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Alzheimer’s Disease and Other Dementias-Novel Therapeutic Approaches-3rd Edition
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Alzheimer’s Disease and Other Dementias-Novel Therapeutic Approaches-3rd Edition

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 2023) | Viewed by 18289

Special Issue Editors

Prof. Dr. Hanna Rosenmann

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Guest Editor
Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah Hebrew University Medical Center, Jerusalem 9112001, Israel
Interests: Alzheimer's disease; tauopathy; neurodegeneration; animal models
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Dan Frenkel

E-Mail Website
Guest Editor
Department of Neurobiology, Faculty of Life Sciences, Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 6997801, Israel
Interests: neuroinflammation; astrocyte; microglia; Alzheimer’s disease; animal model
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Although Alzheimer's disease (AD) and other dementias are being intensively investigated, there is not yet a drug that efficiently interferes with disease pathogenesis. Most cases of AD are sporadic and less than 5%, among them carrying mutations that affect beta amyloid, are early‐onset familial AD that occur before the age of 65 years. Unfortunately, thus far, most of the newly developed drugs for AD treatment have failed in clinical trials. There is an urgent need for new therapies for treating dementias, particularly AD. Otherwise, this disease will continue to attack 5% of people aged over 65 and more than 40% of those aged over 85. Genetic risk factors, such as the presence of ApoE4 or mutations in inflammatory markers, such as TREM2, have been shown to affect disease development and progress. However, preventive approaches, such as maintaining good health (e.g., reducing cardiovascular and metabolic risk factors, enhancing physical and mental activities), seem to have a major impact on reducing disease incidence and delaying its onset. Many research approaches may be suitable for combating dementias, such as identifying disease-causing compounds (toxins), finding new targets, developing new drugs (mono/multi-target) by drug screening or by drug design, cell or organelle therapy, and device development, as well as other creative and innovative unconventional approaches.

This Special Issue will be dedicated to gathering novel therapeutic approaches to treat Alzheimer's disease and other dementias. We welcome submissions, including original papers and reviews, on these essential topics.

Prof. Dr. Hanna Rosenmann
Prof. Dr. Dan Frenkel
Guest Editors

Manuscript Submission Information

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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.

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Keywords

  • dementia
  • prevention of dementia
  • treatment of dementia
  • amyloid
  • tangles
  • tauopathies
  • mild cognitive impairment
  • neurodegenerative pathways
  • toxic elements inducing dementia
  • drug screening
  • drug design
  • cell or organelle therapy
  • device development
  • neurodegeneration
  • neuroinflammation

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Published Papers (7 papers)

