Abstract
Adult hippocampal neurogenesis is a physiological mechanism contributing to hippocampal memory formation. Several studies associated altered hippocampal neurogenesis with aging and Alzheimer's disease (AD). However, whether amyloid-β protein (Aβ)/tau accumulation impairs adult hippocampal neurogenesis and, consequently, the hippocampal circuitry, involved in memory formation, or altered neurogenesis is an epiphenomenon of AD neuropathology contributing negligibly to the AD phenotype, is, especially in humans, still debated. The detrimental effects of Aβ/tau on synaptic function and neuronal viability have been clearly addressed both in in vitro and in vivo experimental models. Until some years ago, studies carried out on in vitro models investigating the action of Aβ/tau on proliferation and differentiation of hippocampal neural stem cells led to contrasting results, mainly due to discrepancies arising from different experimental conditions (e.g., different cellular/animal models, different Aβ and/or tau isoforms, concentrations, and/or aggregation profiles). To date, studies investigating in situ adult hippocampal neurogenesis indicate severe impairment in most of transgenic AD mice; this impairment precedes by several months cognitive dysfunction. Using experimental tools, which only became available in the last few years, research in humans indicated that hippocampal neurogenesis is altered in cognitive declined individuals affected by either mild cognitive impairment or AD as well as in normal cognitive elderly with a significant inverse relationship between the number of newly formed neurons and cognitive impairment. However, despite that such information is available, the question whether impaired neurogenesis contributes to AD pathogenesis or is a mere consequence of Aβ/pTau accumulation is not definitively answered. Herein, we attempted to shed light on this complex and very intriguing topic by reviewing relevant literature on impairment of adult neurogenesis in mouse models of AD and in AD patients analyzing the temporal relationship between the occurrence of altered neurogenesis and the appearance of AD hallmarks and cognitive dysfunctions.
Highlights
HIPPOCAMPAL NEUROGENESIS ANDThe hippocampus is recognized as a brain area primarily involved in memory formation, e.g., pattern separation, emotional memory, and cognitive flexibility (Lazarov and Hollands, 2016; Anacker and Hen, 2017; Hainmueller and Bartos, 2020)
Reviewed by: Orly Lazarov, University of Illinois at Chicago, United States Juan Song, University of North Carolina at Chapel Hill, United States
Studies carried out on in vitro models investigating the action of amyloid-β protein (Aβ)/tau on proliferation and differentiation of hippocampal neural stem cells led to contrasting results, mainly due to discrepancies arising from different experimental conditions
Summary
The hippocampus is recognized as a brain area primarily involved in memory formation, e.g., pattern separation, emotional memory, and cognitive flexibility (Lazarov and Hollands, 2016; Anacker and Hen, 2017; Hainmueller and Bartos, 2020). In the last 15 years, many studies investigated hippocampal neurogenesis [i.e., proliferation and neuronal differentiation of hippocampal neural stem cells (NSCs)] in in vitro and in vivo experimental AD models. More recent results obtained either with lower Aβ concentrations or in cultured NSCs isolated from mouse models harboring the most common genetic alterations observed in FAD indicated impaired proliferation and reduced neuronal differentiation of hippocampus-residing NSCs. In particular, Lee et al (2013) found that exposure of human NSCs to Aβ-containing conditioned medium from SK-NMC cells expressing APP Swedish mutation reduced NSC proliferation, impaired neurogenesis, and promoted gliogenesis via glycogen synthase kinase 3β (GSK-3β) activation. Restoration of Nup153 levels in hippocampal 3 × Tg-AD NSCs promoted their proliferation, migration, and neuronal maturation (Leone et al, 2019)
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