scholarly journals Neuroinflammation and Neurogenesis in Alzheimer’s Disease and Potential Therapeutic Approaches

2020 ◽  
Vol 21 (3) ◽  
pp. 701 ◽  
Author(s):  
Pi-Shan Sung ◽  
Po-Yu Lin ◽  
Chi-Hung Liu ◽  
Hui-Chen Su ◽  
Kuen-Jer Tsai
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Adult Neurogenesis ◽  
Subventricular Zone ◽  
State Of The Art ◽  
Signal Transduction Pathway ◽  
Adult Brain ◽  
Therapeutic Approaches ◽  
Current State ◽  
The Relationship

In adult brain, new neurons are generated throughout adulthood in the subventricular zone and the dentate gyrus; this process is commonly known as adult neurogenesis. The regulation or modulation of adult neurogenesis includes various intrinsic pathways (signal transduction pathway and epigenetic or genetic modulation pathways) or extrinsic pathways (metabolic growth factor modulation, vascular, and immune system pathways). Altered neurogenesis has been identified in Alzheimer’s disease (AD), in both human AD brains and AD rodent models. The exact mechanism of the dysregulation of adult neurogenesis in AD has not been completely elucidated. However, neuroinflammation has been demonstrated to alter adult neurogenesis. The presence of various inflammatory components, such as immune cells, cytokines, or chemokines, plays a role in regulating the survival, proliferation, and maturation of neural stem cells. Neuroinflammation has also been considered as a hallmark neuropathological feature of AD. In this review, we summarize current, state-of-the art perspectives on adult neurogenesis, neuroinflammation, and the relationship between these two phenomena in AD. Furthermore, we discuss the potential therapeutic approaches, focusing on the anti-inflammatory and proneurogenic interventions that have been reported in this field.

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

2020 ◽  
Vol 3 (2) ◽  
pp. 216-242 ◽  
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.   

scholarly journals The State of The Art on Acetylcholinesterase Inhibitors in the Treatment of Alzheimer’s Disease

2021 ◽  
Vol 13 ◽  
pp. 117957352110291
Author(s):  
Immacolata Vecchio ◽  
Luca Sorrentino ◽  
Annamaria Paoletti ◽  
Rosario Marra ◽  
Mariamena Arbitrio
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
State Of The Art ◽  
Acetylcholinesterase Inhibitors ◽  
Therapeutic Approaches ◽  
Clinical Level ◽  
Novel Drugs ◽  
Clinical Benefits ◽  
The Central Nervous System ◽  
The Brain

Alzheimer’s disease (AD) is a chronic disabling disease that affects the central nervous system. The main consequences of AD include the decline of cognitive functions and language disorders. One of the causes leading to AD is the decrease of neurotransmitter acetylcholine (ACh) levels in the brain, in part due to a higher activity of acetylcholinesterase (AChE), the enzyme responsible for its degradation. Many acetylcholinesterase inhibitors (AChEIs), both natural and synthetic, have been developed and used through the years to counteract the progression of the disease. The first of such drugs approved for a therapeutic use was tacrine, that binds through a reversible bond to the enzyme. However, tacrine has since been withdrawn because of its adverse effects. Currently, donepezil and galantamine are very promising AChEIs with clinical benefits. Moreover, rivastigmine is considered a pseudo-irreversible compound with anti-AChE action, providing similar effects at the clinical level. The purpose of this review is to provide an overview of what has been published over the last decade on the effectiveness of AChEIs in AD, analysing the most relevant issues under the clinical and methodological profiles and the consequent possible welfare effects for the whole world. Furthermore, novel drugs and possible therapeutic approaches are also discussed.

scholarly journals Current State of the Art in Preclinical Research in Alzheimer’s Disease - A Focus on Mode of Action in Pharmacological and Non-pharmacological Approaches

2012 ◽  
Vol 7 (4) ◽  
pp. 216
Author(s):  
Kiren Ubhi ◽  
Eliezer Masliah ◽  
◽  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Cholinergic Neurons ◽  
Therapeutic Approaches ◽  
Preclinical Research ◽  
Current State ◽  
Age Related ◽  
Cognitive Disturbances ◽  
Underlying Mechanisms

