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New Advances in Research on Alzheimer's Disease

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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 (30 June 2022) | Viewed by 38362

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Dr. Cristina Cereda

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IRCCS Mondino Foundation, Genomic and Post Genomic Unit, Pavia, Italy
Interests: molecular mechanisms of neurodegeneration; epigenetic and non-coding RNA; biomarker discovery (extracellular vesicles) and DNA damage responses
Special Issues, Collections and Topics in MDPI journals

Dr. Carlo Morasso

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Istituti Clinici Scientifici Maugeri IRCCS, 27100 Pavia, Italy
Interests: biomedical spectroscopy; clinical spectroscopy; Alzheimer’s disease; breast cancer; nanomedicine; raman spectroscopy
Special Issues, Collections and Topics in MDPI journals

Dr. Stella Gagliardi

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IRCCS Mondino Fondation Genomic and Post Genomic Unit, 27100 Pavia PV, Italy
Interests: coding and non coding RNA; gene expression; neurodegenerative diseases; genetic

Special Issue Information

Dear Colleagues,

Alzheimer's disease (AD) is considered to be the most common cause of dementia and is an incurable, progressive neurodegenerative disorder. To date, novel disease-modifying therapies have been shown to provide significant benefits to patients who suffer from this devastating disorder.

Moreover, preventive approaches of this pathology that are based on genetic predisposition, senolytic approaches, diet or intellectual activity are increasingly relevant.

The aim of this Special Issue is to provide (but is not limited to) an overview of the recent advances in the field of “Novel Therapy and Targets for Alzheimer’s Disease”. In addition, data about preventive approaches are welcomed.

We invite researchers to submit original papers and reviews about the discovery of new targets and novel therapies for Alzheimer’s disease. Papers about other types of dementia will also be accepted.

Dr. Cristina Cereda
Dr. Carlo Morasso
Dr. Stella Gagliardi
Guest Editors

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Keywords

Therapy
Prevention
New molecules
Alzheimer’s disease
Genetic
Nanoformulation
Targets
Dementia
Biomarkers discovery

Published Papers (13 papers)

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Research

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23 pages, 3752 KiB

Open AccessArticle

Bisdemethoxycurcumin (BDC)-Loaded H-Ferritin-Nanocages Mediate the Regulation of Inflammation in Alzheimer’s Disease Patients

by Stella Gagliardi, Marta Truffi, Veronica Tinelli, Maria Garofalo, Cecilia Pandini, Matteo Cotta Ramusino, Giulia Perini, Alfredo Costa, Sara Negri, Serena Mazzucchelli, Arianna Bonizzi, Leopoldo Sitia, Maria Busacca, Marta Sevieri, Michela Mocchi, Alessandra Ricciardi, Davide Prosperi, Fabio Corsi, Cristina Cereda and Carlo Morasso

Int. J. Mol. Sci. 2022, 23(16), 9237; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23169237 - 17 Aug 2022

Cited by 4 | Viewed by 2122

Abstract

Background: Bisdemethoxycurcumin (BDC) might be an inflammation inhibitor in Alzheimer’s Disease (AD). However, BDC is almost insoluble in water, poorly absorbed by the organism, and degrades rapidly. We thus developed a new nanoformulation of BDC based on H-Ferritin nanocages (BDC-HFn). Methods: We tested the BDC-HFn solubility, stability, and ability to cross a blood–brain barrier (BBB) model. We tested the effect of BDC-HFn on AD and control (CTR) PBMCs to evaluate the transcriptomic profile by RNA-seq. Results: We developed a nanoformulation with a diameter of 12 nm to improve the solubility and stability. The comparison of the transcriptomics analyses between AD patients before and after BDC-HFn treatment showed a major number of DEG (2517). The pathway analysis showed that chemokines and macrophages activation differed between AD patients and controls after BDC-HFn treatment. BDC-HFn binds endothelial cells from the cerebral cortex and crosses through a BBB in vitro model. Conclusions: Our data showed how BDC-Hfn could improve the stability of BDC. Significant differences in genes associated with inflammation between the same patients before and after BDC-Hfn treatment have been found. Inflammatory genes that are upregulated between AD and CTR after BDC-HFn treatment are converted and downregulated, suggesting a possible therapeutic approach. Full article

