Active DNA Aβ42 vaccination as immunotherapy for Alzheimer disease

AbstractAs a neurodegenerative disorder, Alzheimer disease (AD) is the most common form of dementia found in the aging population. Immunotherapy with passive or active immunizations targeting amyloid beta (Aβ) build-up in the brain may provide a possible treatment option and may help prevent AD from progressing. A number of passive immunizations with anti-Aβ42 antibodies are in different phases of clinical trials. One active immunization approach, AN-1792, was stopped after the development of autoimmune encephalitis in 6% of patients and a second one, CAD106, in which a small Aβ epitope is used, is currently in safety and tolerability studies. Besides active immunizations with proteins or peptides, active immunizations using DNA which codes for the protein against which the immune response will be directed, so called genetic immunizations, provide additional safety as the immune response in DNA immunizations differs quantitatively and qualitatively from the response elicited by peptide immunizations. We summarize in this review our data using DNA Aβ42 immunizations in mouse models and discuss the results together with the results presented by many other groups working on a DNA vaccine as treatment option for AD.

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Immunocompetent Mouse Models in the Search for Effective Immunotherapy in Glioblastoma

Cancers ◽

10.3390/cancers13010019 ◽

2020 ◽

Vol 13 (1) ◽

pp. 19

Author(s):

Roxanne Wouters ◽

Sien Bevers ◽

Matteo Riva ◽

Frederik De Smet ◽

An Coosemans

Keyword(s):

Immune Response ◽

Clinical Trials ◽

Mouse Models ◽

Standard Of Care ◽

Preclinical Studies ◽

Success Rates ◽

Immunocompetent Mouse ◽

Full Spectrum ◽

Effective Immune Response ◽

Radio Chemotherapy

Glioblastoma (GBM) is the most aggressive intrinsic brain tumor in adults. Despite maximal therapy consisting of surgery and radio/chemotherapy, GBM remains largely incurable with a median survival of less than 15 months. GBM has a strong immunosuppressive nature with a multitude of tumor and microenvironment (TME) derived factors that prohibit an effective immune response. To date, all clinical trials failed to provide lasting clinical efficacy, despite the relatively high success rates of preclinical studies to show effectivity of immunotherapy. Various factors may explain this discrepancy, including the inability of a single mouse model to fully recapitulate the complexity and heterogeneity of GBM. It is therefore critical to understand the features and limitations of each model, which should probably be combined to grab the full spectrum of the disease. In this review, we summarize the available knowledge concerning immune composition, stem cell characteristics and response to standard-of-care and immunotherapeutics for the most commonly available immunocompetent mouse models of GBM.

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Role of Neuroinflammation in Adult Neurogenesis and Alzheimer Disease: Therapeutic Approaches

Mediators of Inflammation ◽

10.1155/2013/260925 ◽

2013 ◽

Vol 2013 ◽

pp. 1-9 ◽

Cited By ~ 75

Author(s):

Almudena Fuster-Matanzo ◽

María Llorens-Martín ◽

Félix Hernández ◽

Jesús Avila

Keyword(s):

Immune Response ◽

Alzheimer Disease ◽

Adult Neurogenesis ◽

The Elderly ◽

Therapeutic Approaches ◽

Common Cause ◽

The Central Nervous System ◽

Chronic Activation ◽

The Brain

Neuroinflammation, a specialized immune response that takes place in the central nervous system, has been linked to neurodegenerative diseases, and specially, it has been considered as a hallmark of Alzheimer disease, the most common cause of dementia in the elderly nowadays. Furthermore, neuroinflammation has been demonstrated to affect important processes in the brain, such as the formation of new neurons, commonly known as adult neurogenesis. For this, many therapeutic approaches have been developed in order to avoid or mitigate the deleterious effects caused by the chronic activation of the immune response. Considering this, in this paper we revise the relationships between neuroinflammation, Alzheimer disease, and adult neurogenesis, as well as the current therapeutic approaches that have been developed in the field.

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Viral vector delivery of neurotrophic factors for Parkinson's disease therapy

Expert Reviews in Molecular Medicine ◽

10.1017/erm.2015.6 ◽

2015 ◽

Vol 17 ◽

Cited By ~ 20

Author(s):

Martin J. Kelly ◽

Gerard W. O'Keeffe ◽

Aideen M. Sullivan

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Clinical Trials ◽

Neurotrophic Factors ◽

Neurotrophic Factor ◽

Dopaminergic Neurons ◽

Viral Vectors ◽

Viral Vector ◽

Neurodegenerative Disorder ◽

The Brain

Parkinson's disease (PD) is a neurodegenerative disorder characterised by the progressive loss of midbrain dopaminergic neurons, which causes motor impairments. Current treatments involve dopamine replacement to address the disease symptoms rather than its cause. Factors that promote the survival of dopaminergic neurons have been proposed as novel therapies for PD. Several dopaminergic neurotrophic factors (NTFs) have been examined for their ability to protect and/or restore degenerating dopaminergic neurons, both in animal models and in clinical trials. These include glial cell line-derived neurotrophic factor, neurturin, cerebral dopamine neurotrophic factor and growth/differentiation factor 5. Delivery of these NTFs via injection or infusion to the brain raises several practical problems. A new delivery approach for NTFs involves the use of recombinant viral vectors to enable long-term expression of these factors in brain cells. Vectors used include those based on adenoviruses, adeno-associated viruses and lentiviruses. Here we review progress to date on the potential of each of these four NTFs as novel therapeutic strategies for PD, as well as the challenges that have arisen, from pre-clinical analysis to clinical trials. We conclude by discussing recently-developed approaches to optimise the delivery of NTF-carrying viral vectors to the brain.