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14 pages, 4319 KiB  
Article
Amyloid Precursor Protein and Tau Peptides Linked Together Ameliorate Loss of Cognition in an Alzheimer’s Disease Animal Model
by Ruth Maron, Yaron Vinik, Michael Tsoory, Meir Wilchek and Ruth Arnon
Int. J. Mol. Sci. 2023, 24(15), 12527; https://doi.org/10.3390/ijms241512527 - 7 Aug 2023
Viewed by 1258
Abstract
The major proteins involved in Alzheimer’s disease (AD) are amyloid precursor protein (APP) and Tau. We demonstrate that APP1 (390–412) and Tau1 (19–34), linked together with either a flexible or a rigid peptide bridge, are able to inhibit, in vitro, the interaction between [...] Read more.
The major proteins involved in Alzheimer’s disease (AD) are amyloid precursor protein (APP) and Tau. We demonstrate that APP1 (390–412) and Tau1 (19–34), linked together with either a flexible or a rigid peptide bridge, are able to inhibit, in vitro, the interaction between APP and Tau proteins. Furthermore, nasal administration of biotin-labelled Flex peptide for two weeks indicated the localization of the peptide around and close to plaques in the hippocampus area. In vivo studies in 5xFAD transgenic (Tg) mice, which exhibit plaque load and mild cognitive decline at four months of age, show that nasal administration of the flexible linked peptide reduced amyloid plaque burden. Additionally, nasal treatment with either flexible or rigid linked peptides prevented cognitive function deterioration. A significant treatment effect was achieved when either treatment was initiated at the age of three months, before severe cognitive deficiency is evident, or at five months, when such deficiency is already observed. The nasally treated mice demonstrated a cognitive ability not significantly different from the non-Tg littermate controls. Testing the effect of the flexible peptide by gavage feeding on the cognitive function of 5xFAD Tg mice demonstrated that feeding as well as nasal treatment significantly improves the cognitive ability of Tg mice compared to control PBS-treated mice. Full article
(This article belongs to the Special Issue Alzheimer’s Disease and Other Dementias-Novel Therapeutic Approaches-3rd Edition)
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18 pages, 3472 KiB  
Article
Novel Vaccine against Pathological Pyroglutamate-Modified Amyloid Beta for Prevention of Alzheimer’s Disease
by Karen Zagorski, Olga King, Armine Hovakimyan, Irina Petrushina, Tatevik Antonyan, Gor Chailyan, Manush Ghazaryan, Krzysztof L. Hyrc, Jean Paul Chadarevian, Hayk Davtyan, Mathew Blurton-Jones, David H. Cribbs, Michael G. Agadjanyan and Anahit Ghochikyan
Int. J. Mol. Sci. 2023, 24(12), 9797; https://doi.org/10.3390/ijms24129797 - 6 Jun 2023
Cited by 2 | Viewed by 2560
Abstract
Post-translationally modified N-terminally truncated amyloid beta peptide with a cyclized form of glutamate at position 3 (pE3Aβ) is a highly pathogenic molecule with increased neurotoxicity and propensity for aggregation. In the brains of Alzheimer’s Disease (AD) cases, pE3Aβ represents [...] Read more.
Post-translationally modified N-terminally truncated amyloid beta peptide with a cyclized form of glutamate at position 3 (pE3Aβ) is a highly pathogenic molecule with increased neurotoxicity and propensity for aggregation. In the brains of Alzheimer’s Disease (AD) cases, pE3Aβ represents a major constituent of the amyloid plaque. The data show that pE3Aβ formation is increased at early pre-symptomatic disease stages, while tau phosphorylation and aggregation mostly occur at later stages of the disease. This suggests that pE3Aβ accumulation may be an early event in the disease pathogenesis and can be prophylactically targeted to prevent the onset of AD. The vaccine (AV-1986R/A) was generated by chemically conjugating the pE3Aβ3-11 fragment to our universal immunogenic vaccine platform MultiTEP, then formulated in AdvaxCpG adjuvant. AV-1986R/A showed high immunogenicity and selectivity, with endpoint titers in the range of 105–106 against pE3Aβ and 103–104 against the full-sized peptide in the 5XFAD AD mouse model. The vaccination showed efficient clearance of the pathology, including non-pyroglutamate-modified plaques, from the mice brains. AV-1986R/A is a novel promising candidate for the immunoprevention of AD. It is the first late preclinical candidate which selectively targets a pathology-specific form of amyloid with minimal immunoreactivity against the full-size peptide. Successful translation into clinic may offer a new avenue for the prevention of AD via vaccination of cognitively unimpaired individuals at risk of disease. Full article