(This article belongs to the Special Issue New Advances in Research on Alzheimer's Disease)

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15 pages, 2459 KiB

Open AccessArticle

Increased Acetylcholine Levels and Other Brain Effects in 5XFAD Mice after Treatment with 8,14-Dihydroxy Metabolite of Efavirenz

by Natalia Mast, Yong Li and Irina A. Pikuleva

Int. J. Mol. Sci. 2022, 23(14), 7669; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23147669 - 11 Jul 2022

Cited by 2 | Viewed by 2006

Abstract

Efavirenz (EFV), an FDA-approved anti-HIV drug, has off-target binding to CYP46A1, the CNS enzyme which converts cholesterol to 24-hydroxycholesterol. At small doses, EFV allosterically activates CYP46A1 in mice and humans and mitigates some of the Alzheimer’s disease manifestations in 5XFAD mice, an animal model. Notably, in vitro, all phase 1 EFV hydroxymetabolites activate CYP46A1 as well and bind either to the allosteric site for EFV, neurotransmitters or both. Herein, we treated 5XFAD mice with 8,14-dihydroxyEFV, the binder to the neurotransmitter allosteric site, which elicits the highest CYP46A1 activation in vitro. We found that treated animals of both sexes had activation of CYP46A1 and cholesterol turnover in the brain, decreased content of the amyloid beta 42 peptide, increased levels of acetyl-CoA and acetylcholine, and altered expression of the brain marker proteins. In addition, male mice had improved performance in the Barnes Maze test and increased expression of the acetylcholine-related genes. This work expands our knowledge of the beneficial CYP46A1 activation effects and demonstrates that 8,14-dihydroxyEFV crosses the blood–brain barrier and has therapeutic potential as a CYP46A1 activator. Full article

(This article belongs to the Special Issue New Advances in Research on Alzheimer's Disease)

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15 pages, 4475 KiB

Open AccessArticle

Recombinant Integrin β1 Signal Peptide Blocks Gliosis Induced by Aβ Oligomers

by Carolina Ortiz-Sanz, Francisco Llavero, Jone Zuazo-Ibarra, Uxue Balantzategi, Tania Quintela-López, Ane Wyssenbach, Estibaliz Capetillo-Zarate, Carlos Matute, Elena Alberdi and José L. Zugaza

Int. J. Mol. Sci. 2022, 23(10), 5747; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23105747 - 20 May 2022

Cited by 1 | Viewed by 1757

Abstract

Glial cells participate actively in the early cognitive decline in Alzheimer’s disease (AD) pathology. In fact, recent studies have found molecular and functional abnormalities in astrocytes and microglia in both animal models and brains of patients suffering from this pathology. In this regard, reactive gliosis intimately associated with amyloid plaques has become a pathological hallmark of AD. A recent study from our laboratory reports that astrocyte reactivity is caused by a direct interaction between amyloid beta (Aβ) oligomers and integrin β1. Here, we have generated four recombinant peptides including the extracellular domain of integrin β1, and evaluated their capacity both to bind in vitro to Aβ oligomers and to prevent in vivo Aβ oligomer-induced gliosis and endoplasmic reticulum stress. We have identified the minimal region of integrin β1 that binds to Aβ oligomers. This region is called signal peptide and corresponds to the first 20 amino acids of the integrin β1 N-terminal domain. This recombinant integrin β1 signal peptide prevented Aβ oligomer-induced ROS generation in primary astrocyte cultures. Furthermore, we carried out intrahippocampal injection in adult mice of recombinant integrin β1 signal peptide combined with or without Aβ oligomers and we evaluated by immunohistochemistry both astrogliosis and microgliosis as well as endoplasmic reticulum stress. The results show that recombinant integrin β1 signal peptide precluded both astrogliosis and microgliosis and endoplasmic reticulum stress mediated by Aβ oligomers in vivo. We have developed a molecular tool that blocks the activation of the molecular cascade that mediates gliosis via Aβ oligomer/integrin β1 signaling. Full article