Alzheimer’s disease (AD) is an age-related neurodegenerative disorder characterised by progressive memory deficits and other cognitive disturbances. Neuropathologically, AD is characterised by synaptic deficits, progressive loss of neocortical, limbic and basal forebrain cholinergic neurons and the abnormal extracellular accumulation of amyloid-beta (Aß) and the intracellular aggregation of the cvtoskeletal protein tau. Currently available AD therapies either only temporarily delay disease progression or address the symptoms but are unable to alter the underlying mechanisms of disease. Therefore, ongoing AD research is focused at better understanding pathogenesis and at developing disease-modifying experimental therapeutic approaches. This review will summarise the main areas of preclinical research for AD therapeutics that includes those aimed at modulating the processing of amyloid precursor protein (APP) and the production of Aß; ameliorating the pathological accumulation of Aß or tau; augmenting neuroprotective activities in the AD brain; and augmenting neurorestoration in the AD brain. The review will also discuss a novel multimodal therapeutic approach to AD using Cerebrolysin, a peptidergic mixture with neurotrophic-like effects.

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

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.

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

2021 ◽  
Vol 22 (19) ◽  
pp. 10744
Author(s):  
Bolanle Fatimat 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

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.

ADULT NEUROGENESIS: ALTERATIONS WITH AGING AND ALZHEIMER’S DISEASE DEVELOPMENT

2021 ◽  
pp. 1080-1087
Author(s):  
А. О. Бурняшева ◽  
Н. А. Стефанова ◽  
Е. А. Рудницкая
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Adult Neurogenesis ◽  
Neurodegenerative Disorder ◽  
Brain Plasticity ◽  
The Elderly ◽  
Adult Brain ◽  
Molecular Control ◽  
Neurogenic Niche ◽  
Age Related

Нейрогенез в головном мозге взрослого организма - один из важнейших механизмов пластичности, который проявляется увеличением числа клеток, участвующих в структурной перестройке нейрональных сетей и формированием синапсов, и способствует увеличению функциональных возможностей головного мозга. С возрастом и при развитии нейродегенеративных расстройств происходит нарушение микроокружения нейрогенной ниши, ослабление контроля и, как следствие, значительное снижение нейрогенеза, что, в свою очередь, может способствовать ухудшению когнитивных способностей и развитию деменции. Наиболее распространённой сенильной деменцией является болезнь Альцгеймера - неизлечимое заболевание нейродегенеративной природы, при котором одними из первых поражаются гиппокамп и энторинальная кора - ключевые нейрогенные ниши зрелого головного мозга, что приводит к нарушению нейрогенеза и способствует дальнейшей прогрессии дегенеративных процессов. На сегодняшний день механизмы, лежащие в основе сопровождающих развитие болезни Альцгеймера изменений нейрогенеза, остаются до конца неясными и являются предметом интенсивного изучения исследователей во всём мире как потенциальная мишень для коррекции патологических изменений. Adult neurogenesis is one of the key mechanisms of the brain plasticity. Increase in the number of cells participating in the rearrangement of the neuronal circuits and synaptic formation facilitates the increase of brain’s functional capacity. However, aging as well as neurodegenerative disorders lead to the disruption of the neurogenic niche microenvironment and the loss of molecular control, which in turn results in the significant decline of the neurogenesis. These events may contribute to the cognitive decline and the consequent development of dementia. Alzheimer’s disease is a progressive incurable age-related neurodegenerative disorder in the elderly and the most prevalent cause of dementia. Hippocampus and entorhinal cortex are the key neurogenic niches in the adult brain and one of the most vulnerable brain areas during the development of Alzheimer’s disease. Thus, neurodegeneration associated with the development of Alzheimer’s disease affects adult neurogenesis. However, to date the mechanisms underlying this connection are unclear, and the investigation of these mechanisms is a promising strategy to find the approaches to correct the Alzheimer’s disease pathology.

