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Alzheimer's disease: From Molecular Basis to Therapy

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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 (15 June 2022) | Viewed by 36636

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Special Issue Editors

Dr. Greg T. Sutherland

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Guest Editor

Charles Perkins Centre and School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Camperdown, NSW 2050, Australia
Interests: neuropathology; brain transcriptomics; neurogenetics; Alzheimer’s disease; alcohol-related brain injury
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. James Duce

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Guest Editor

ALBORADA Drug Discovery Institute, University of Cambridge, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0AH, UK
Interests: Drug discovery; proteostasis; metal dyshomeostasis; pathological proteins; Alzheimer’s disease

Special Issue Information

Dear Colleagues,

Alzheimer’s disease (AD) manifests as a chronic deterioration in cognition, primarily in memory, resulting from neuronal loss in specific regions of the brain. Genetics and pathology suggest that beta-amyloid build-up is the key process in the disease, but efforts to pharmaceutically reduce beta-amyloid have not resulted in an expected slowing of cognitive decline. Assuming that amyloid reduction is insufficient for therapeutic relief, other targets are required, and this necessitates new knowledge on AD pathogenesis. In this respect, the increasingly complex multidimensional molecular (multi-omic) data being generated from clinical samples and AD models are both exciting and extremely challenging. The scope of this Special Issue is an exploration of the different approaches that research groups are using to narrow this knowledge gap around AD pathogenesis. Authors are invited to submit original research or review articles which address linking molecular studies to novel therapeutic avenues or preventive strategies for AD.

Dr. Greg Sutherland
Prof. Dr. James Duce
Guest Editors

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
risk factors
multi-omics
systems biology
machine learning
clinical samples
model systems
drug discovery
precision medicine and precision prevention

Published Papers (11 papers)

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Research

Jump to: Review

16 pages, 611 KiB

Open AccessArticle

Vascular Dysfunction Is Central to Alzheimer’s Disease Pathogenesis in APOE e4 Carriers

by Andrew N. McCorkindale, Hamish D. Mundell, Boris Guennewig and Greg T. Sutherland

Int. J. Mol. Sci. 2022, 23(13), 7106; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23137106 - 26 Jun 2022

Cited by 4 | Viewed by 2698

Abstract

Alzheimer’s disease (AD) is the most common form of dementia and the leading risk factor, after age, is possession of the apolipoprotein E epsilon 4 allele (APOE4). Approximately 50% of AD patients carry one or two copies of APOE4 but the mechanisms by which it confers risk are still unknown. APOE4 carriers are reported to demonstrate changes in brain structure, cognition, and neuropathology, but findings have been inconsistent across studies. In the present study, we used multi-modal data to characterise the effects of APOE4 on the brain, to investigate whether AD pathology manifests differently in APOE4 carriers, and to determine if AD pathomechanisms are different between carriers and non-carriers. Brain structural differences in APOE4 carriers were characterised by applying machine learning to over 2000 brain MRI measurements from 33,384 non-demented UK biobank study participants. APOE4 carriers showed brain changes consistent with vascular dysfunction, such as reduced white matter integrity in posterior brain regions. The relationship between APOE4 and AD pathology was explored among the 1260 individuals from the Religious Orders Study and Memory and Aging Project (ROSMAP). APOE4 status had a greater effect on amyloid than tau load, particularly amyloid in the posterior cortical regions. APOE status was also highly correlated with cerebral amyloid angiopathy (CAA). Bulk tissue brain transcriptomic data from ROSMAP and a similar dataset from the Mount Sinai Brain Bank showed that differentially expressed genes between the dementia and non-dementia groups were enriched for vascular-related processes (e.g., “angiogenesis”) in APOE4 carriers only. Immune-related transcripts were more strongly correlated with AD pathology in APOE4 carriers with some transcripts such as TREM2 and positively correlated with pathology severity in APOE4 carriers, but negatively in non-carriers. Overall, cumulative evidence from the largest neuroimaging, pathology, and transcriptomic studies available suggests that vascular dysfunction is key to the development of AD in APOE4 carriers. However, further studies are required to tease out non-APOE4-specific mechanisms. Full article