(This article belongs to the Special Issue New Advances in Research on Alzheimer's Disease)

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13 pages, 1018 KiB

Open AccessArticle

Increase in Mitochondrial D-Loop Region Methylation Levels in Mild Cognitive Impairment Individuals

by Andrea Stoccoro, Filippo Baldacci, Roberto Ceravolo, Linda Giampietri, Gloria Tognoni, Gabriele Siciliano, Lucia Migliore and Fabio Coppedè

Int. J. Mol. Sci. 2022, 23(10), 5393; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23105393 - 12 May 2022

Cited by 9 | Viewed by 1667

Abstract

Methylation levels of the mitochondrial displacement loop (D-loop) region have been reported to be altered in the brain and blood of Alzheimer’s disease (AD) patients. Moreover, a dynamic D-loop methylation pattern was observed in the brain of transgenic AD mice along with disease progression. However, investigations on the blood cells of AD patients in the prodromal phases of the disease have not been performed so far. The aim of this study was to analyze D-loop methylation levels by means of the MS-HRM technique in the peripheral blood cells of 14 mild cognitive impairment (MCI) patients, 18 early stage AD patients, 70 advanced stage AD patients, and 105 healthy control subjects. We found higher D-loop methylation levels in MCI patients than in control subjects and AD patients. Moreover, higher D-loop methylation levels were observed in control subjects than in AD patients in advanced stages of the disease, but not in those at early stages. The present pilot study shows that peripheral D-loop methylation levels differ in patients at different stages of AD pathology, suggesting that further studies deserve to be performed in order to validate the usefulness of D-loop methylation analysis as a peripheral biomarker for the early detection of AD. Full article

(This article belongs to the Special Issue New Advances in Research on Alzheimer's Disease)

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19 pages, 2908 KiB

Open AccessArticle

Consecutive Aromatic Residues Are Required for Improved Efficacy of β-Sheet Breakers

by Adam Jarmuła, Monika Zubalska and Dariusz Stępkowski

Int. J. Mol. Sci. 2022, 23(9), 5247; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23095247 - 08 May 2022

Cited by 2 | Viewed by 1742

Abstract

Alzheimer’s disease is a fatal neurodegenerative malady which up to very recently did not have approved therapy modifying its course. After controversial approval of aducanumab (monoclonal antibody clearing β-amyloid plaques) by FDA for use in very early stages of disease, possibly new avenue opened for the treatment of patients. In line with this approach is search for compounds blocking aggregation into amyloid oligomers subsequently forming fibrils or compounds helping in getting rid of plaques formed by β-amyloid fibrils. Here we present in silico work on 627 sixtapeptide β-sheet breakers (BSBs) containing consecutive three aromatic residues. Three of these BSBs caused dissociation of one or two β-amyloid chains from U-shaped β-amyloid protofibril model 2BEG after docking and subsequent molecular dynamics simulations. Thorough analysis of our results let us postulate that the first steps of binding these successful BSBs involve π–π interactions with stacked chains of F19 and later also with F20 (F3 and F4 in 2BEG model of protofibril). The consecutive location of aromatic residues in BSBs makes them more attractive for chains of stacked F3 and F4 within the 2BEG model. Spotted by us, BSBs may be prospective lead compounds for an anti-Alzheimer’s therapy. Full article

(This article belongs to the Special Issue New Advances in Research on Alzheimer's Disease)

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15 pages, 3065 KiB

Open AccessArticle

Reduced Levels of ABCA1 Transporter Are Responsible for the Cholesterol Efflux Impairment in β-Amyloid-Induced Reactive Astrocytes: Potential Rescue from Biomimetic HDLs

by Giulia Sierri, Roberta Dal Magro, Barbara Vergani, Biagio Eugenio Leone, Beatrice Formicola, Lorenzo Taiarol, Stefano Fagioli, Marcelo Kravicz, Lucio Tremolizzo, Laura Calabresi and Francesca Re

Int. J. Mol. Sci. 2022, 23(1), 102; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23010102 - 22 Dec 2021

