International Journal of Molecular Sciences

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18 pages, 58242 KiB

Open AccessArticle

Insoluble Vascular Amyloid Deposits Trigger Disruption of the Neurovascular Unit in Alzheimer’s Disease Brains

by Luis O. Soto-Rojas, B. Berenice Campa-Córdoba, Charles R. Harrington, Andrés Salas-Casas, Mario Hernandes-Alejandro, Ignacio Villanueva-Fierro, Marely Bravo-Muñoz, Linda Garcés-Ramírez, Fidel De La Cruz-López, Miguel Ángel Ontiveros-Torres, Goar Gevorkian, Mar Pacheco-Herrero and José Luna-Muñoz

Int. J. Mol. Sci. 2021, 22(7), 3654; https://doi.org/10.3390/ijms22073654 - 01 Apr 2021

Cited by 16 | Viewed by 3981

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease, characterized histopathologically by intra-neuronal tau-related lesions and by the accumulation of amyloid β-peptide (Aβ) in the brain parenchyma and around cerebral blood vessels. According to the vascular hypothesis of AD, an alteration in the neurovascular unit [...] Read more.

Alzheimer’s disease (AD) is a neurodegenerative disease, characterized histopathologically by intra-neuronal tau-related lesions and by the accumulation of amyloid β-peptide (Aβ) in the brain parenchyma and around cerebral blood vessels. According to the vascular hypothesis of AD, an alteration in the neurovascular unit (NVU) could lead to Aβ vascular accumulation and promote neuronal dysfunction, accelerating neurodegeneration and dementia. To date, the effects of insoluble vascular Aβ deposits on the NVU and the blood–brain barrier (BBB) are unknown. In this study, we analyze different Aβ species and their association with the cells that make up the NVU. We evaluated post-mortem AD brain tissue. Multiple immunofluorescence assays were performed against different species of Aβ and the main elements that constitute the NVU. Our results showed that there are insoluble vascular deposits of both full-length and truncated Aβ species. Besides, insoluble aggregates are associated with a decrease in the phenotype of the cellular components that constitute the NVU and with BBB disruption. This approach could help identify new therapeutic targets against key molecules and receptors in the NVU that can prevent the accumulation of vascular fibrillar Aβ in AD. Full article

(This article belongs to the Special Issue Alzheimer’s Disease and Other Dementias-Novel Therapeutic Approaches)

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17 pages, 24122 KiB

Open AccessArticle

Broad Kinase Inhibition Mitigates Early Neuronal Dysfunction in Tauopathy

by Shon A. Koren, Matthew J. Hamm, Ryan Cloyd, Sarah N. Fontaine, Emad Chishti, Chiara Lanzillotta, Jennifer Rodriguez-Rivera, Alexandria Ingram, Michelle Bell, Sara M. Galvis-Escobar, Nicholas Zulia, Fabio Di Domenico, Duc Duong, Nicholas T. Seyfried, David Powell, Moriel Vandsburger, Tal Frolinger, Anika M. S. Hartz, John Koren III, Jeffrey M. Axten, Nicholas J. Laping and Jose F. Abisambra Show full author list Hide full author list

Int. J. Mol. Sci. 2021, 22(3), 1186; https://doi.org/10.3390/ijms22031186 - 26 Jan 2021

Cited by 6 | Viewed by 2883

Abstract

Tauopathies are a group of more than twenty known disorders that involve progressive neurodegeneration, cognitive decline and pathological tau accumulation. Current therapeutic strategies provide only limited, late-stage symptomatic treatment. This is partly due to lack of understanding of the molecular mechanisms linking tau [...] Read more.