(This article belongs to the Special Issue Alzheimer’s Disease and Other Dementias-Novel Therapeutic Approaches-3rd Edition)
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15 pages, 1626 KiB  
Article
A Combination of Caffeine Supplementation and Enriched Environment in an Alzheimer’s Disease Mouse Model
by Martina Stazi, Silvia Zampar, Hans-Wolfgang Klafki, Thomas Meyer and Oliver Wirths
Int. J. Mol. Sci. 2023, 24(3), 2155; https://doi.org/10.3390/ijms24032155 - 21 Jan 2023
Cited by 5 | Viewed by 2564
Abstract
A variety of factors has been associated with healthy brain aging, and epidemiological studies suggest that physical activity and nutritional supplements such as caffeine may reduce the risk of developing dementia and, in particular, Alzheimer’s disease (AD) in later life. Caffeine is known [...] Read more.
A variety of factors has been associated with healthy brain aging, and epidemiological studies suggest that physical activity and nutritional supplements such as caffeine may reduce the risk of developing dementia and, in particular, Alzheimer’s disease (AD) in later life. Caffeine is known to act as a cognitive enhancer but has been also shown to positively affect exercise performance in endurance activities. We have previously observed that chronic oral caffeine supplementation and a treatment paradigm encompassing physical and cognitive stimulation by enriched environment (EE) housing can improve learning and memory performance and ameliorate hippocampal neuron loss in the Tg4-42 mouse model of AD. Here, we investigated whether these effects were synergistic. To that end, previous findings on individual treatments were complemented with unpublished, additional data and analyzed in depth by ANOVA followed by Bonferroni multiple comparison post tests. We further evaluated whether plasma neurofilament light chain levels reflect neuropathological and behavioral changes observed in the experimental groups. While a treatment combining physical activity and caffeine supplementation significantly improved learning and memory function compared to standard-housed vehicle-treated Tg4-42 in tasks such as the Morris water maze, no major additive effect outperforming the effects of the single interventions was observed. Full article
(This article belongs to the Special Issue Alzheimer’s Disease and Other Dementias-Novel Therapeutic Approaches-3rd Edition)
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17 pages, 3915 KiB  
Article
dNAGLU Extends Life Span and Promotes Fitness and Stress Resistance in Drosophila
by Rubing Xue, Ke Yang, Fuhui Xiao, Liping Yang, Guijun Chen, Yongxuan Li, Yunshuang Ye, Kangning Chen, Sheryl T. Smith, Gonghua Li, Qingpeng Kong and Jumin Zhou
Int. J. Mol. Sci. 2022, 23(22), 14433; https://doi.org/10.3390/ijms232214433 - 20 Nov 2022
Cited by 2 | Viewed by 2431
Abstract
To identify new factors that promote longevity and healthy aging, we studied Drosophila CG13397, an ortholog of the human NAGLU gene, a lysosomal enzyme overexpressed in centenarians. We found that the overexpression of CG13397 (dNAGLU) ubiquitously, or tissue specifically, in [...] Read more.
To identify new factors that promote longevity and healthy aging, we studied Drosophila CG13397, an ortholog of the human NAGLU gene, a lysosomal enzyme overexpressed in centenarians. We found that the overexpression of CG13397 (dNAGLU) ubiquitously, or tissue specifically, in the nervous system or fat body could extend fly life span. It also extended the life span of flies overexpressing human Aβ42, in a Drosophila Alzheimer’s disease (AD) model. To investigate whether dNAGLU could influence health span, we analyzed the effect of its overexpression on AD flies and found that it improved the climbing ability and stress resistance, including