Cited by 9 | Viewed by 2615

Abstract

The cerebral synthesis of cholesterol is mainly handled by astrocytes, which are also responsible for apoproteins’ synthesis and lipoproteins’ assembly required for the cholesterol transport in the brain parenchyma. In Alzheimer disease (AD), these processes are impaired, likely because of the astrogliosis, a process characterized by morphological and functional changes in astrocytes. Several ATP-binding cassette transporters expressed by brain cells are involved in the formation of nascent discoidal lipoproteins, but the effect of beta-amyloid (Aβ) assemblies on this process is not fully understood. In this study, we investigated how of Aβ_1-42-induced astrogliosis affects the metabolism of cholesterol in vitro. We detected an impairment in the cholesterol efflux of reactive astrocytes attributable to reduced levels of ABCA1 transporters that could explain the decreased lipoproteins’ levels detected in AD patients. To approach this issue, we designed biomimetic HDLs and evaluated their performance as cholesterol acceptors. The results demonstrated the ability of apoA-I nanodiscs to cross the blood–brain barrier in vitro and to promote the cholesterol efflux from astrocytes, making them suitable as a potential supportive treatment for AD to compensate the depletion of cerebral HDLs. Full article

(This article belongs to the Special Issue New Advances in Research on Alzheimer's Disease)

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17 pages, 9975 KiB

Open AccessArticle

Targeting MicroRNA-485-3p Blocks Alzheimer’s Disease Progression

by Han Seok Koh, SangJoon Lee, Hyo Jin Lee, Jae-Woong Min, Takeshi Iwatsubo, Charlotte E. Teunissen, Hyun-Jeong Cho and Jin-Hyeob Ryu

Int. J. Mol. Sci. 2021, 22(23), 13136; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222313136 - 04 Dec 2021

Cited by 20 | Viewed by 5676 | Correction

Abstract

Alzheimer’s disease (AD) is a form of dementia characterized by progressive memory decline and cognitive dysfunction. With only one FDA-approved therapy, effective treatment strategies for AD are urgently needed. In this study, we found that microRNA-485-3p (miR-485-3p) was overexpressed in the brain tissues, cerebrospinal fluid, and plasma of patients with AD, and its antisense oligonucleotide (ASO) reduced Aβ plaque accumulation, tau pathology development, neuroinflammation, and cognitive decline in a transgenic mouse model of AD. Mechanistically, miR-485-3p ASO enhanced Aβ clearance via CD36-mediated phagocytosis of Aβ in vitro and in vivo. Furthermore, miR-485-3p ASO administration reduced apoptosis, thereby effectively decreasing truncated tau levels. Moreover, miR-485-3p ASO treatment reduced secretion of proinflammatory cytokines, including IL-1β and TNF-α, and eventually relieved cognitive impairment. Collectively, our findings suggest that miR-485-3p is a useful biomarker of the inflammatory pathophysiology of AD and that miR-485-3p ASO represents a potential therapeutic candidate for managing AD pathology and cognitive decline. Full article

(This article belongs to the Special Issue New Advances in Research on Alzheimer's Disease)

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15 pages, 25039 KiB

Open AccessArticle

Gene Therapy Strategy for Alzheimer’s and Parkinson’s Diseases Aimed at Preventing the Formation of Neurotoxic Oligomers in SH-SY5Y Cells

by Assou El-Battari, Léa Rodriguez, Henri Chahinian, Olivier Delézay, Jacques Fantini, Nouara Yahi and Coralie Di Scala

Int. J. Mol. Sci. 2021, 22(21), 11550; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222111550 - 26 Oct 2021