(This article belongs to the Special Issue Alzheimer's disease: From Molecular Basis to Therapy)

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13 pages, 2305 KiB

Open AccessArticle

MicroPET Imaging Assessment of Brain Tau and Amyloid Deposition in 6 × Tg Alzheimer’s Disease Model Mice

by ShinWoo Kang, Jinho Kim, Sang-Yoon Lee, Nobuyuki Okamura and Keun-A Chang

Int. J. Mol. Sci. 2022, 23(10), 5485; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23105485 - 14 May 2022

Cited by 2 | Viewed by 2156

Abstract

Alzheimer’s disease (AD) is characterized by the deposition of extracellular amyloid plaques and intracellular accumulation of neurofibrillary tangles (NFT). Amyloid beta (Aβ) and tau imaging are widely used for diagnosing and monitoring AD in clinical settings. We evaluated the pathology of a recently developed 6 × Tg − AD (6 × Tg) mouse model by crossbreeding 5 × FAD mice with mice expressing mutant (P301L) tau protein using micro-positron emission tomography (PET) image analysis. PET studies were performed in these 6 × Tg mice using [¹⁸F]Flutemetamol, which is an amyloid PET radiotracer; [¹⁸F]THK5351 and [¹⁸F]MK6240, which are tau PET radiotracers; moreover, [¹⁸F]DPA714, which is a translocator protein (TSPO) radiotracer, and comparisons were made with age-matched mice of their respective parental strains. We compared group differences in standardized uptake value ratio (SUVR), kinetic parameters, biodistribution, and histopathology. [¹⁸F]Flutemetamol images showed prominent cortical uptake and matched well with 6E10 staining images from 2-month-old 6 × Tg mice. [¹⁸F]Flutemetamol images showed a significant correlation with [¹⁸F]DPA714 in the cortex and hippocampus. [¹⁸F]THK5351 images revealed prominent hippocampal uptake and matched well with AT8 immunostaining images in 4-month-old 6 × Tg mice. Moreover, [¹⁸F]THK5351 images were confirmed using [¹⁸F]MK6240, which revealed significant correlations in the cortex and hippocampus. Uptake of [¹⁸F]THK5351 or [¹⁸F]MK6240 was highly correlated with [¹⁸F]Flutemetamol in 4-month-old 6 × Tg mice. In conclusion, PET imaging revealed significant age-related uptake of Aβ, tau, and TSPO in 6 × Tg mice, which was highly correlated with age-dependent pathology. Full article

(This article belongs to the Special Issue Alzheimer's disease: From Molecular Basis to Therapy)

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15 pages, 1474 KiB

Open AccessArticle

Overlap between Central and Peripheral Transcriptomes in Parkinson’s Disease but Not Alzheimer’s Disease

by Kosar Hooshmand, Glenda M. Halliday, Sandy S. Pineda, Greg T. Sutherland and Boris Guennewig

Int. J. Mol. Sci. 2022, 23(9), 5200; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23095200 - 06 May 2022

Cited by 5 | Viewed by 3301

Abstract

Most neurodegenerative disorders take decades to develop, and their early detection is challenged by confounding non-pathological ageing processes. Therefore, the discovery of genes and molecular pathways in both peripheral and brain tissues that are highly predictive of disease evolution is necessary. To find genes that influence Alzheimer’s disease (AD) and Parkinson’s disease (PD) pathogenesis, human RNA-Seq transcriptomic data from Brodmann Area 9 (BA9) of the dorsolateral prefrontal cortex (DLPFC), whole blood (WB), and peripheral blood mononuclear cells (PBMC) were analysed using a combination of differential gene expression and a random forest-based machine learning algorithm. The results suggest that there is little overlap between PD and AD, and the AD brain signature is unique mainly compared to blood-based samples. Moreover, the AD-BA9 was characterised by changes in ‘nervous system development’ with Myocyte-specific enhancer factor 2C (Mef2C), encoding a transcription factor that induces microglia activation, a prominent feature. The peripheral AD transcriptome was associated with alterations in ‘viral process’, and FYN, which has been previously shown to link amyloid-beta and tau, was the prominent feature. However, in the absence of any overlap with the central transcriptome, it is unclear whether peripheral FYN levels reflect AD severity or progression. In PD, central and peripheral signatures are characterised by anomalies in ‘exocytosis’ and specific genes related to the SNARE complex, including Vesicle-associated membrane protein 2 (VAMP2), Syntaxin 1A (STX1A), and p21-activated kinase 1 (PAK1). This is consistent with our current understanding of the physiological role of alpha-synuclein and how alpha-synuclein oligomers compromise vesicle docking and neurotransmission. Overall, the results describe distinct disease-specific pathomechanisms, both within the brain and peripherally, for the two most common neurodegenerative disorders. Full article

