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Special Issue "Amyloid-beta and Neurological Diseases"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (29 February 2016).

Special Issue Editors

Guest Editor
Dr. Amal Kaddoumi

Department of Basic Pharmaceutical Sciences, College of Pharmacy, The University of Louisiana at Monroe, Monroe, LA 71209-0497, USA
E-Mail
Phone: 318-342-1460
Interests: Alzheimer’s disease; cerebral amyloid angiopathy; blood–brain barrier; amyloid-beta clearance; kinetics; CNS drugs; screening and drug development
Guest Editor
Dr. Loqman Mohamed

Department of Basic Pharmaceutical Sciences, College of Pharmacy, The University of Louisiana at Monroe, Monroe, LA 71209-0497, USA
E-Mail
Phone: 318-342-1728
Interests: Alzheimer’s disease; cerebral amyloid angiopathy; blood–brain barrier; amyloid-beta clearance; kinetics; Acetylcholinesterase inhibitors

Special Issue Information

Dear Colleagues,

We are pleased to invite you to contribute to our Special Issue of International Journal of Molecular Sciences (IJMS), entitled “Amyloid-β and Neurological Diseases”. This issue will cover a selection of recent research topics and current review articles, reporting the latest updates on amyloid pathogenesis and related neurological diseases.

Neurodegenerative diseases exhibit distinct pathological features; however, amyloid-β (Aβ) is apparent in several neurodegenerative diseases, such as Alzheimer’s disease (AD), cerebral amyloid angiopathy (CAA), and Down syndrome (DS). Aβ is generated from β-amyloid precursor protein (APP) through sequential cleavage by β-secretase and γ-secretase complex. Aβ accumulation appears to trigger a cascade of pathological events, including formation of neurofibrillary tangles, inflammatory reactions, increased oxidative stress, and mitochondrial dysfunction resulting in the neuropathological and clinical manifestations of dementia.

Multiple lines of evidence demonstrate that overproduction or accumulation of Aβ in the brain is a primary cause of AD and attenuation of Aβ generation and/or enhancement of its clearance has become a topic of extreme interest in amyloid pathogenesis and AD related disorders. DS is almost always caused by the presence of three complete copies of chromosome 21 that lead to an overproduction of gene products encoded by this chromosome including APP. Thus, DS patients display similar pathology to AD patients and could benefit from the ongoing efforts to develop pharmacological treatments for AD. The accumulation of Aβ in the blood vessels of the brain as a result of its impaired clearance can result in the development of CAA, which presents concomitantly with AD at a high frequency, highlighting a potentially important role for vascular Aβ in dementias, such as AD. Therefore, understanding the production and clearance of Aβ and how these underlying processes may be pathologically altered are crucial for future AD, DS, and CAA therapeutic strategies.

The objective of this Special issue is to present and discuss Aβ pathogenesis in neurological diseases from various perspectives, which is essential to advance our understanding to improve and accelerate the development of novel treatments.

Several of the leading researchers in the area of Aβ and neurodegeneration have accepted to contribute to this Special Issue of IJMS in order to provide an updated, state-of-the-art view on these topics, as well as to indicate novel research avenues.

Dr. Amal Kaddoumi
Dr. Loqman Mohamed
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 papers will be 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

  • Aging
  • Alzheimer’s disease
  • Amyloid-β
  • Amyloid-β production
  • Amyloid-β clearance
  • Amyloid-β degradation
  • Amyloid pathogenesis
  • Amyloid precursor protein
  • Biomarkers
  • Blood–brain barrier
  • Cerebral amyloid angiopathy
  • Cerebrospinal fluid
  • Dementia
  • Diagnosis
  • Down Syndrome
  • Familial AD
  • Genetics
  • Imaging
  • Interventions
  • Neurodegeneration
  • Neuroinflammation
  • Sporadic AD
  • Therapeutics
  • Vascular Aβ

Published Papers (7 papers)