Cited by 10 | Viewed by 2879

Abstract

We present here a gene therapy approach aimed at preventing the formation of Ca²⁺-permeable amyloid pore oligomers that are considered as the most neurotoxic structures in both Alzheimer’s and Parkinson’s diseases. Our study is based on the design of a small peptide inhibitor (AmyP53) that combines the ganglioside recognition properties of the β-amyloid peptide (Aβ, Alzheimer) and α-synuclein (α-syn, Parkinson). As gangliosides mediate the initial binding step of these amyloid proteins to lipid rafts of the brain cell membranes, AmyP53 blocks, at the earliest step, the Ca²⁺ cascade that leads to neurodegeneration. Using a lentivirus vector, we genetically modified brain cells to express the therapeutic coding sequence of AmyP53 in a secreted form, rendering these cells totally resistant to oligomer formation by either Aβ or α-syn. This protection was specific, as control mCherry-transfected cells remained fully sensitive to these oligomers. AmyP53 was secreted at therapeutic concentrations in the supernatant of cultured cells, so that the therapy was effective for both transfected cells and their neighbors. This study is the first to demonstrate that a unique gene therapy approach aimed at preventing the formation of neurotoxic oligomers by targeting brain gangliosides may be considered for the treatment of two major neurodegenerative disorders, Alzheimer’s and Parkinson’s diseases. Full article

(This article belongs to the Special Issue New Advances in Research on Alzheimer's Disease)

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Review

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10 pages, 1037 KiB

Open AccessReview

Biomarkers for Alzheimer’s Disease in the Current State: A Narrative Review

by Serafettin Gunes, Yumi Aizawa, Takuma Sugashi, Masahiro Sugimoto and Pedro Pereira Rodrigues

Int. J. Mol. Sci. 2022, 23(9), 4962; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23094962 - 29 Apr 2022

Cited by 19 | Viewed by 3912

Abstract

Alzheimer’s disease (AD) has become a problem, owing to its high prevalence in an aging society with no treatment available after onset. However, early diagnosis is essential for preventive intervention to delay disease onset due to its slow progression. The current AD diagnostic methods are typically invasive and expensive, limiting their potential for widespread use. Thus, the development of biomarkers in available biofluids, such as blood, urine, and saliva, which enables low or non-invasive, reasonable, and objective evaluation of AD status, is an urgent task. Here, we reviewed studies that examined biomarker candidates for the early detection of AD. Some of the candidates showed potential biomarkers, but further validation studies are needed. We also reviewed studies for non-invasive biomarkers of AD. Given the complexity of the AD continuum, multiple biomarkers with machine-learning-classification methods have been recently used to enhance diagnostic accuracy and characterize individual AD phenotypes. Artificial intelligence and new body fluid-based biomarkers, in combination with other risk factors, will provide a novel solution that may revolutionize the early diagnosis of AD. Full article

(This article belongs to the Special Issue New Advances in Research on Alzheimer's Disease)

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21 pages, 405 KiB

Open AccessReview

Circular RNAs: Emblematic Players of Neurogenesis and Neurodegeneration

by Marianna D’Anca, Francesca R. Buccellato, Chiara Fenoglio and Daniela Galimberti

Int. J. Mol. Sci. 2022, 23(8), 4134; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23084134 - 08 Apr 2022

Cited by 17 | Viewed by 2625

Abstract

In the fascinating landscape of non-coding RNAs (ncRNAs), circular RNAs (circRNAs) are peeping out as a new promising and appreciated class of molecules with great potential as diagnostic and prognostic biomarkers. They come from circularization of single-stranded RNA molecules covalently closed and generated through alternative mRNA splicing. Dismissed for many years, similar to aberrant splicing by-products, nowadays, their role has been regained. They are able to regulate the expression of linear mRNA transcripts at different levels acting as miRNA sponges, interacting with ribonucleoproteins or exerting a control on gene expression. On the other hand, being extremely conserved across phyla and stable, cell and tissue specific, mostly abundant than the linear RNAs, it is not surprising that they should have critical biological functions. Curiously, circRNAs are particularly expressed in brain and they build up during aging and age-related diseases. These extraordinary peculiarities make circRNAs potentially suitable as promising molecular biomarkers, especially of aging and neurodegenerative diseases. This review aims to explore new evidence on circRNAs, emphasizing their role in aging and pathogenesis of major neurodegenerative disorders, Alzheimer’s disease, frontotemporal dementia, and Parkinson’s diseases with a look toward their potential usefulness in biomarker searching. Full article

(This article belongs to the Special Issue New Advances in Research on Alzheimer's Disease)

24 pages, 1663 KiB

Open AccessReview

Magnetic Resonance Imaging in Animal Models of Alzheimer’s Disease Amyloidosis

by Ruiqing Ni

Int. J. Mol. Sci. 2021, 22(23), 12768; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222312768 - 25 Nov 2021

