proNGF Involvement in the Adult Neurogenesis Dysfunction in Alzheimer’s Disease

In recent decades, neurogenesis in the adult brain has been well demonstrated in a number of animal species, including humans. Interestingly, work with rodents has shown that adult neurogenesis in the dentate gyrus (DG) of the hippocampus is vital for some cognitive aspects, as increasing neurogenesis improves memory, while its disruption triggers the opposite effect. Adult neurogenesis declines with age and has been suggested to play a role in impaired progressive learning and memory loss seen in Alzheimer’s disease (AD). Therefore, therapeutic strategies designed to boost adult hippocampal neurogenesis may be beneficial for the treatment of AD. The precursor forms of neurotrophins, such as pro-NGF, display remarkable increase during AD in the hippocampus and entorhinal cortex. In contrast to mature NGF, pro-NGF exerts adverse functions in survival, proliferation, and differentiation. Hence, we hypothesized that pro-NGF and its p75 neurotrophin receptor (p75NTR) contribute to disrupting adult hippocampal neurogenesis during AD. To test this hypothesis, in this study, we took advantage of the availability of mouse models of AD (APP/PS1), which display memory impairment, and AD human samples to address the role of pro-NGF/p75NTR signaling in different aspects of adult neurogenesis. First, we observed that DG doublecortin (DCX) + progenitors express p75NTR both, in healthy humans and control animals, although the percentage of DCX+ cells are significantly reduced in AD. Interestingly, the expression of p75NTR in these progenitors is significantly decreased in AD conditions compared to controls. In order to assess the contribution of the pro-NGF/p75NTR pathway to the memory deficits of APP/PS1 mice, we injected pro-NGF neutralizing antibodies (anti-proNGF) into the DG of control and APP/PS1 mice and animals are subjected to a Morris water maze test. Intriguingly, we observed that anti-pro-NGF significantly restored memory performance of APP/PS1 animals and significantly increase the percentage of DCX+ progenitors in the DG region of these animals. In summary, our results suggest that pro-NGF is involved in disrupting spatial memory in AD, at least in part by blocking adult neurogenesis. Moreover, we propose that adult neurogenesis alteration should be taken into consideration for better understanding of AD pathology. Additionally, we provide a new molecular entry point (pro-NGF/p75NTR signaling) as a promising therapeutic target in AD.

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Pro-NGF Disrupts Adult Neurogenesis in Humans and Mice Affected by Alzheimer's Disease

10.21203/rs.3.rs-605715/v1 ◽

2021 ◽

Author(s):

Bolanle Olabiyi ◽

Catherine Fleitas ◽

Bahira Zammou ◽

Isidro Ferrer ◽

Claire Rampon ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Adult Neurogenesis ◽

Neutralizing Antibodies ◽

Hippocampal Neurogenesis ◽

Adult Brain ◽

Adult Hippocampal Neurogenesis ◽

Neurotrophin Receptor ◽

Morris Water Maze Test ◽

Healthy Humans

Abstract In recent decades, neurogenesis in adult brain has been well demonstrated in a number of animal species, including humans. Interestingly, work with rodents has shown that adult neurogenesis in the dentate gyrus (DG) of the hippocampus is vital for some cognitive aspects, as increasing neurogenesis improves memory while its disruption triggers the opposite effect. Adult neurogenesis declines with age and has been suggested to play a role in impaired progressive learning and memory loss seen in Alzheimer’s disease (AD). Therefore, therapeutic strategies designed to boost adult hippocampal neurogenesis may be beneficial for the treatment of AD. The precursor forms of neurotrophins, such as pro-NGF, display remarkable increase during AD in the hippocampus and entorhinal cortex. In contrast to mature NGF, pro-NGF exerts adverse functions in survival, proliferation and differentiation. Hence, we hypothesized that pro-NGF and its receptor p75NTR contribute to disrupting adult hippocampal neurogenesis during AD. In this study, we took advantage of the availability of mouse models of AD (APP/PS1) and AD human samples to address the role of pro-NGF/p75NTR signalling in different aspects of adult neurogenesis. Neuroprogenitors of adult mice and human DG samples were identified by immunofluorescence with doublecortin (DCX) antibodies. Interestingly, DCX + progenitors in healthy humans and control animals express p75 neurotrophin receptor (p75NTR). However, this expression is notably decreased in AD conditions. In APP/PS1 mice, memory and cognition were severely impaired. In order to assess the contribution of the pro-NGF/p75NTR pathway to these memory deficits, we injected pro-NGF neutralizing antibodies (ANTI-PRONGF) into the DG of control and APP/PS1 mice which memory was evaluated in Morris water maze test. We observed that anti-pro-NGF injection significantly improved the performance of APP/PS1 animals, but not controls. Interestingly, improved memory in APP/PS1 animals after injection of ANTI-PRONGF correlated with an increase in DCX + progenitors in the DG region of these animals. In summary, our results suggest that pro-NGF is involved in disrupting spatial memory in AD, at least in part by blocking adult neurogenesis. Moreover, we propose that adult neurogenesis alteration could serve as alternative approach towards understanding AD pathology, and additionally offer pro-NGF/p75NTR signalling as a promising therapeutic target.