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Research

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Open AccessArticle
Assessing the Effects of Acute Amyloid β Oligomer Exposure in the Rat
Int. J. Mol. Sci. 2016, 17(9), 1390; https://doi.org/10.3390/ijms17091390
Received: 17 July 2016 / Revised: 16 August 2016 / Accepted: 18 August 2016 / Published: 24 August 2016
Cited by 4 | PDF Full-text (3610 KB) | HTML Full-text | XML Full-text
Abstract
Alzheimer’s disease (AD) is the most common form of dementia, yet there are no therapeutic treatments that can either cure or delay its onset. Currently, the pathogenesis of AD is still uncertain, especially with respect to how the disease develops from a normal [...] Read more.
Alzheimer’s disease (AD) is the most common form of dementia, yet there are no therapeutic treatments that can either cure or delay its onset. Currently, the pathogenesis of AD is still uncertain, especially with respect to how the disease develops from a normal healthy brain. Amyloid β oligomers (AβO) are highly neurotoxic proteins and are considered potential initiators to the pathogenesis of AD. Rat brains were exposed to AβO via bilateral intracerebroventricular injections. Rats were then euthanized at either 1, 3, 7 or 21-days post surgery. Rat behavioural testing was performed using the Morris water maze and open field tests. Post-mortem brain tissue was immunolabelled for Aβ, microglia, and cholinergic neurons. Rats exposed to AβO showed deficits in spatial learning and anxiety-like behaviour. Acute positive staining for Aβ was only observed in the corpus callosum surrounding the lateral ventricles. AβO exposed rat brains also showed a delayed increase in activated microglia within the corpus callosum and a decreased number of cholinergic neurons within the basal forebrain. Acute exposure to AβO resulted in mild learning and memory impairments with co-concomitant white matter pathology within the corpus callosum and cholinergic cell loss within the basal forebrain. Results suggest that acute exposure to AβO in the rat may be a useful tool in assessing the early phases for the pathogenesis of AD. Full article
(This article belongs to the Special Issue Amyloid-beta and Neurological Diseases)
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Open AccessArticle
Statin Therapy and the Development of Cerebral Amyloid Angiopathy—A Rodent in Vivo Approach
Int. J. Mol. Sci. 2016, 17(1), 126; https://doi.org/10.3390/ijms17010126
Received: 16 December 2015 / Revised: 4 January 2016 / Accepted: 12 January 2016 / Published: 19 January 2016
Cited by 1 | PDF Full-text (3116 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Background: Cerebral amyloid angiopathy (CAA) is characterized by vascular deposition of amyloid β (Aβ) with a higher incidence of cerebral microbleeds (cMBs) and spontaneous hemorrhage. Since statins are known for their benefit in vascular disease we tested for the effect on CAA. Methods: [...] Read more.
Background: Cerebral amyloid angiopathy (CAA) is characterized by vascular deposition of amyloid β (Aβ) with a higher incidence of cerebral microbleeds (cMBs) and spontaneous hemorrhage. Since statins are known for their benefit in vascular disease we tested for the effect on CAA. Methods: APP23-transgenic mice received atorvastatin-supplemented food starting at the age of eight months (n = 13), 12 months (n = 7), and 16 months (n = 6), respectively. Controls (n = 16) received standard food only. At 24 months of age cMBs were determined with T2*-weighted 9.4T magnetic resonance imaging and graded by size. Results: Control mice displayed an average of 35 ± 18.5 cMBs (mean ± standard deviation), compared to 29.3 ± 9.8 in mice with eight months (p = 0.49), 24.9 ± 21.3 with 12 months (p = 0.26), and 27.8 ± 15.4 with 16 months of atorvastatin treatment (p = 0.27). In combined analysis treated mice showed lower absolute numbers (27.4 ± 15.6, p = 0.16) compared to controls and also after adjustment for cMB size (p = 0.13). Conclusion: Despite to a non-significant trend towards fewer cMBs our results failed to provide evidence for beneficial effects of long-term atorvastatin treatment in the APP23-transgenic mouse model of CAA. A higher risk for bleeding complications was not observed. Full article
(This article belongs to the Special Issue Amyloid-beta and Neurological Diseases)
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Open AccessCommunication
New Insights to Clathrin and Adaptor Protein 2 for the Design and Development of Therapeutic Strategies
Int. J. Mol. Sci. 2015, 16(12), 29446-29453; https://doi.org/10.3390/ijms161226181
Received: 2 October 2015 / Revised: 18 November 2015 / Accepted: 30 November 2015 / Published: 10 December 2015
Cited by 13 | PDF Full-text (1559 KB) | HTML Full-text | XML Full-text
Abstract
The Amyloid Precursor Protein (APP) has been extensively studied for its role as the precursor of the β-amyloid protein (Aβ) in Alzheimer’s disease (AD). However, our understanding of the normal function of APP is still patchy. Emerging evidence indicates that a dysfunction in [...] Read more.