(This article belongs to the Special Issue Alzheimer's disease: From Molecular Basis to Therapy)

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22 pages, 3107 KiB

Open AccessArticle

PTPRD and DCC Are Novel BACE1 Substrates Differentially Expressed in Alzheimer’s Disease: A Data Mining and Bioinformatics Study

by Hannah A. Taylor, Katie J. Simmons, Eva M. Clavane, Christopher J. Trevelyan, Jane M. Brown, Lena Przemyłska, Nicole T. Watt, Laura C. Matthews and Paul J. Meakin

Int. J. Mol. Sci. 2022, 23(9), 4568; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23094568 - 20 Apr 2022

Cited by 3 | Viewed by 3256

Abstract

The β-site Amyloid precursor protein Cleaving Enzyme 1 (BACE1) is an extensively studied therapeutic target for Alzheimer’s disease (AD), owing to its role in the production of neurotoxic amyloid beta (Aβ) peptides. However, despite numerous BACE1 inhibitors entering clinical trials, none have successfully improved AD pathogenesis, despite effectively lowering Aβ concentrations. This can, in part, be attributed to an incomplete understanding of BACE1, including its physiological functions and substrate specificity. We propose that BACE1 has additional important physiological functions, mediated through substrates still to be identified. Thus, to address this, we computationally analysed a list of 533 BACE1 dependent proteins, identified from the literature, for potential BACE1 substrates, and compared them against proteins differentially expressed in AD. We identified 15 novel BACE1 substrates that were specifically altered in AD. To confirm our analysis, we validated Protein tyrosine phosphatase receptor type D (PTPRD) and Netrin receptor DCC (DCC) using Western blotting. These findings shed light on the BACE1 inhibitor failings and could enable the design of substrate-specific inhibitors to target alternative BACE1 substrates. Furthermore, it gives us a greater understanding of the roles of BACE1 and its dysfunction in AD. Full article

(This article belongs to the Special Issue Alzheimer's disease: From Molecular Basis to Therapy)

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22 pages, 44532 KiB

Open AccessArticle

Host Tau Genotype Specifically Designs and Regulates Tau Seeding and Spreading and Host Tau Transformation Following Intrahippocampal Injection of Identical Tau AD Inoculum

by Pol Andrés-Benito, Margarita Carmona, Mónica Jordán, Joaquín Fernández-Irigoyen, Enrique Santamaría, José Antoni del Rio and Isidro Ferrer

Int. J. Mol. Sci. 2022, 23(2), 718; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23020718 - 10 Jan 2022