desiccation and hunger, suggesting that dNAGLU improved fly health span. We found that the deposition of Aβ42 in the mushroom body, which is the fly central nervous system, was reduced, and the lysosomal activity in the intestine was increased in dNAGLU over-expressing flies. When NAGLU was overexpressed in human U251-APP cells, which expresses a mutant form of the Aβ-precursor protein (APP), APP-p.M671L, these cells exhibited stronger lysosomal activity and and enhanced expression of lysosomal pathway genes. The concentration of Aβ42 in the cell supernatant was reduced, and the growth arrest caused by APP expression was reversed, suggesting that NAGLU could play a wider role beyond its catalytic activity to enhance lysosomal activity. These results also suggest that NAGLU overexpression could be explored to promote healthy aging and to prevent the onset of neurodegenerative diseases, including AD. Full article
(This article belongs to the Special Issue Alzheimer’s Disease and Other Dementias-Novel Therapeutic Approaches-3rd Edition)
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20 pages, 4227 KiB  
Article
In Silico and In Vitro Studies of Benzothiazole-Isothioureas Derivatives as a Multitarget Compound for Alzheimer’s Disease
by Martha Cecilia Rosales Hernández, Leticia Guadalupe Fragoso Morales, José Correa Basurto, Marycruz Olvera Valdez, Efrén Venancio García Báez, Dania Guadalupe Román Vázquez, Ana Paola Anaya García and Alejandro Cruz
Int. J. Mol. Sci. 2022, 23(21), 12945; https://doi.org/10.3390/ijms232112945 - 26 Oct 2022
Cited by 5 | Viewed by 2451
Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder. Inhibiting acetylcholinesterase (AChE), amyloid beta (Aβ1-42) aggregation and avoiding the oxidative stress could prevent the progression of AD. Benzothiazole groups have shown neuroprotective activity whereas isothioureas groups act as AChE inhibitors and antioxidants. [...] Read more.
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder. Inhibiting acetylcholinesterase (AChE), amyloid beta (Aβ1-42) aggregation and avoiding the oxidative stress could prevent the progression of AD. Benzothiazole groups have shown neuroprotective activity whereas isothioureas groups act as AChE inhibitors and antioxidants. Therefore, 22 benzothiazole-isothiourea derivatives (3a–v) were evaluated by docking simulations as inhibitors of AChE and Aβ1-42 aggregation. In silico studies showed that 3f, 3r and 3t had a delta G (ΔG) value better than curcumin and galantamine on Aβ1-42 and AChE, respectively. The physicochemical and pharmacokinetics predictions showed that only 3t does not violate Lipinski’s rule of five, though it has moderated cytotoxicity activity. Then, 3f, 3r and 3t were synthetized and chemically characterized for their in vitro evaluation including their antioxidant activity and their cytotoxicity in PC12 cells. 3r was able to inhibit AChE, avoid Aβ1-42 aggregation and exhibit antioxidant activity; nevertheless, it showed cytotoxic against PC12 cells. Compound 3t showed the best anti-Aβ1-42 aggregation and inhibitory AChE activity and, despite that predictor, showed that it could be cytotoxic; in vitro with PC12 cell was negative. Therefore, 3t could be employed as a scaffold to develop new molecules with multitarget activity for AD and, due to physicochemical and pharmacokinetics predictions, it could be administered in vivo using liposomes due to is not able to cross the BBB. Full article
(This article belongs to the Special Issue Alzheimer’s Disease and Other Dementias-Novel Therapeutic Approaches-3rd Edition)
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18 pages, 3630 KiB  
Article
TRAIL-R Deficient Mice Are Protected from Neurotoxic Effects of Amyloid-β
by Giulia Di Benedetto, Chiara Burgaletto, Maria Francesca Serapide, Rosario Caltabiano, Antonio Munafò, Carlo Maria Bellanca, Rosaria Di Mauro, Renato Bernardini and Giuseppina Cantarella
Int. J. Mol. Sci. 2022, 23(19), 11625; https://doi.org/10.3390/ijms231911625 - 1 Oct 2022
Cited by 5 | Viewed by 2785
Abstract
TRAIL, a member of TNF superfamily, is a potent inducer of neuronal death. Neurotoxic effects of TRAIL appear mediated by its death receptor TRAIL-R2/DR5. To assess the role of TRAIL/TRAIL-R2 pathway in AD-related neurodegeneration, we studied the impact of the treatment with amyloid-β [...] Read more.