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Retinal Changes in Transgenic Mouse Models of Alzheimer’s Disease

Current Alzheimer Research ◽

10.2174/1567205018666210414113634 ◽

2021 ◽

Vol 18 ◽

Author(s):

Li Guo ◽

Nivedita Ravindran ◽

Daniel Hill ◽

M. Francesca Cordeiro

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Models ◽

Neurodegenerative Disorder ◽

Neuronal Loss ◽

Immunohistochemical Analysis ◽

Therapeutic Effects ◽

The Central Nervous System ◽

New Treatments ◽

The Brain

: Alzheimer’s disease (AD) is a neurodegenerative disorder, the most common form of dementia. AD is characterized by amyloid-ß (Aß) plaques and neurofibrillary tangles (NFT) in the brain, in association with neuronal loss and synaptic failure, causing cognitive deficits. Accurate and early diagnosis is currently unavailable in lifespan, hampering early intervention of potential new treatments. Visual deficits have been well-documented in AD patients, and the pathological changes identified in the brain are also believed to be found in the retina, an integral part of the central nervous system. Retinal changes can be detected by real-time non-invasive imaging due to the transparent nature of the ocular media, potentially allowing an earlier diagnosis as well as monitoring disease progression and treatment outcome. Animal models are essential for AD research, and this review has a focus on retinal changes in various transgenic AD mouse models with retinal imaging and immunohistochemical analysis as well as therapeutic effects in those models. We also discuss the limitations of transgenic AD models in clinical translations.

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Exploring Potential of Alkaloidal Phytochemicals Targeting Neuroinflammatory Signaling of Alzheimer's Disease

Current Pharmaceutical Design ◽

10.2174/1381612826666200531151004 ◽

2020 ◽

Vol 26 ◽

Cited By ~ 3

Author(s):

Md. Sahab Uddin ◽

Md. Tanvir Kabir ◽

Abdullah Al Mamun ◽

Tapan Behl ◽

Rasha A. Mansouri ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Immune Response ◽

Immune Responses ◽

Immune Cells ◽

Neurodegenerative Disorder ◽

Amyloid Plaques ◽

Favorable Effect ◽

Phytochemical Compounds ◽

The Brain

: Alzheimer's disease (AD) is a chronic neurodegenerative disorder that is marked by cognitive dysfunctions and existence of neuropathological hallmarks such as amyloid plaques, and neurofibrillary tangles. It has been observed that a persistent immune response in the brain has appeared as another neuropathological hallmark in AD. The persistent activation of the microglia, the brain’s resident macrophages, and other immune cells has been shown to aggravate both tau and amyloid pathology and may consider as a connection in the AD pathogenesis. However, the basic mechanisms that link immune responses in the pathogenesis of AD are unclear until now since the process of neuroinflammation can have either a harmful or favorable effect on AD, according to the phase of the disease. Numerous researches recommend that nutritional fruits, as well as vegetables, possess neurodefensive properties against the detrimental effects of neuroinflammation and aging. Moreover, these effects are controlled by diverse phytochemical compounds that are found in plants and demonstrate anti-inflammatory, neuroprotective as well as other beneficial actions. In this review, we focus on the link of neuroinflammation in AD as well as highlight the probable mechanisms of alkaloidal phytochemicals to combat neuroinflammatory aspect of AD.

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Rationale for the Development of 2-Aminobenzamide Histone Deacetylase Inhibitors as Therapeutics for Friedreich Ataxia

Journal of Child Neurology ◽

10.1177/0883073812448533 ◽

2012 ◽

Vol 27 (9) ◽

pp. 1164-1173 ◽

Cited By ~ 29

Author(s):

Elisabetta Soragni ◽

Chunping Xu ◽

Heather L. Plasterer ◽

Vincent Jacques ◽

James R. Rusche ◽

...

Keyword(s):

Clinical Trials ◽

Histone Deacetylase ◽

Mouse Models ◽

Messenger Rna ◽

Histone Deacetylase Inhibitors ◽

Friedreich Ataxia ◽

Model Compounds ◽

Present Evidence ◽

The Brain ◽

Potential Therapeutics

Numerous studies have pointed to histone deacetylase inhibitors as potential therapeutics for various neurodegenerative diseases, and clinical trials with several histone deacetylase inhibitors have been performed or are under way. However, histone deacetylase inhibitors tested to date either are highly cytotoxic or have very low specificities for different histone deacetylase enzymes. The authors’ laboratories have identified a novel class of histone deacetylase inhibitors (2-aminobenzamides) that reverses heterochromatin-mediated silencing of the frataxin ( FXN) gene in Friedreich ataxia. The authors have identified the histone deacetylase enzyme isotype target of these compounds and present evidence that compounds that target this enzyme selectively increase FXN expression from pathogenic alleles. Studies with model compounds show that these histone deacetylase inhibitors increase FXN messenger RNA levels in the brain in mouse models for Friedreich ataxia and relieve neurological symptoms observed in mouse models and support the notion that this class of molecules may serve as therapeutics for the human disease.