Cited by 7 | Viewed by 1855

Abstract

Several studies have demonstrated the different characteristics of tau seeding and spreading following intracerebral inoculation in murine models of tau-enriched fractions of brain homogenates from AD and other tauopathies. The present study is centered on the importance of host tau in tau seeding and the molecular changes associated with the transformation of host tau into abnormal tau. The brains of three adult murine genotypes expressing different forms of tau—WT (murine 4Rtau), hTau (homozygous transgenic mice knock-out for murine tau protein and heterozygous expressing human forms of 3Rtau and 4Rtau proteins), and mtWT (homozygous transgenic mice knock-out for murine tau protein)—were analyzed following unilateral hippocampal inoculation of sarkosyl-insoluble tau fractions from the same AD and control cases. The present study reveals that (a) host tau is mandatory for tau seeding and spreading following tau inoculation from sarkosyl-insoluble fractions obtained from AD brains; (b) tau seeding does not occur following intracerebral inoculation of sarkosyl-insoluble fractions from controls; (c) tau seeding and spreading are characterized by variable genotype-dependent tau phosphorylation and tau nitration, MAP2 phosphorylation, and variable activation of kinases that co-localize with abnormal tau deposits; (d) transformation of host tau into abnormal tau is an active process associated with the activation of specific kinases; (e) tau seeding is accompanied by modifications in tau splicing, resulting in the expression of new 3Rtau and 4Rtau isoforms, thus indicating that inoculated tau seeds have the capacity to model exon 10 splicing of the host mapt or MAPT with a genotype-dependent pattern; (e) selective regional and cellular vulnerabilities, and different molecular compositions of the deposits, are dependent on the host tau of mice injected with identical AD tau inocula. Full article

(This article belongs to the Special Issue Alzheimer's disease: From Molecular Basis to Therapy)

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16 pages, 2499 KiB

Open AccessArticle

Primary Cilia Structure Is Prolonged in Enteric Neurons of 5xFAD Alzheimer’s Disease Model Mice

by Vu Thu Thuy Nguyen, Lena Brücker, Ann-Kathrin Volz, Julia C. Baumgärtner, Malena dos Santos Guilherme, Francesco Valeri, Helen May-Simera and Kristina Endres

Int. J. Mol. Sci. 2021, 22(24), 13564; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222413564 - 17 Dec 2021

Cited by 6 | Viewed by 2898

Abstract

Neurodegenerative diseases such as Alzheimer’s disease (AD) have long been acknowledged as mere disorders of the central nervous system (CNS). However, in recent years the gut with its autonomous nervous system and the multitude of microbial commensals has come into focus. Changes in gut properties have been described in patients and animal disease models such as altered enzyme secretion or architecture of the enteric nervous system. The underlying cellular mechanisms have so far only been poorly investigated. An important organelle for integrating potentially toxic signals such as the AD characteristic A-beta peptide is the primary cilium. This microtubule-based signaling organelle regulates numerous cellular processes. Even though the role of primary cilia in a variety of developmental and disease processes has recently been recognized, the contribution of defective ciliary signaling to neurodegenerative diseases such as AD, however, has not been investigated in detail so far. The AD mouse model 5xFAD was used to analyze possible changes in gut functionality by organ bath measurement of peristalsis movement. Subsequently, we cultured primary enteric neurons from mutant mice and wild type littermate controls and assessed for cellular pathomechanisms. Neurite mass was quantified within transwell culturing experiments. Using a combination of different markers for the primary cilium, cilia number and length were determined using fluorescence microscopy. 5xFAD mice showed altered gut anatomy, motility, and neurite mass of enteric neurons. Moreover, primary cilia could be demonstrated on the surface of enteric neurons and exhibited an elongated phenotype in 5xFAD mice. In parallel, we observed reduced β-Catenin expression, a key signaling molecule that regulates Wnt signaling, which is regulated in part via ciliary associated mechanisms. Both results could be recapitulated via in vitro treatments of enteric neurons from wild type mice with A-beta. So far, only a few reports on the probable role of primary cilia in AD can be found. Here, we reveal for the first time an architectural altered phenotype of primary cilia in the enteric nervous system of AD model mice, elicited potentially by neurotoxic A-beta. Potential changes on the sub-organelle level—also in CNS-derived neurons—require further investigations. Full article

(This article belongs to the Special Issue Alzheimer's disease: From Molecular Basis to Therapy)

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15 pages, 4251 KiB

Open AccessArticle

Serum Corticosterone and Insulin Resistance as Early Biomarkers in the hAPP23 Overexpressing Mouse Model of Alzheimer’s Disease

by Jhana O. Hendrickx, Sofie De Moudt, Elke Calus, Wim Martinet, Pieter-Jan D. F. Guns, Lynn Roth, Peter P. De Deyn, Debby Van Dam and Guido R. Y. De Meyer

