and Guillemot 2014, Horgusluoglu, Nudelman et al 2016). Known modulators of adult neurogenesis include signaling transduction, vascular and immune systems, metabolic factors, and epigenetic regulation (Urban and Guillemot 2014, Borsini, Zunszain et al 2015, Horgusluoglu, Nudelman et al 2016).…”

“…Known modulators of adult neurogenesis include signaling transduction, vascular and immune systems, metabolic factors, and epigenetic regulation (Urban and Guillemot 2014, Borsini, Zunszain et al 2015, Horgusluoglu, Nudelman et al 2016). In particular, multiple factors such as neurotrophic factors, transcription factors, and cell cycle regulators control NSC proliferation, maintenance in neurogenic niche, and differentiation into mature neurons; these factors play role in networks of signaling molecules that influence each other during construction of neural circuits, and contribute to learning and memory (Fig.…”

Effects of Isx-9 and stress on adult hippocampal neurogenesis: Experimental considerations and future perspectives

“…6 Given that a decline in adult hippocampal neurogenesis may contribute to brain dysfunction in several neuropathologies, the development of strategies that stimulate adult neurogenesis may be of therapeutic value for the mitigation of these neuropathological processes. 7,8 The development of synthetic small molecules that can mimic the effects of growth factors and/or activate signaling cascades that normally regulate the different stages of the neurogenic process is an attractive means to enhance neurogenesis, 9 and promote cognitive function in the healthy brain. 10,11 The small molecule compound Isoxazole-9 [Isx-9; N-cyclopropyl-5-(thiophen-2-yl)isoxazole-3-carboxamide], has been shown to stimulate neuronal differentiation in vitro, 12 and in vivo in healthy mice.…”

“…In conclusion, given the importance of adult hippocampal neurogenesis to the modulation of cognitive and affective processes, [1][2][3][4][5]10 and its contribution to the pathophysiology of several neurologic conditions, 7,8,38 Isx-9 shows promise as an agent that may reverse deficits in hippocampal-dependent processes. Future studies will elucidate whether this molecule, or other synthetic compounds structurally and functionally related to Isx-9 with extended half-lives (thus reducing the frequency of administration) and better solubility, can restore neurochemical, morphological and behavioral impairments in animal models of neurodegenerative diseases and psychiatric disorders.…”