Tauopathies are a group of more than twenty known disorders that involve progressive neurodegeneration, cognitive decline and pathological tau accumulation. Current therapeutic strategies provide only limited, late-stage symptomatic treatment. This is partly due to lack of understanding of the molecular mechanisms linking tau and cellular dysfunction, especially during the early stages of disease progression. In this study, we treated early stage tau transgenic mice with a multi-target kinase inhibitor to identify novel substrates that contribute to cognitive impairment and exhibit therapeutic potential. Drug treatment significantly ameliorated brain atrophy and cognitive function as determined by behavioral testing and a sensitive imaging technique called manganese-enhanced magnetic resonance imaging (MEMRI) with quantitative R1 mapping. Surprisingly, these benefits occurred despite unchanged hyperphosphorylated tau levels. To elucidate the mechanism behind these improved cognitive outcomes, we performed quantitative proteomics to determine the altered protein network during this early stage in tauopathy and compare this model with the human Alzheimer’s disease (AD) proteome. We identified a cluster of preserved pathways shared with human tauopathy with striking potential for broad multi-target kinase intervention. We further report high confidence candidate proteins as novel therapeutically relevant targets for the treatment of tauopathy. Proteomics data are available via ProteomeXchange with identifier PXD023562. Full article

(This article belongs to the Special Issue Alzheimer’s Disease and Other Dementias-Novel Therapeutic Approaches)

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22 pages, 12431 KiB

Open AccessArticle

Both Amyloid-β Peptide and Tau Protein Are Affected by an Anti-Amyloid-β Antibody Fragment in Elderly 3xTg-AD Mice

by Alejandro R. Roda, Laia Montoliu-Gaya, Gabriel Serra-Mir and Sandra Villegas

Int. J. Mol. Sci. 2020, 21(18), 6630; https://doi.org/10.3390/ijms21186630 - 10 Sep 2020

Cited by 11 | Viewed by 4054

Abstract

Alzheimer’s disease (AD) is the most common dementia worldwide. According to the amyloid hypothesis, the early accumulation of the Aβ-peptide triggers tau phosphorylation, synaptic dysfunction, and eventually neuronal death leading to cognitive impairment, as well as behavioral and psychological symptoms of dementia. ScFv-h3D6 [...] Read more.

Alzheimer’s disease (AD) is the most common dementia worldwide. According to the amyloid hypothesis, the early accumulation of the Aβ-peptide triggers tau phosphorylation, synaptic dysfunction, and eventually neuronal death leading to cognitive impairment, as well as behavioral and psychological symptoms of dementia. ScFv-h3D6 is a single-chain variable fragment that has already shown its ability to diminish the amyloid burden in 5-month-old 3xTg-AD mice. However, tau pathology is not evident at this early stage of the disease in this mouse model. In this study, the effects of scFv-h3D6 on Aβ and tau pathologies have been assessed in 22-month-old 3xTg-AD mice. Briefly, 3xTg-AD female mice were treated for 2 weeks with scFv-h3D6 and compared with 3xTg-AD and non-transgenic (NTg) mice treated with PBS. The treatment with scFv-h3D6 was unequivocally effective in reducing the area of Aβ staining. Furthermore, a tendency for a reduction in tau levels was also observed after treatment that points to the interplay between Aβ and tau pathologies. The pro-inflammatory state observed in the 3xTg-AD mice did not progress after scFv-h3D6 treatment. In addition, the treatment did not alter the levels of apolipoprotein E or apolipoprotein J. Thus, a 2-week treatment with scFv-h3D6 was able to reduce AD-like pathology in elderly 3xTg-AD female mice. Full article

(This article belongs to the Special Issue Alzheimer’s Disease and Other Dementias-Novel Therapeutic Approaches)

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14 pages, 5165 KiB

Open AccessArticle

Inhibition of Colony-Stimulating Factor 1 Receptor by PLX3397 Prevents Amyloid Beta Pathology and Rescues Dopaminergic Signaling in Aging 5xFAD Mice

by Yeonghoon Son, Ye Ji Jeong, Na-Rae Shin, Se Jong Oh, Kyung Rok Nam, Hyung-Do Choi, Jae Yong Choi and Hae-June Lee

Int. J. Mol. Sci. 2020, 21(15), 5553; https://doi.org/10.3390/ijms21155553 - 03 Aug 2020

Cited by 27 | Viewed by 3892

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disease. In this study, to investigate the effect of microglial elimination on AD progression, we administered PLX3397, a selective colony-stimulating factor 1 receptor inhibitor, to the mouse model of AD (5xFAD mice). Amyloid-beta (Aβ) deposition and [...] Read more.