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Does Impairment of Adult Neurogenesis Contribute to Pathophysiology of Alzheimer's Disease? A Still Open Question

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2020.578211 ◽

2021 ◽

Vol 13 ◽

Author(s):

Domenica Donatella Li Puma ◽

Roberto Piacentini ◽

Claudio Grassi

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Adult Neurogenesis ◽

Memory Formation ◽

Hippocampal Neurogenesis ◽

Synaptic Function ◽

Adult Hippocampal Neurogenesis ◽

Amyloid Β Protein

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.

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Adult Hippocampal Neurogenesis in Alzheimer’s Disease: An Overview of Human and Animal Studies with Implications for Therapeutic Perspectives Aimed at Memory Recovery

Neural Plasticity ◽

10.1155/2022/9959044 ◽

2022 ◽

Vol 2022 ◽

pp. 1-18

Author(s):

Stefano Farioli-Vecchioli ◽

Valentina Ricci ◽

Silvia Middei

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Adult Neurogenesis ◽

Animal Studies ◽

Neurodegenerative Disorder ◽

Memory Loss ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Newborn Neurons ◽

Impaired Neurogenesis

The mammalian hippocampal dentate gyrus is a niche for adult neurogenesis from neural stem cells. Newborn neurons integrate into existing neuronal networks, where they play a key role in hippocampal functions, including learning and memory. In the ageing brain, neurogenic capability progressively declines while in parallel increases the risk for developing Alzheimer’s disease (AD), the main neurodegenerative disorder associated with memory loss. Numerous studies have investigated whether impaired adult neurogenesis contributes to memory decline in AD. Here, we review the literature on adult hippocampal neurogenesis (AHN) and AD by focusing on both human and mouse model studies. First, we describe key steps of AHN, report recent evidence of this phenomenon in humans, and describe the specific contribution of newborn neurons to memory, as evinced by animal studies. Next, we review articles investigating AHN in AD patients and critically examine the discrepancies among different studies over the last two decades. Also, we summarize researches investigating AHN in AD mouse models, and from these studies, we extrapolate the contribution of molecular factors linking AD-related changes to impaired neurogenesis. Lastly, we examine animal studies that link impaired neurogenesis to specific memory dysfunctions in AD and review treatments that have the potential to rescue memory capacities in AD by stimulating AHN.

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Molecular markers characterization determining cell fate specification in an adult neurogenesis model of Alzheimer’s disease

10.1101/2020.08.06.239111 ◽

2020 ◽

Author(s):

Idoia Blanco-Luquin ◽

Juan Cabello ◽

Amaya Urdánoz-Casado ◽

Blanca Acha ◽

Eva Ma Gómez-Orte ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mrna Expression ◽

Cell Fate ◽

Adult Neurogenesis ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Altered Expression ◽

Model Of Alzheimer’S Disease

ABSTRACTAdult hippocampal neurogenesis (AHN) study is still a challenge. In addition to methodological difficulties is the controversy of results derived of human or animal system approaches. In view of the proven link between AHN and learning and memory impairment, we generated a straightforward in vitro model to recapitulate adult neurogenesis in the context of Alzheimer’s disease (AD).Neural progenitor cells (NPCs) monolayer culture was differentiated for a period of 29 days and Aβ peptide 1-42 was administered once a week. mRNA expression of NEUROD1, NCAM1, TUBB3, RBFOX3, CALB1 and GFAP genes was determined by RT-qPCR.Phenotypic changes were observed during directed differentiation. Except for GFAP and CALB1, these changes correlated with altered expression profile of all genes since 9 days. Only TUBB3 expression remained constant while NEUROD1, NCAM1 and RBFOX3 expression increased over time. Moreover, Aβ treated NPCs showed transient decreases of mRNA expression for NCAM1, TUBB3 and RBFOX3 genes at 9 or 19 days.Our in vitro human NPCs model is framed within the multistep process of AHN in the SGZ of the DG. Remarkably, its transcriptional assessment might reflect alterations detected in AD human patients, deepening our understanding of the disorder and possibly of its pathogenesis.SUMMARY STATEMENTTranscriptional profile of a number of genes recapitulating particular stages of Adult hippocampal neurogenesis in the context of Alzheimer’s disease

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Astrocyte-derived ApoE is Required for the Maturation of Injury-induced Hippocampal Neurons and Regulates Cognitive Recovery After Traumatic Brain Injury

10.1101/2021.01.13.425890 ◽

2021 ◽

Author(s):

Tzong-Shiue Yu ◽

Yacine Tensaouti ◽

Elizabeth P. Stephanz ◽

Elizabeth E. Rafikian ◽

Mu Yang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Traumatic Brain Injury ◽