The Amyloid Precursor Protein (APP) has been extensively studied for its role as the precursor of the β-amyloid protein (Aβ) in Alzheimer’s disease (AD). However, our understanding of the normal function of APP is still patchy. Emerging evidence indicates that a dysfunction in APP trafficking and degradation can be responsible for neuronal deficits and progressive degeneration in humans. We recently reported that the Y682 mutation in the 682YENPTY687 domain of APP affects its binding to specific adaptor proteins and leads to its anomalous trafficking, to defects in the autophagy machinery and to neuronal degeneration. In order to identify adaptors that influence APP function, we performed pull-down experiments followed by quantitative mass spectrometry (MS) on hippocampal tissue extracts of three month-old mice incubated with either the 682YENPTY687 peptide, its mutated form, 682GENPTY687 or its phosphorylated form, 682pYENPTY687. Our experiments resulted in the identification of two proteins involved in APP internalization and trafficking: Clathrin heavy chain (hc) and its Adaptor Protein 2 (AP-2). Overall our results consolidate and refine the importance of Y682 in APP normal functions from an animal model of premature aging and dementia. Additionally, they open the perspective to consider Clathrin hc and AP-2 as potential targets for the design and development of new therapeutic strategies. Full article
(This article belongs to the Special Issue Amyloid-beta and Neurological Diseases)
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Open AccessArticle
Aβ1-25-Derived Sphingolipid-Domain Tracer Peptide SBD Interacts with Membrane Ganglioside Clusters via a Coil-Helix-Coil Motif
Int. J. Mol. Sci. 2015, 16(11), 26318-26332; https://doi.org/10.3390/ijms161125955
Received: 18 August 2015 / Revised: 19 October 2015 / Accepted: 22 October 2015 / Published: 3 November 2015
Cited by 2 | PDF Full-text (6520 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The Amyloid-β (Aβ)-derived, sphingolipid binding domain (SBD) peptide is a fluorescently tagged probe used to trace the diffusion behavior of sphingolipid-containing microdomains in cell membranes through binding to a constellation of glycosphingolipids, sphingomyelin, and cholesterol. However, the molecular details of the binding mechanism [...] Read more.
The Amyloid-β (Aβ)-derived, sphingolipid binding domain (SBD) peptide is a fluorescently tagged probe used to trace the diffusion behavior of sphingolipid-containing microdomains in cell membranes through binding to a constellation of glycosphingolipids, sphingomyelin, and cholesterol. However, the molecular details of the binding mechanism between SBD and plasma membrane domains remain unclear. Here, to investigate how the peptide recognizes the lipid surface at an atomically detailed level, SBD peptides in the environment of raft-like bilayers were examined in micro-seconds-long molecular dynamics simulations. We found that SBD adopted a coil-helix-coil structural motif, which binds to multiple GT1b gangliosides via salt bridges and CH–π interactions. Our simulation results demonstrate that the CH–π and electrostatic forces between SBD monomers and GT1b gangliosides clusters are the main driving forces in the binding process. The presence of the fluorescent dye and linker molecules do not change the binding mechanism of SBD probes with gangliosides, which involves the helix-turn-helix structural motif that was suggested to constitute a glycolipid binding domain common to some sphingolipid interacting proteins, including HIV gp120, prion, and Aβ. Full article
(This article belongs to the Special Issue Amyloid-beta and Neurological Diseases)
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Open AccessArticle
Folic Acid Inhibits Amyloid β-Peptide Production through Modulating DNA Methyltransferase Activity in N2a-APP Cells
Int. J. Mol. Sci. 2015, 16(10), 25002-25013; https://doi.org/10.3390/ijms161025002
Received: 29 August 2015 / Revised: 20 September 2015 / Accepted: 12 October 2015 / Published: 20 October 2015
Cited by 11 | PDF Full-text (1049 KB) | HTML Full-text | XML Full-text
Abstract
Alzheimer’s disease (AD) is a common neurodegenerative disease resulting in progressive dementia, and is a principal cause of dementia among older adults. Folate acts through one-carbon metabolism to support the methylation of multiple substrates. We hypothesized that folic acid supplementation modulates DNA methyltransferase [...] Read more.
Alzheimer’s disease (AD) is a common neurodegenerative disease resulting in progressive dementia, and is a principal cause of dementia among older adults. Folate acts through one-carbon metabolism to support the methylation of multiple substrates. We hypothesized that folic acid supplementation modulates DNA methyltransferase (DNMT) activity and may alter amyloid β-peptide (Aβ) production in AD. Mouse Neuro-2a cells expressing human APP695 were incubated with folic acid (2.8–40 μmol/L), and with or without zebularine (the DNMT inhibitor). DNMT activity, cell viability, Aβ and DNMTs expression were then examined. The results showed that folic acid stimulated DNMT gene and protein expression, and DNMT activity. Furthermore, folic acid decreased Aβ protein production, whereas inhibition of DNMT activity by zebularine increased Aβ production. The results indicate that folic acid induces methylation potential-dependent DNMT enzymes, thereby attenuating Aβ production. Full article
(This article belongs to the Special Issue Amyloid-beta and Neurological Diseases)
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Review