Int. J. Mol. Sci. 2021, 22(13), 6656; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22136656 - 22 Jun 2021

Cited by 11 | Viewed by 2428

Abstract

Increasing epidemiological evidence highlights the association between systemic insulin resistance and Alzheimer’s disease (AD). As insulin resistance can be caused by high-stress hormone levels and since hypercortisolism appears to be an important risk factor of AD, we aimed to investigate the systemic insulin functionality and circulating stress hormone levels in a mutant humanized amyloid precursor protein (APP) overexpressing (hAPP23+/−) AD mouse model. Memory and spatial learning of male hAPP23+/− and C57BL/6 (wild type, WT) mice were assessed by a Morris Water Maze (MWM) test at the age of 4 and 12 months. The systemic metabolism was examined by intraperitoneal glucose and insulin tolerance tests (GTT, ITT). Insulin and corticosterone levels were determined in serum. In the hippocampus, parietal and occipital cortex of hAPP23+/− brains, amyloid-beta (Aβ) deposits were present at 12 months of age. MWM demonstrated a cognitive decline in hAPP23+/− mice at 12 but not at 4 months, evidenced by increasing total path lengths and deteriorating probe trials compared to WT mice. hAPP23+/− animals presented increased serum corticosterone levels compared to WT mice at both 4 and 12 months. hAPP23+/− mice exhibited peripheral insulin resistance compared to WT mice at 4 months, which stabilized at 12 months of age. Serum insulin levels were similar between genotypes at 4 months of age but were significantly higher in hAPP23+/− mice at 12 months of age. Peripheral glucose homeostasis remained unchanged. These results indicate that peripheral insulin resistance combined with elevated circulating stress hormone levels could be potential biomarkers of the pre-symptomatic phase of AD. Full article

(This article belongs to the Special Issue Alzheimer's disease: From Molecular Basis to Therapy)

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Review

Jump to: Research

30 pages, 1291 KiB

Open AccessReview

Ceramide/Sphingosine 1-Phosphate Axis as a Key Target for Diagnosis and Treatment in Alzheimer’s Disease and Other Neurodegenerative Diseases

by Antía Custodia, Daniel Romaus-Sanjurjo, Marta Aramburu-Núñez, Diego Álvarez-Rafael, Laura Vázquez-Vázquez, Javier Camino-Castiñeiras, Yago Leira, Juan Manuel Pías-Peleteiro, José Manuel Aldrey, Tomás Sobrino and Alberto Ouro

Int. J. Mol. Sci. 2022, 23(15), 8082; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23158082 - 22 Jul 2022

Cited by 8 | Viewed by 4141

Abstract

Alzheimer’s disease (AD) is considered the most prevalent neurodegenerative disease and the leading cause of dementia worldwide. Sphingolipids, such as ceramide or sphingosine 1-phosphate, are bioactive molecules implicated in structural and signaling functions. Metabolic dysfunction in the highly conserved pathways to produce sphingolipids may lead to or be a consequence of an underlying disease. Recent studies on transcriptomics and sphingolipidomics have observed alterations in sphingolipid metabolism of both enzymes and metabolites involved in their synthesis in several neurodegenerative diseases, including AD. In this review, we highlight the most relevant findings related to ceramide and neurodegeneration, with a special focus on AD. Full article

(This article belongs to the Special Issue Alzheimer's disease: From Molecular Basis to Therapy)

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21 pages, 1728 KiB

Open AccessReview

The Interplay between cGMP and Calcium Signaling in Alzheimer’s Disease

by Aileen Jehle and Olga Garaschuk

Int. J. Mol. Sci. 2022, 23(13), 7048; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23137048 - 24 Jun 2022

