Therapeutic potential of neurogenesis and melatonin regulation in Alzheimer's disease

Mihardja, Mazel; Roy, Jaydeep; Wong, Kan Yin; Aquili, Luca; Heng, Boon Chin; Chan, Y.; Fung, Man Lung; Lim, Lee Wei

doi:10.1111/nyas.14436

Cited by 31 publications

(26 citation statements)

References 130 publications

(318 reference statements)

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“…The factors influencing the experience- and exercise-dependent stimulation of neurogenesis have been intensively pursued given the potential to harness this knowledge for therapeutic benefit in conditions associated with cognitive decline such as Alzheimer’s disease ( Chohan, 2020 , Mihardja et al, 2020 ). One potential approach is to develop exercise- or environment-mimetic drugs that activate the pathways recruited by enrichment for clinical benefits in patients ( Guerrieri et al, 2017 , Shepherd et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Mitogen and Stress-activated Protein Kinase 1 Negatively Regulates Hippocampal Neurogenesis

et al. 2021

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Graphical abstract The dentate gyrus (DG) in rodent hippocampus is a site of neurogenesis. Newly developing neurons can be identified through immunostaining for doublecortin (DCX). We have found that genetic inactivation of the kinase activity of MSK1 (in red) results in an increase in the number of DCX-positive (DCX + ) cells. This suggests that MSK1 negatively regulates neurogenesis in the subgranular zone, potentially to limit the number of new neurons in the dentate gyrus and maintain the stability of neuronal networks.

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Section: Discussionmentioning

confidence: 99%

Mitogen and Stress-activated Protein Kinase 1 Negatively Regulates Hippocampal Neurogenesis

et al. 2021

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“…In a postmortem study, it was recently demonstrated that AD patients had decreased neurogenesis and neuronal differentiation levels in contrast to healthy subjects; this fact was inferred from doublecortin staining in the dentate gyrus of the hippocampus [2]. Importantly, melatonin can increase neurogenesis [72,76], the immature neurons survival [77], and dendrites complexity [39] in animal models, suggesting that the administration of this indoleamine to AD patients may help stimulate neuronal production, survival, and elongation of their neurites, needed to form synaptic contacts and preserve circuitry integrity.…”

Section: Discussionmentioning

confidence: 99%

“…In this regard, if melatonin can scavenge free radicals to mitigate oxidative stress avoiding neuronal apoptosis and simultaneously preserve the integrity of the dendritic arbors, and also improves sleep-wake patterns [83,84], then aged population with reduced circulating levels of this indoleamine and sleep disorders might have increased vulnerability to suffer neurodegeneration after even a moderate pro-oxidant event. Furthermore, since melatonin induces neurogenesis, promotes survival of new neurons in the hippocampus [53,72,76,77], modulates overall neuroplasticity [75], and regulates main functions such as metabolism or sleep, low melatonin levels and/or a misalignment of its biosynthesis due to circadian disruption [72], could be an additional mechanism underlying impaired brain functioning and impoverishment of quality of life in AD patients.…”

Section: Discussionmentioning

confidence: 99%

Melatonin Rescues the Dendrite Collapse Induced by the Pro-Oxidant Toxin Okadaic Acid in Organotypic Cultures of Rat Hilar Hippocampus

et al. 2020

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The pro-oxidant compound okadaic acid (OKA) mimics alterations found in Alzheimer’s disease (AD) as oxidative stress and tau hyperphosphorylation, leading to neurodegeneration and cognitive decline. Although loss of dendrite complexity occurs in AD, the study of this post-synaptic domain in chemical-induced models remains unexplored. Moreover, there is a growing expectation for therapeutic adjuvants to counteract these brain dysfunctions. Melatonin, a free-radical scavenger, inhibits tau hyperphosphorylation, modulates phosphatases, and strengthens dendritic arbors. Thus, we determined if OKA alters the dendritic arbors of hilar hippocampal neurons and whether melatonin prevents, counteracts, or reverses these damages. Rat organotypic cultures were incubated with vehicle, OKA, melatonin, and combined treatments with melatonin either before, simultaneously, or after OKA. DNA breaks were assessed by TUNEL assay and nuclei were counterstained with DAPI. Additionally, MAP2 was immunostained to assess the dendritic arbor properties by the Sholl method. In hippocampal hilus, OKA increased DNA fragmentation and reduced the number of MAP2(+) cells, whereas melatonin protected against oxidation and apoptosis. Additionally, OKA decreased the dendritic arbor complexity and melatonin not only counteracted, but also prevented and reversed the dendritic arbor retraction, highlighting its role in post-synaptic domain integrity preservation against neurodegenerative events in hippocampal neurons.

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“…Restoring rhythmicity via chronotherapy may ameliorate the symptoms of myriad neurological disorders that involve aberrant adult neurogenesis (Albrecht, 2017; Leung et al., 2020; McClung, 2013; Schnell, Albrecht, et al., 2014). In this regard, the circadian hormone melatonin appears to be a very promising therapeutic candidate for depression, Alzheimer's disease, neurodegenerative diseases and CNS injuries (Leung et al., 2020; Mihardja et al., 2020; Song, 2019; Valdes‐Tovar et al., 2018). In vitro, melatonin promoted survival of new neurons derived from hippocampal NSPCs, and increased survival of NSCPs and post‐mitotic immature neurons, which may explain its antidepressant effects in the Porsolt swim test (Ramirez‐Rodriguez et al., 2009).…”

Section: Circadian Control Of Stem Cell Behaviourmentioning

confidence: 99%

Regulation of tissue regeneration by the circadian clock

Ruby

Major

Hinrichsen

2021

Eur J of Neuroscience

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Circadian rhythms are regulated by a highly conserved transcriptional/translational feedback loop that maintains approximately 24‐hr periodicity from cellular to organismal levels. Much research effort is being devoted to understanding how the outputs of the master clock affect peripheral oscillators, and in turn, numerous biological processes. Recent studies have revealed roles for circadian timing in the regulation of numerous cellular behaviours in support of complex tissue regeneration. One such role involves the interaction between the circadian clockwork and the cell cycle. The molecular mechanisms that control the cell cycle create a system of regulation that allows for high fidelity DNA synthesis, mitosis and apoptosis. In recent years, it has become clear that clock gene products are required for proper DNA synthesis and cell cycle progression, and conversely, elements of the cell cycle cascade feedback to influence molecular circadian timing mechanisms. It is through this crosstalk that the circadian system orchestrates stem cell proliferation, niche exit and control of the signalling pathways that govern differentiation and self‐renewal. In this review, we discuss the evidence for circadian control of tissue homeostasis and repair and suggest new avenues for research.

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Therapeutic potential of neurogenesis and melatonin regulation in Alzheimer's disease

Cited by 31 publications

References 130 publications

Mitogen and Stress-activated Protein Kinase 1 Negatively Regulates Hippocampal Neurogenesis

Mitogen and Stress-activated Protein Kinase 1 Negatively Regulates Hippocampal Neurogenesis

Melatonin Rescues the Dendrite Collapse Induced by the Pro-Oxidant Toxin Okadaic Acid in Organotypic Cultures of Rat Hilar Hippocampus

Regulation of tissue regeneration by the circadian clock

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