Alzheimer’s disease (AD) is a progressive neurodegenerative disease. In this study, to investigate the effect of microglial elimination on AD progression, we administered PLX3397, a selective colony-stimulating factor 1 receptor inhibitor, to the mouse model of AD (5xFAD mice). Amyloid-beta (Aβ) deposition and amyloid precursor protein (APP), carboxyl-terminal fragment β, ionized calcium-binding adaptor molecule 1, synaptophysin, and postsynaptic density (PSD)-95 levels were evaluated in the cortex and hippocampus. In addition, the receptor density changes in dopamine D2 receptor (D2R) and metabotropic glutamate receptor 5 were evaluated using positron emission tomography (PET). D2R, tyrosine hydroxylase (TH), and dopamine transporter (DAT) levels were analyzed in the brains of Tg (5xFAD) mice using immunohistochemistry. PLX3397 administration significantly decreased Aβ deposition following microglial depletion in the cortex and hippocampus of Tg mice. In the neuro-PET studies, the binding values for D2R in the Tg mice were lower than those in the wild type mice; however, after PLX3397 treatment, the binding dramatically increased. PLX3397 administration also reversed the changes in synaptophysin and PSD-95 expression in the brain. Furthermore, the D2R and TH expression in the brains of Tg mice was significantly lower than that in the wild type; however, after PLX3397 administration, the D2R and TH levels were significantly higher than those in untreated Tg mice. Thus, our findings show that administering PLX3397 to aged 5xFAD mice could prevent amyloid pathology, concomitant with the rescue of dopaminergic signaling, suggesting that targeting microglia may serve as a useful therapeutic option for neurodegenerative diseases, including AD. Full article

(This article belongs to the Special Issue Alzheimer’s Disease and Other Dementias-Novel Therapeutic Approaches)

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19 pages, 5510 KiB

Open AccessArticle

Neuroprotective and Anti-Inflammatory Effects of Low–Moderate Dose Ionizing Radiation in Models of Alzheimer’s Disease

by Sujin Kim, Yunkwon Nam, Chanyang Kim, Hyewon Lee, Seojin Hong, Hyeon Soo Kim, Soo Jung Shin, Yong Ho Park, Han Ngoc Mai, Sang-Muk Oh, Kyoung Soo Kim, Doo-Han Yoo, Weon Kuu Chung, Hyunju Chung and Minho Moon

Int. J. Mol. Sci. 2020, 21(10), 3678; https://doi.org/10.3390/ijms21103678 - 23 May 2020

Cited by 37 | Viewed by 5554

Abstract

Alzheimer’s disease (AD) is the most common cause of dementia. The neuropathological features of AD include amyloid-β (Aβ) deposition and hyperphosphorylated tau accumulation. Although several clinical trials have been conducted to identify a cure for AD, no effective drug or treatment has been [...] Read more.

Alzheimer’s disease (AD) is the most common cause of dementia. The neuropathological features of AD include amyloid-β (Aβ) deposition and hyperphosphorylated tau accumulation. Although several clinical trials have been conducted to identify a cure for AD, no effective drug or treatment has been identified thus far. Recently, the potential use of non-pharmacological interventions to prevent or treat AD has gained attention. Low-dose ionizing radiation (LDIR) is a non-pharmacological intervention which is currently being evaluated in clinical trials for AD patients. However, the mechanisms underlying the therapeutic effects of LDIR therapy have not yet been established. In this study, we examined the effect of LDIR on Aβ accumulation and Aβ-mediated pathology. To investigate the short-term effects of low–moderate dose ionizing radiation (LMDIR), a total of 9 Gy (1.8 Gy per fraction for five times) were radiated to 4-month-old 5XFAD mice, an Aβ-overexpressing transgenic mouse model of AD, and then sacrificed at 4 days after last exposure to LMDIR. Comparing sham-exposed and LMDIR-exposed 5XFAD mice indicated that short-term exposure to LMDIR did not affect Aβ accumulation in the brain, but significantly ameliorated synaptic degeneration, neuronal loss, and neuroinflammation in the hippocampal formation and cerebral cortex. In addition, a direct neuroprotective effect was confirmed in SH-SY5Y neuronal cells treated with Aβ_1–42 (2 μM) after single irradiation (1 Gy). In BV-2 microglial cells exposed to Aβ and/or LMDIR, LMDIR therapy significantly inhibited the production of pro-inflammatory molecules and activation of the nuclear factor-kappa B (NF-κB) pathway. These results indicate that LMDIR directly ameliorated neurodegeneration and neuroinflammation in vivo and in vitro. Collectively, our findings suggest that the therapeutic benefits of LMDIR in AD may be mediated by its neuroprotective and anti-inflammatory effects. Full article