Cited by 18 | Viewed by 5462

Abstract

Amyloid-beta (Aβ) plays an important role in the pathogenesis of Alzheimer’s disease. Aberrant Aβ accumulation induces neuroinflammation, cerebrovascular alterations, and synaptic deficits, leading to cognitive impairment. Animal models recapitulating the Aβ pathology, such as transgenic, knock-in mouse and rat models, have facilitated the understanding of disease mechanisms and the development of therapeutics targeting Aβ. There is a rapid advance in high-field MRI in small animals. Versatile high-field magnetic resonance imaging (MRI) sequences, such as diffusion tensor imaging, arterial spin labeling, resting-state functional MRI, anatomical MRI, and MR spectroscopy, as well as contrast agents, have been developed for preclinical imaging in animal models. These tools have enabled high-resolution in vivo structural, functional, and molecular readouts with a whole-brain field of view. MRI has been used to visualize non-invasively the Aβ deposits, synaptic deficits, regional brain atrophy, impairment in white matter integrity, functional connectivity, and cerebrovascular and glymphatic system in animal models of Alzheimer’s disease amyloidosis. Many of the readouts are translational toward clinical MRI applications in patients with Alzheimer’s disease. In this review, we summarize the recent advances in MRI for visualizing the pathophysiology in amyloidosis animal models. We discuss the outstanding challenges in brain imaging using MRI in small animals and propose future outlook in visualizing Aβ-related alterations in the brains of animal models. Full article

(This article belongs to the Special Issue New Advances in Research on Alzheimer's Disease)

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5 pages, 392 KiB

Open AccessOpinion

A New Bistable Switch Model of Alzheimer’s Disease Pathogenesis

by Bruno Burlando, Serena Losacco, Viviana Villa, Ernesto Fedele and Roberta Ricciarelli

Int. J. Mol. Sci. 2022, 23(13), 7061; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23137061 - 25 Jun 2022

Cited by 1 | Viewed by 1931

Abstract

We propose a model to explain the pathogenesis of Alzheimer’s disease (AD) based on the theory that any disease affecting a healthy organism originates from a bistable feedback loop that shifts the system from a physiological to a pathological condition. We focused on the known double inhibitory loop involving the cellular prion protein (PrPC) and the enzyme BACE1 that produces amyloid-beta (Aβ) peptides. BACE1 is inhibited by PrPC, but its inhibitory activity is lost when PrPC binds to Aβ oligomers (Aβo). Excessive Aβo formation would switch the loop to a pathogenic condition involving the Aβo-PrPC-mGluR5 complex, Fyn kinase activation, tau, and NMDAR phosphorylation, ultimately leading to neurodegeneration. Based on the emerging role of cyclic nucleotides in Aβ production, and thereby in synaptic plasticity and cognitive processes, cAMP and cGMP can be considered as modulatory factors capable of inducing the transition from a physiological steady state to a pathogenic one. This would imply that critical pharmacological targets for AD treatment lie within pathways that lead to an imbalance of cyclic nucleotides in neurons. If this hypothesis is confirmed, it will provide precise indications for the development of preventive or therapeutic treatments for the disease. Full article

(This article belongs to the Special Issue New Advances in Research on Alzheimer's Disease)

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1 pages, 158 KiB

Open AccessCorrection

Correction: Koh et al. Targeting MicroRNA-485-3p Blocks Alzheimer’s Disease Progression. Int. J. Mol. Sci. 2021, 22, 13136

by Han Seok Koh, SangJoon Lee, Hyo Jin Lee, Jae-Woong Min, Takeshi Iwatsubo, Charlotte E. Teunissen, Hyun-Jeong Cho and Jin-Hyeob Ryu

Int. J. Mol. Sci. 2022, 23(7), 3566; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23073566 - 25 Mar 2022

Cited by 1 | Viewed by 1482

Abstract

The authors wish to make the following corrections to this paper [...] Full article

(This article belongs to the Special Issue New Advances in Research on Alzheimer's Disease)

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