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Transcriptional correlates of the pathological phenotype in a Huntington’s disease mouse model

Scientific Reports ◽

10.1038/s41598-019-55177-9 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 5

Author(s):

Andrea Gallardo-Orihuela ◽

Irati Hervás-Corpión ◽

Carmen Hierro-Bujalance ◽

Daniel Sanchez-Sotano ◽

Gema Jiménez-Gómez ◽

...

Keyword(s):

Mouse Models ◽

Neuronal Development ◽

Neurodegenerative Disorder ◽

Disease Onset ◽

Cag Repeats ◽

Brain Areas ◽

Transcriptional Dysregulation ◽

Transcriptional Alterations ◽

Exon 1 ◽

The Brain

AbstractHuntington disease (HD) is a fatal neurodegenerative disorder without a cure that is caused by an aberrant expansion of CAG repeats in exon 1 of the huntingtin (HTT) gene. Although a negative correlation between the number of CAG repeats and the age of disease onset is established, additional factors may contribute to the high heterogeneity of the complex manifestation of symptoms among patients. This variability is also observed in mouse models, even under controlled genetic and environmental conditions. To better understand this phenomenon, we analysed the R6/1 strain in search of potential correlates between pathological motor/cognitive phenotypical traits and transcriptional alterations. HD-related genes (e.g., Penk, Plk5, Itpka), despite being downregulated across the examined brain areas (the prefrontal cortex, striatum, hippocampus and cerebellum), exhibited tissue-specific correlations with particular phenotypical traits that were attributable to the contribution of the brain region to that trait (e.g., striatum and rotarod performance, cerebellum and feet clasping). Focusing on the striatum, we determined that the transcriptional dysregulation associated with HD was partially exacerbated in mice that showed poor overall phenotypical scores, especially in genes with relevant roles in striatal functioning (e.g., Pde10a, Drd1, Drd2, Ppp1r1b). However, we also observed transcripts associated with relatively better outcomes, such as Nfya (CCAAT-binding transcription factor NF-Y subunit A) plus others related to neuronal development, apoptosis and differentiation. In this study, we demonstrated that altered brain transcription can be related to the manifestation of HD-like symptoms in mouse models and that this can be extrapolated to the highly heterogeneous population of HD patients.

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Dysregulation of the Gut-Brain Axis, Dysbiosis and Influence of Numerous Factors on Gut Microbiota Associated Parkinson’s Disease

Current Neuropharmacology ◽

10.2174/1570159x18666200606233050 ◽

2020 ◽

Vol 19 (2) ◽

pp. 233-247 ◽

Cited By ~ 4

Author(s):

Gagandeep Kaur ◽

Tapan Behl ◽

Simona Bungau ◽

Arun Kumar ◽

Md Sahab Uddin ◽

...

Keyword(s):

Parkinson’S Disease ◽

Immune Response ◽

Parkinson's Disease ◽

Nervous System ◽

Autonomic Nervous System ◽

Neurological Disorders ◽

Neurodegenerative Disorder ◽

Microbial Composition ◽

Neuroendocrine Mechanisms ◽

The Brain

Background: Parkinson’s disease (PD) has been one of the substantial social, medical concern and, burdens of the present time. PD is a gradually devastating neurodegenerative disorder of the neurological function marked with αsynucleinopathy affecting numerous regions of the brain-gut axis, as well as the central, enteric, and autonomic nervous system. Its etiology is a widely disputed topic. Objective: This review emphasizes to find out the correlation among the microbial composition and the observable disturbances in the metabolites of the microbial species and its impact on the immune response, which may have a concrete implication on the occurrence, persistence and, pathophysiology of PD via the gut-brain axis. Methods: An in-depth research and the database was developed from the available peer reviewed articles till date (March 2020) utilizing numerous search engines like PubMed, MEDLINE and, other internet sources. Results: Progressively increasing shreds of evidence have proved the fact that dysbiosis in the gut microbiome plays a central role in many neurological disorders, such as PD. Indeed, a disordered microbiome-gut-brain axis in PD could be focused on gastrointestinal afflictions that manifest primarily several years prior to the diagnosis, authenticating a concept wherein the pathological pathway progresses from the intestine reaching the brain. Conclusion: The microbiota greatly affects the bidirectional interaction between the brain and the gut via synchronized neurological, immunological, and neuroendocrine mechanisms. It can be concluded that a multitude of factors discussed in this review steadily induce the onset of dysbacteriosis that may exacerbate the etiologic mechanism of Parkinson’s disease.

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