Cited by 9 | Viewed by 4680

Abstract

Cyclic guanosine monophosphate (cGMP) is a ubiquitous second messenger and a key molecule in many important signaling cascades in the body and brain, including phototransduction, olfaction, vasodilation, and functional hyperemia. Additionally, cGMP is involved in long-term potentiation (LTP), a cellular correlate of learning and memory, and recent studies have identified the cGMP-increasing drug Sildenafil as a potential risk modifier in Alzheimer’s disease (AD). AD development is accompanied by a net increase in the expression of nitric oxide (NO) synthases but a decreased activity of soluble guanylate cyclases, so the exact sign and extent of AD-mediated imbalance remain unclear. Moreover, human patients and mouse models of the disease present with entangled deregulation of both cGMP and Ca²⁺ signaling, e.g., causing changes in cGMP-mediated Ca²⁺ release from the intracellular stores as well as Ca²⁺-mediated cGMP production. Still, the mechanisms governing such interplay are poorly understood. Here, we review the recent data on mechanisms underlying the brain cGMP signaling and its interconnection with Ca²⁺ signaling. We also discuss the recent evidence stressing the importance of such interplay for normal brain function as well as in Alzheimer’s disease. Full article

(This article belongs to the Special Issue Alzheimer's disease: From Molecular Basis to Therapy)

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24 pages, 1232 KiB

Open AccessReview

A Review of the Current Mammalian Models of Alzheimer’s Disease and Challenges That Need to Be Overcome

by Natasha Elizabeth Mckean, Renee Robyn Handley and Russell Grant Snell

Int. J. Mol. Sci. 2021, 22(23), 13168; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222313168 - 06 Dec 2021

Cited by 28 | Viewed by 4477

Abstract

Alzheimer’s disease (AD) is one of the looming health crises of the near future. Increasing lifespans and better medical treatment for other conditions mean that the prevalence of this disease is expected to triple by 2050. The impact of AD includes both the large toll on individuals and their families as well as a large financial cost to society. So far, we have no way to prevent, slow, or cure the disease. Current medications can only alleviate some of the symptoms temporarily. Many animal models of AD have been created, with the first transgenic mouse model in 1995. Mouse models have been beset by challenges, and no mouse model fully captures the symptomatology of AD without multiple genetic mutations and/or transgenes, some of which have never been implicated in human AD. Over 25 years later, many mouse models have been given an AD-like disease and then ‘cured’ in the lab, only for the treatments to fail in clinical trials. This review argues that small animal models are insufficient for modelling complex disorders such as AD. In order to find effective treatments for AD, we need to create large animal models with brains and lifespan that are closer to humans, and underlying genetics that already predispose them to AD-like phenotypes. Full article

(This article belongs to the Special Issue Alzheimer's disease: From Molecular Basis to Therapy)

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14 pages, 693 KiB

Open AccessReview

miRNAs as Therapeutic Tools in Alzheimer’s Disease

by Chang Youn Lee, In Soo Ryu, Jin-Hyeob Ryu and Hyun-Jeong Cho

Int. J. Mol. Sci. 2021, 22(23), 13012; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222313012 - 01 Dec 2021

Cited by 20 | Viewed by 3121

Abstract

Alzheimer’s disease (AD), an age-dependent, progressive neurodegenerative disorder, is the most common type of dementia, accounting for 50–70% of all dementia cases. Due to the increasing incidence and corresponding socioeconomic burden of dementia, it has rapidly emerged as a challenge to public health worldwide. The characteristics of AD include the development of extracellular amyloid-beta plaques and intracellular neurofibrillary tangles, vascular changes, neuronal inflammation, and progressive brain atrophy. However, the complexity of the biology of AD has hindered progress in elucidating the underlying pathophysiological mechanisms of AD, and the development of effective treatments. MicroRNAs (miRNAs, which are endogenous, noncoding RNAs of approximately 22 nucleotides that function as posttranscriptional regulators of various genes) are attracting attention as powerful tools for studying the mechanisms of diseases, as they are involved in several biological processes and diseases, including AD. AD is a multifactorial disease, and several reports have suggested that miRNAs play an important role in the pathological processes of AD. In this review, the basic biology of miRNAs is described, and the function and physiology of miRNAs in the pathological processes of AD are highlighted. In addition, the limitations of current pharmaceutical therapies for the treatment of AD and the development of miRNA-based next-generation therapies are discussed. Full article

(This article belongs to the Special Issue Alzheimer's disease: From Molecular Basis to Therapy)

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