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Pathophysiology of Alzheimer and the Drug Pipeline
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Pathophysiology of Alzheimer and the Drug Pipeline

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (28 February 2021) | Viewed by 22574

Special Issue Editors

Dr. Stephane Epelbaum

E-Mail Website
Guest Editor
Paris Brain Institute, Sorbonne Universite, Pitie Salpetriere Hospital, Neurology Department, Paris, France
Interests: Alzheimer's disease; clinical trials; longitudinal cohort studies; cognition; neuroscience
Dr. Femke H. Bouwman

E-Mail Website1 Website2
Guest Editor
Alzheimercentrum, PK -1 Z 044, Postbus 7057, 1007 MB, Amsterdam
Interests: Alzheimer’s disease; CSF and PET biomarkers of dementias; retina as a biomarker for AD; neurodegenerative neuropathology

Special Issue Information

Dear Colleagues,

Drug development for Alzheimer’s disease is currently one of the major biomedical challenges worldwide. In recent years, the amount of knowledge accumulated concerning the pathophysiology of the disease but also the means to diagnose or prognosticate it has grown steadily and exponentially. Only therapeutic research remains insufficiently fruitful to date. Through this Special Issue of the International Journal of Molecular Science, we will study advances concerning the pathophysiological aspects of the disease and how, little by little, they lead to an optimization of the therapeutic research pipeline. We will tackle subjects as varied as the conceptualization of Alzheimer’s disease on the ontological level, which should allow refining the targeting of procedures with therapeutic aims, as well as advances in neuropathology which show us the concept of comorbidity in a new light and allow going beyond the misleading concept of "unique" disease. Finally, we will study the flourishing field of biomarkers of Alzheimer’s disease and related diseases that will eventually allow accessing a precise map of the etiology of cognitive decline according to the paradigm of personalized medicine.

Dr. Stephane Epelbaum
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Alzheimer’s disease
  • Pathophysiology
  • Neuropathology
  • Biomarkers

Published Papers (3 papers)