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Open AccessReview
Hypertension and Dementia: Epidemiological and Experimental Evidence Revealing a Detrimental Relationship
Int. J. Mol. Sci. 2016, 17(3), 347; https://doi.org/10.3390/ijms17030347
Received: 21 December 2015 / Revised: 20 February 2016 / Accepted: 29 February 2016 / Published: 8 March 2016
Cited by 17 | PDF Full-text (406 KB) | HTML Full-text | XML Full-text
Abstract
Hypertension and dementia represent two major public health challenges worldwide, notably in the elderly population. Although these two conditions have classically been recognized as two distinct diseases, mounting epidemiological, clinical and experimental evidence suggest that hypertension and dementia are strictly intertwined. Here, we [...] Read more.
Hypertension and dementia represent two major public health challenges worldwide, notably in the elderly population. Although these two conditions have classically been recognized as two distinct diseases, mounting epidemiological, clinical and experimental evidence suggest that hypertension and dementia are strictly intertwined. Here, we briefly report how hypertension profoundly affects brain homeostasis, both at the structural and functional level. Chronic high blood pressure modifies the cerebral vasculature, increasing the risk of Aβ clearance impairment. The latter, excluding genetic etiologies, is considered one of the main causes of Aβ deposition in the brain. Studies have shown that hypertension induces cerebral arterial stiffening and microvascular dysfunction, thus contributing to dementia pathophysiology. This review examines the existing and the updated literature which has attempted to explain and clarify the relationship between hypertension and dementia at the pathophysiological level. Full article
(This article belongs to the Special Issue Amyloid-beta and Neurological Diseases)
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Open AccessReview
Amyloid-β and Astrocytes Interplay in Amyloid-β Related Disorders
Int. J. Mol. Sci. 2016, 17(3), 338; https://doi.org/10.3390/ijms17030338
Received: 19 December 2015 / Revised: 14 February 2016 / Accepted: 24 February 2016 / Published: 4 March 2016
Cited by 25 | PDF Full-text (262 KB) | HTML Full-text | XML Full-text
Abstract
Amyloid-β (Aβ) pathology is known to promote chronic inflammatory responses in the brain. It was thought previously that Aβ is only associated with Alzheimer’s disease and Down syndrome. However, studies have shown its involvement in many other neurological disorders. The role of astrocytes [...] Read more.
Amyloid-β (Aβ) pathology is known to promote chronic inflammatory responses in the brain. It was thought previously that Aβ is only associated with Alzheimer’s disease and Down syndrome. However, studies have shown its involvement in many other neurological disorders. The role of astrocytes in handling the excess levels of Aβ has been highlighted in the literature. Astrocytes have a distinctive function in both neuronal support and protection, thus its involvement in Aβ pathological process may tip the balance toward chronic inflammation and neuronal death. In this review we describe the involvement of astrocytes in Aβ related disorders including Alzheimer’s disease, Down syndrome, cerebral amyloid angiopathy, and frontotemporal dementia. Full article
(This article belongs to the Special Issue Amyloid-beta and Neurological Diseases)
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Graphical abstract

Int. J. Mol. Sci. EISSN 1422-0067 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
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