TRAIL, a member of TNF superfamily, is a potent inducer of neuronal death. Neurotoxic effects of TRAIL appear mediated by its death receptor TRAIL-R2/DR5. To assess the role of TRAIL/TRAIL-R2 pathway in AD-related neurodegeneration, we studied the impact of the treatment with amyloid-β (Aβ) upon cell viability and inflammation in TRAIL-R-deficient mice (TRAIL-R−/−). Here, we demonstrate that the lack of TRAIL-R2 protects from death cultured TRAIL-R−/− mouse embryonic hippocampal cells after treatment with either Aβ1-42 or TRAIL. Consistently, stereotaxic injection of Aβ1-42 resulted in blunted caspase activation, as well as in reduction of JNK phosphorylation and increased AKT phosphorylation in TRAIL-R−/− mice. Moreover, the lack of TRAIL-R2 was associated with blunted constitutive p53 expression in mice that have undergone Aβ1-42 treatment, as well as in decrease of phosphorylated forms of tau and GSK3β proteins. Likewise, TRAIL-R2 appears essential to both TRAIL and Aβ-mediated neurotoxicity and inflammation. Indeed, hippocampi of TRAIL-R−/− mice challenged with Aβ1-42, showed a slight expression of microglial (Iba-1) and astrocytic (GFAP) markers along with attenuated levels of IL-1β, TNF-α, NOS2 and COX2. In conclusion, the bulk of these results demonstrate that the constitutive lack of TRAIL-R2 is associated with a substantial reduction of noxious effects of Aβ1-42, providing further evidence on the prominent role played by TRAIL in course of Aβ-related neurodegeneration and confirming that the TRAIL system represents a potential target for innovative AD therapy. Full article
(This article belongs to the Special Issue Alzheimer’s Disease and Other Dementias-Novel Therapeutic Approaches-3rd Edition)
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13 pages, 1163 KiB  
Article
An Ultra-Low Dose of ∆9-Tetrahydrocannabinol Alleviates Alzheimer’s Disease-Related Cognitive Impairments and Modulates TrkB Receptor Expression in a 5XFAD Mouse Model
by Keren Nitzan, Leah Ellenbogen, Ziv Bentulila, Dekel David, Motty Franko, Emanuela P. Break, Michal Zoharetz, Alon Shamir, Yosef Sarne and Ravid Doron
Int. J. Mol. Sci. 2022, 23(16), 9449; https://doi.org/10.3390/ijms23169449 - 21 Aug 2022
Cited by 9 | Viewed by 3428
Abstract
Alzheimer’s disease (AD) is the most common form of dementia, but there is still no available treatment. Δ9-tetrahydrocannabinol (THC) is emerging as a promising therapeutic agent. Using THC in conventional high doses may have deleterious effects. Therefore, we propose to use an ultra-low [...] Read more.
Alzheimer’s disease (AD) is the most common form of dementia, but there is still no available treatment. Δ9-tetrahydrocannabinol (THC) is emerging as a promising therapeutic agent. Using THC in conventional high doses may have deleterious effects. Therefore, we propose to use an ultra-low dose of THC (ULD-THC). We previously published that a single injection of ULD-THC ameliorated cognitive functioning in several models of brain injuries as well as in naturally aging mice. Here, 5xFAD AD model mice received a single treatment of ULD-THC (0.002 mg/kg) after disease onset and were examined in two separate experiments for cognitive functions, neurotropic, and inflammatory factors in the hippocampus. We show that a single injection of ULD-THC alleviated cognitive impairments in 6- and 12-month-old 5xFAD mice. On the biochemical level, our results indicate an imbalance between the truncated TrkB receptor isoform and the full receptor, with AD mice showing a greater tendency to express the truncated receptor, and ULD-THC improved this imbalance. We also investigated the expression of three AD-related inflammatory markers and found an ameliorating effect of ULD-THC. The current research demonstrates for the first time the beneficial effects of a single ultra-low dose of THC in a mouse model of AD after disease onset. Full article
(This article belongs to the Special Issue Alzheimer’s Disease and Other Dementias-Novel Therapeutic Approaches-3rd Edition)
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