Brain Injury ◽

Hippocampal Neurons ◽

Hippocampal Neurogenesis ◽

Conditional Knockout ◽

Adult Hippocampal Neurogenesis ◽

Morris Water Maze Test ◽

Reversal Training

AbstractPolymorphisms in the apolipoprotein E (ApoE) gene confer a major genetic risk for the development of late-onset Alzheimer’s disease (AD) and are predictive of outcome following traumatic brain injury (TBI). Alterations in adult hippocampal neurogenesis have long been associated with both the development of AD and recovery following TBI, and ApoE is known to play a role in this process. In order to determine how ApoE might influence hippocampal injury-induced neurogenesis, we developed a novel conditional system whereby functional ApoE from astrocytes was ablated just prior to injury. While successfully ablating 90% of astrocytic ApoE just prior to a closed cortical impact injury in mice, we observed an attenuation in the development of newly born neurons using a GFP-expressing retrovirus, but not in existing hippocampal neurons visualized with a Golgi stain. Intriguingly, animals with a “double-hit”, i.e. injury and ApoE conditionally inactivated in astrocytes, demonstrated the most pronounced impairments in the hippocampal-dependent Morris water maze test, failing to exhibit spatial memory after both acquisition and reversal training trials. In comparison, conditional knockout mice without injury displayed impairments but only in the reversal phase of the test, suggesting accumulative effects of astrocytic ApoE deficiency and traumatic brain injury on AD-like phenotypes. Together, these findings demonstrate that astrocytic ApoE is required for functional injury-induced neurogenesis following traumatic brain injury.Significance StatementApoE has long been implicated in the development of Alzheimer’s disease and recovery from traumatic brain injury via unknown mechanisms. Using a novel conditional ablation model of mouse ApoE and subsequent tracing of individual hippocampal neurons, we demonstrate its requirement in injury-induced neurogenesis for proper dendritic arborization and cognitive function in hippocampal-dependent learning and memory tasks.

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Association of adult hippocampal neurogenesis with alzheimer’s disease

International Journal of Community Medicine and Public Health ◽

10.18203/2394-6040.ijcmph20205006 ◽

2020 ◽

Vol 7 (12) ◽

pp. 5208

Author(s):

Atryee Gope

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Stem Cell ◽

Neural Stem Cell ◽

Hippocampal Neurons ◽

Hippocampal Neurogenesis ◽

Adult Brain ◽

Adult Hippocampal Neurogenesis ◽

Sharp Decline ◽

Cell Based Therapy

Neurogenesis in the adult brain has been reported to occur within three distinct regions, of which Hippocampus is the most studied one because of its importance in cognition and memory. Alzheimer’s disease attributes to almost 62% of all dementia cases. A recent study has established a link between adult hippocampal neurogenesis and alzheimer’s disease wherein a sharp decline in AHN is observed in patients suffering from alzheimer’s. This review summarizes alzheimer’s disease, the decline in AHN in alzheimer’s patients and probes into the efficacy of the newly generated hippocampal neurons in the context of memory and cognition. It also discusses the potential of targeting reduced AHN in alzheimer’s patients using neural stem cell-based therapy.

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Role of melatonin in regulating neurogenesis: Implications for the neurodegenerative pathology and analogous therapeutics for Alzheimer’s disease

Melatonin Research ◽

10.32794/mr11250059 ◽

2020 ◽

Vol 3 (2) ◽

pp. 216-242 ◽

Cited By ~ 1

Author(s):

Mayuri Shukla ◽

Areechun Sotthibundhu ◽

Piyarat Govitrapong

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Adult Neurogenesis ◽

Adult Brain ◽

Therapeutic Approaches ◽

Therapeutic Implications ◽

Cell Proliferation And Differentiation ◽

Proliferation And Differentiation ◽

Progenitor Cell Proliferation

The revelation of adult brain exhibiting neurogenesis has established that the brain possesses great plasticity and that neurons could be spawned in the neurogenic zones where hippocampal adult neurogenesis attributes to learning and memory processes. With strong implications in brain functional homeostasis, aging and cognition, various aspects of adult neurogenesis reveal exuberant mechanistic associations thereby further aiding in facilitating the therapeutic approaches regarding the development of neurodegenerative processes in Alzheimer’s Disease (AD). Impaired neurogenesis has been significantly evident in AD with compromised hippocampal function and cognitive deficits. Melatonin the pineal indolamine augments neurogenesis and has been linked to AD development as its levels are compromised with disease progression. Here, in this review, we discuss and appraise the mechanisms via which melatonin regulates neurogenesis in pathophysiological conditions which would unravel the molecular basis in such conditions and its role in endogenous brain repair. Also, its components as key regulators of neural stem and progenitor cell proliferation and differentiation in the embryonic and adult brain would aid in accentuating the therapeutic implications of this indoleamine in line of prevention and treatment of AD.

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