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Review

17 pages, 2216 KiB  
Review
The Glucose Metabolic Pathway as A Potential Target for Therapeutics: Crucial Role of Glycosylation in Alzheimer’s Disease
by Vidyasagar Naik Bukke, Rosanna Villani, Moola Archana, Agata Wawrzyniak, Krzysztof Balawender, Stanislaw Orkisz, Luca Ferraro, Gaetano Serviddio and Tommaso Cassano
Int. J. Mol. Sci. 2020, 21(20), 7739; https://doi.org/10.3390/ijms21207739 - 19 Oct 2020
Cited by 12 | Viewed by 6926
Abstract
Glucose uptake in the brain decreases because of normal aging but this decline is accelerated in Alzheimer’s disease (AD) patients. In fact, positron emission tomography (PET) studies have shown that metabolic reductions in AD patients occur decades before the onset of symptoms, suggesting [...] Read more.
Glucose uptake in the brain decreases because of normal aging but this decline is accelerated in Alzheimer’s disease (AD) patients. In fact, positron emission tomography (PET) studies have shown that metabolic reductions in AD patients occur decades before the onset of symptoms, suggesting that metabolic deficits may be an upstream event in at least some late-onset cases. A decrease in availability of glucose content induces a considerable impairment/downregulation of glycosylation, which is an important post-translational modification. Glycosylation is an important and highly regulated mechanism of secondary protein processing within cells and it plays a crucial role in modulating stability of proteins, as carbohydrates are important in achieving the proper three-dimensional conformation of glycoproteins. Moreover, glycosylation acts as a metabolic sensor that links glucose metabolism to normal neuronal functioning. All the proteins involved in β-amyloid (Aβ) precursor protein metabolism have been identified as candidates of glycosylation highlighting the possibility that Aβ metabolism could be regulated by their glycosylation. Within this framework, the present review aims to summarize the current understanding on the role of glycosylation in the etiopathology of AD, emphasizing the idea that glucose metabolic pathway may represent an alternative therapeutic option for targeting AD. From this perspective, the pharmacological modulation of glycosylation levels may represent a ‘sweet approach’ to treat AD targeting new mechanisms independent of the amyloid cascade and with comparable impacts in familial and sporadic AD. Full article
(This article belongs to the Special Issue Pathophysiology of Alzheimer and the Drug Pipeline)
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24 pages, 1426 KiB  
Review
Exploring the Potential of Therapeutic Agents Targeted towards Mitigating the Events Associated with Amyloid-β Cascade in Alzheimer’s Disease
by Tapan Behl, Ishnoor Kaur, Ovidiu Fratila, Roxana Brata and Simona Bungau
Int. J. Mol. Sci. 2020, 21(20), 7443; https://doi.org/10.3390/ijms21207443 - 9 Oct 2020
Cited by 33 | Viewed by 4643
Abstract
One of the most commonly occurring neurodegenerative disorders, Alzheimer’s disease (AD), encompasses the loss of cognitive and memory potential, impaired learning, dementia and behavioral defects, and has been prevalent since the 1900s. The accelerating occurrence of AD is expected to reach 65.7 million [...] Read more.
One of the most commonly occurring neurodegenerative disorders, Alzheimer’s disease (AD), encompasses the loss of cognitive and memory potential, impaired learning, dementia and behavioral defects, and has been prevalent since the 1900s. The accelerating occurrence of AD is expected to reach 65.7 million by 2030. The disease results in neural atrophy and disrupted inter-neuronal connections. Amongst multiple AD pathogenesis hypotheses, the amyloid beta (Aβ) cascade is the most relevant and accepted form of the hypothesis, which suggests that Aβ monomers are formed as a result of the cleavage of amyloid precursor protein (APP), followed by the conversion of these monomers to toxic oligomers, which in turn develop β-sheets, fibrils and plaques. The review targets the events in the amyloid hypothesis and elaborates suitable therapeutic agents that function by hindering the steps of plaque formation and lowering Aβ levels in the brain. The authors discuss treatment possibilities, including the inhibition of β- and γ-secretase-mediated enzymatic cleavage of APP, the immune response generating active immunotherapy and passive immunotherapeutic approaches targeting monoclonal antibodies towards Aβ aggregates, the removal of amyloid aggregates by the activation of enzymatic pathways or the regulation of Aβ circulation, glucagon-like peptide-1 (GLP-1)-mediated curbed accumulation and the neurotoxic potential of Aβ aggregates, bapineuzumab-mediated vascular permeability alterations, statin-mediated Aβ peptide degradation, the potential role of ibuprofen and the significance of natural drugs and dyes in hindering the amyloid cascade events. Thus, the authors aim to highlight the treatment perspective, targeting the amyloid hypothesis, while simultaneously emphasizing the need to conduct further investigations, in order to provide an opportunity to neurologists to develop novel and reliable treatment therapies for the retardation of AD progression. Full article
(This article belongs to the Special Issue Pathophysiology of Alzheimer and the Drug Pipeline)
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33 pages, 858 KiB  
Review
Revisiting the Amyloid Cascade Hypothesis: From Anti-Aβ Therapeutics to Auspicious New Ways for Alzheimer’s Disease
by Md. Sahab Uddin, Md. Tanvir Kabir, Md. Sohanur Rahman, Tapan Behl, Philippe Jeandet, Ghulam Md Ashraf, Agnieszka Najda, May N. Bin-Jumah, Hesham R. El-Seedi and Mohamed M. Abdel-Daim
Int. J. Mol. Sci. 2020, 21(16), 5858; https://doi.org/10.3390/ijms21165858 - 14 Aug 2020
Cited by 85 | Viewed by 10578
Abstract
Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder related to age, characterized by the cerebral deposition of fibrils, which are made from the amyloid-β (Aβ), a peptide of 40–42 amino acids. The conversion of Aβ into neurotoxic oligomeric, fibrillar, and protofibrillar assemblies [...] Read more.
Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder related to age, characterized by the cerebral deposition of fibrils, which are made from the amyloid-β (Aβ), a peptide of 40–42 amino acids. The conversion of Aβ into neurotoxic oligomeric, fibrillar, and protofibrillar assemblies is supposed to be the main pathological event in AD. After Aβ accumulation, the clinical symptoms fall out predominantly due to the deficient brain clearance of the peptide. For several years, researchers have attempted to decline the Aβ monomer, oligomer, and aggregate levels, as well as plaques, employing agents that facilitate the reduction of Aβ and antagonize Aβ aggregation, or raise Aβ clearance from brain. Unluckily, broad clinical trials with mild to moderate AD participants have shown that these approaches were unsuccessful. Several clinical trials are running involving patients whose disease is at an early stage, but the preliminary outcomes are not clinically impressive. Many studies have been conducted against oligomers of Aβ which are the utmost neurotoxic molecular species. Trials with monoclonal antibodies directed against Aβ oligomers have exhibited exciting findings. Nevertheless, Aβ oligomers maintain equivalent states in both monomeric and aggregation forms; so, previously administered drugs that precisely decrease Aβ monomer or Aβ plaques ought to have displayed valuable clinical benefits. In this article, Aβ-based therapeutic strategies are discussed and several promising new ways to fight against AD are appraised. Full article
(This article belongs to the Special Issue Pathophysiology of Alzheimer and the Drug Pipeline)
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