Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer’s disease

Moreno‐Jiménez, Elena P.; Flor‐García, Miguel; Terreros‐Roncal, Julia; Rábano, Alberto; Cafini, Fabio; Pallas‐Bazarra, Noemí; Ávila, Jesús; Llorens‐Martin, María

doi:10.1038/s41591-019-0375-9

Cited by 1,185 publications

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“…These cells are slowly dividing or quiescent, and after activation proliferate asymmetrically to generate intermediate progenitor cells (IPCs) that differentiate into neuroblasts that develop into immature neurons and subsequently to mature granule cells that form synaptic connections and become integrated into the hippocampal circuitry . Although the extent of neurogenesis in the adult human hippocampus has been questioned, compelling evidence indicates that adult hippocampal neurogenesis is conserved in mammals including humans . Adult neurogenesis contributes to the plasticity of the hippocampal circuit, and has been implicated in spatial learning and memory, pattern separation, and cognitive flexibility …”

Section: Introductionmentioning

confidence: 99%

Wnt5a promotes differentiation and development of adult-born neurons in the hippocampus by noncanonical Wnt signaling

et al. 2019

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In the adult hippocampus, new neurons are generated in the dentate gyrus. The Wnt signaling pathway regulates this process, but little is known about the endogenous Wnt ligands involved. We investigated the role of Wnt5a on adult hippocampal neurogenesis. Wnt5a regulates neuronal morphogenesis during embryonic development, and maintains dendritic architecture of pyramidal neurons in the adult hippocampus. Here, we determined that Wnt5a knockdown in the mouse dentate gyrus by lentivirus‐mediated shRNA impaired neuronal differentiation of progenitor cells, and reduced dendritic development of adult‐born neurons. In cultured adult hippocampal progenitors (AHPs), Wnt5a knockdown reduced neuronal differentiation and morphological development of AHP‐derived neurons, whereas treatment with Wnt5a had the opposite effect. Interestingly, no changes in astrocytic differentiation were observed in vivo or in vitro, suggesting that Wnt5a does not affect fate‐commitment. By using specific inhibitors, we determined that Wnt5a signals through CaMKII to induce neurogenesis, and promotes dendritic development of newborn neurons through activating Wnt/JNK and Wnt/CaMKII signaling. Our results indicate Wnt5a as a niche factor in the adult hippocampus that promotes neuronal differentiation and development through activation of noncanonical Wnt signaling pathways.

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Section: Introductionmentioning

confidence: 99%

Wnt5a promotes differentiation and development of adult-born neurons in the hippocampus by noncanonical Wnt signaling

et al. 2019

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“…Human evolution might adopt efficient ways to provide the capacity of hippocampal plasticity that the individual requires. It is believed that adult neurogenesis confers an unparalleled degree of plasticity to allow brain's response to environmental and situational demands . It is urgent to seek new and efficient ways to study the generation of new neurons in adult humans.…”

Section: Discussionmentioning

confidence: 99%

“…It is believed that adult neurogenesis confers an unparalleled degree of plasticity to allow brain's response to environmental and situational demands. 48,51,52 It is urgent to seek new and efficient ways to study the generation of new neurons in adult humans. Notwithstanding the ongoing debate, adult neurogenesis is reported to contribute to the maintenance of cognitive function in various animal models.…”

Section: Discussionmentioning

confidence: 99%

“…Notwithstanding the ongoing debate, adult neurogenesis is reported to contribute to the maintenance of cognitive function in various animal models. 51,53,54 Prior studies by our group and others using mouse models have indicated that aNPCs show a reduced proliferative activity compared with those derived from embryonic and neonatal mice, as demonstrated by the decreased expression of nestin (an NPC marker) and reduced neurosphere formation and neuronal differentiation. 10,55 Several investigations in rodents and humans further revealed that physical exercise may be linked to aNPC activation.…”

Section: Discussionmentioning

confidence: 99%

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Proteasome activation by insulin-like growth factor-1/nuclear factor erythroid 2-related factor 2 signaling promotes exercise-induced neurogenesis