The Phosphoinositide Signal Transduction Pathway in the Pathogenesis of Alzheimer’s Disease

2018 ◽  
Vol 15 (4) ◽  
pp. 355-362 ◽  
Author(s):  
Vincenza Rita Lo Vasco
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Signal Transduction ◽  
Membrane Trafficking ◽  
Hormone Secretion ◽  
Signal Transduction Pathway ◽  
Brain Morphology ◽  
Signal Transduction Pathways ◽  
Transduction Pathway ◽  
Cell Functions

Background: During aging and in age-associated disorders, such as Alzheimer's Disease (AD), learning abilities decline. Probably, disturbances in signal transduction in brain cells underlie the cognitive decline. The phosphorylation/dephosphorylation imbalance occurring in degenerating neurons was recently related to abnormal activity of one or more signal transduction pathways. AD is known to be associated with altered neuronal Ca<sup>2+</sup> homeostasis, as Ca<sup>2+</sup> accumulates in affected neurons leading to functional impairment. It is becoming more and more evident the involvement of signal transduction pathways acting upon Ca<sup>2+</sup> metabolism and phosphorylation regulation of proteins. A growing interest raised around the role of signal transduction systems in a number of human diseases including neurodegenerative diseases, with special regard to the systems related to the phosphoinositide (PI) pathway and AD. The PI signal transduction pathway plays a crucial role, being involved in a variety of cell functions, such as hormone secretion, neurotransmitter signal transduction, cell growth, membrane trafficking, ion channel activity, cytoskeleton regulation, cell cycle control, apoptosis, cell and tissue polarity, and contributes to regulate the Ca<sup>2+</sup> levels in the nervous tissue. Conclusion: A number of observations indicated that PI-specific phospholipase C (PLC) enzymes might be involved in the alteration of neurotransmission. To understand the role and the timing of action of the signalling pathways recruited during the brain morphology changes during the AD progression might help to elucidate the aetiopathogenesis of the disease, paving the way to prognosis refinement and/or novel molecular therapeutic strategies.

MiR-335-5p Inhibits β-Amyloid (Aβ) Accumulation to Attenuate Cognitive Deficits Through Targeting c-jun-N-terminal Kinase 3 in Alzheimer’s Disease

2020 ◽  
Vol 17 (1) ◽  
pp. 93-101 ◽  
Author(s):  
Dan Wang ◽  
Zhifu Fei ◽  
Song Luo ◽  
Hai Wang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transgenic Mice ◽  
Western Blot ◽  
Mrna Expression ◽  
Cognitive Deficits ◽  
Protein Levels ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
The Relationship

Objectives: Alzheimer's disease (AD), also known as senile dementia, is a common neurodegenerative disease characterized by progressive cognitive impairment and personality changes. Numerous evidences have suggested that microRNAs (miRNAs) are involved in the pathogenesis and development of AD. However, the exact role of miR-335-5p in the progression of AD is still not clearly clarified. Methods: The protein and mRNA levels were measured by western blot and RNA extraction and quantitative real-time PCR (qRT-PCR), respectively. The relationship between miR-335-5p and c-jun-N-terminal kinase 3 (JNK3) was confirmed by dual-luciferase reporter assay. SH-SY5Y cells were transfected with APP mutant gene to establish the in vitro AD cell model. Flow cytometry and western blot were performed to evaluate cell apoptosis. The APP/PS1 transgenic mice were used as an in vivo AD model. Morris water maze test was performed to assess the effect of miR- 335-5p on the cognitive deficits in APP/PS1 transgenic mice. Results: The JNK3 mRNA expression and protein levels of JNK3 and β-Amyloid (Aβ) were significantly up-regulated, and the mRNA expression of miR-335-5p was down-regulated in the brain tissues of AD patients. The expression levels of miR-335-5p and JNK3 were significantly inversely correlated. Further, the dual Luciferase assay verified the relationship between miR-335- 5p and JNK3. Overexpression of miR-335-5p significantly decreased the protein levels of JNK3 and Aβ and inhibited apoptosis in SH-SY5Y/APPswe cells, whereas the inhibition of miR-335-5p obtained the opposite results. Moreover, the overexpression of miR-335-5p remarkably improved the cognitive abilities of APP/PS1 mice. Conclusion: The results revealed that the increased JNK3 expression, negatively regulated by miR-335-5p, may be a potential mechanism that contributes to Aβ accumulation and AD progression, indicating a novel approach for AD treatment.

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