et al. 2019

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Physical exercise-induced enhancement of learning and memory and alleviation of agerelated cognitive decline in humans have been widely acknowledged. However, the mechanistic relationship between exercise and cognitive improvement remains largely unknown. In this study, we found that exercise-elicited cognitive benefits were accompanied by adaptive hippocampal proteasome activation. Voluntary wheel running increased hippocampal proteasome activity in adult and middle-aged mice, contributing to an acceleration of neurogenesis that could be reversed by intrahippocampal injection of the proteasome inhibitor MG132. We further found that increased levels of insulin-like growth factor-1 (IGF-1) in both serum and hippocampus may be essential for exerciseinduced proteasome activation. Our in vitro study demonstrated that IGF-1 stimulated proteasome activity in cultured adult neural progenitor cells (NPCs) by promoting nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2), followed by elevated expressions of proteasome subunits such as PSMB5. In contrast, pretreating adult mice with the selective IGF-1R inhibitor picropodophyllin diminished exercise-induced neurogenesis, concurrent with reduced Nrf2 nuclear translocation and proteasome activity.Likewise, lowering Nrf2 expression by RNA interference with bilateral intrahippocampal injections of recombinant adeno-associated viral particles significantly suppressed exercise-induced proteasome activation and attenuated cognitive function. Collectively, our work demonstrates that proteasome activation in hippocampus through IGF-1/Nrf2 signaling is a key adaptive mechanism underlying exercise-related neurogenesis, which may serve as a potential targetable pathway in neurodegeneration. K E Y W O R D Sadult neurogenesis, exercise, insulin-like growth factor-1, nuclear factor erythroid 2-related factor 2, neural progenitor cell, proteasome

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“…159 Regarding glia, the clustering of microglia around A -containing senile plaques has long been noted, 160 169 and arguably other areas, with age-related changes in the rate of neuronal cell division. Furthermore, such neurogenesis drops sharply in patients with AD 170,171 or (in mice) with short telomeres 172 or increased age. 105 Moreover, telomerase expression may be protective, particularly against hyperphosphorylated tau production in both humans and mice.…”

Section: Upstream Variablesmentioning

confidence: 99%

A unified model of dementias and age‐related neurodegeneration

Fossel

2020

Alzheimer's & Dementia

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Those working with Alzheimer's and other dementias have been frustrated by the implacability of these diseases. Regardless of limited symptomatic treatment, 1 there are no proven disease-modifying interventions. Despite huge and growing costs of care, 2 a pipeline of candidate drugs, 3 >400 registered trials, 4 tens of thousands of patients, 5 billions of dollars in both US federal 6 and pharmaceutical company investment, 7,8 more than a century of clinical expertise, and thousands of professional careers, dozens of pharmaceutical and biotechnology firms have foundered and failed 9 in attempts to prevent, slow, or alter the course of the dementias.This article presents a novel model to explain the relationships between age-related neurodegenerative disorders (eg, dementias) and the underlying molecular mechanisms of the aging process. The hypothesis is prompted by the fact that accepted conceptual models have failed to yield effective interventions for Alzheimer's or other dementias. 10 This article is a specific response to the Alzheimer's & Dementia editorial of November 2015, 11 which called for a systemic re-evaluation of our current models and their ability to answer fundamental questions regarding complex brain disorders and their relationship to clinical dementia, as well as the failure to yield effective clinical interventions.The article is divided into three parts. The first part explores current models of age-related neurogenerative diseases. The second part proposes a specific model and details both its working and its implications.The third part applies the model to answering the 10 key questions proposed by the Alzheimer's & Dementia editorial. The intent is to provide a conceptual model that accords with known data and proposes a novel point of clinical intervention. The model is intended to provoke discussion and provide a point of departure, rather than to offer a complete and final model for age-related neurodegenerative disease. The value of any such model rests on the outcome of clinical trials, but the model offers potentially innovative pathways to such trials. Current dementia modelsAlthough there is no general explanation for the failure to identify an effective intervention, there is growing consensus that a major factor is the lack of a comprehensive model for the dementias. 12 Over the past century, 13 several models have attained varying degrees of acceptance.Such models generally assume (or imply) a predominant single cause of Alzheimer's disease (AD; Figure 1).Such models suggest that, although several factors may contribute to the pathology, most Alzheimer's pathology results from a single predominant cause, such as amyloid plaque. In Figure 1, A (the predominant cause) is the leading causal factor, whereas B, C, D, and E represent contributing (but less significant or even incidental) factors.Until recently, the foremost among such explanations has been amyloid (A ) theory, [14][15][16][17] in various iterations. Other candidates have been tau tangles, 18-20 mitochondrial dysfun...

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Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer’s disease

Abstract: Reprints and permissions information is available at www.nature.com/reprints.

Cited by 1,185 publications

References 31 publications

Wnt5a promotes differentiation and development of adult-born neurons in the hippocampus by noncanonical Wnt signaling

Wnt5a promotes differentiation and development of adult-born neurons in the hippocampus by noncanonical Wnt signaling

Proteasome activation by insulin-like growth factor-1/nuclear factor erythroid 2-related factor 2 signaling promotes exercise-induced neurogenesis

A unified model of dementias and age‐related neurodegeneration

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