(This article belongs to the Special Issue Alzheimer’s Disease and Other Dementias-Novel Therapeutic Approaches)

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16 pages, 3723 KiB

Open AccessArticle

Infusion of Plasma from Exercised Mice Ameliorates Cognitive Dysfunction by Increasing Hippocampal Neuroplasticity and Mitochondrial Functions in 3xTg-AD Mice

by Tae-Woon Kim, Sang-Seo Park, Joon-Young Park and Hye-Sang Park

Int. J. Mol. Sci. 2020, 21(9), 3291; https://doi.org/10.3390/ijms21093291 - 06 May 2020

Cited by 15 | Viewed by 4152

Abstract

Alzheimer’s disease is the most common neurodegenerative brain disease causing dementia. It is characterized by slow onset and gradual worsening of memory and other cognitive functions. Recently, parabiosis and infusion of plasma from young mice have been proposed to have positive effects in [...] Read more.

Alzheimer’s disease is the most common neurodegenerative brain disease causing dementia. It is characterized by slow onset and gradual worsening of memory and other cognitive functions. Recently, parabiosis and infusion of plasma from young mice have been proposed to have positive effects in aging and Alzheimer’s disease. Therefore, this study examined whether infusion of plasma from exercised mice improved cognitive functions related to the hippocampus in a 3xTg-Alzheimer’s disease (AD) model. We collected plasma from young mice that had exercised for 3 months and injected 100 µL of plasma into the tail vein of 12-month-old 3xTg-AD mice 10 times at 3-day intervals. We then analyzed spatial learning and memory, long-term memory, hippocampal GSK3β/tau proteins, synaptic proteins, mitochondrial function, apoptosis, and neurogenesis. In the hippocampus of 3xTg-AD mice, infusion of plasma from exercised mice improved neuroplasticity and mitochondrial function and suppressed apoptosis, ultimately improving cognitive function. However, there was no improvement in tau hyperphosphorylation. This study showed that plasma from exercised mice could have a protective effect on cognitive dysfunction and neural circuits associated with AD via a tau-independent mechanism involving elevated brain-derived neurotrophic factor due to exercise. Full article

(This article belongs to the Special Issue Alzheimer’s Disease and Other Dementias-Novel Therapeutic Approaches)

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18 pages, 2775 KiB

Open AccessArticle

Peptide Interference with APP and Tau Association: Relevance to Alzheimer’s Disease Amelioration

by Ruth Maron, Gad Armony, Michael Tsoory, Meir Wilchek, Dan Frenkel and Ruth Arnon

Int. J. Mol. Sci. 2020, 21(9), 3270; https://doi.org/10.3390/ijms21093270 - 05 May 2020

Cited by 5 | Viewed by 3174

Abstract

The two major proteins involved in Alzheimer’s disease (AD) are the amyloid precursor protein (APP) and Tau. Here, we demonstrate that these two proteins can bind to each other. Four possible peptides APP1 (390–412), APP2 (713–730), Tau1 (19–34) and Tau2 (331–348), were predicted [...] Read more.

The two major proteins involved in Alzheimer’s disease (AD) are the amyloid precursor protein (APP) and Tau. Here, we demonstrate that these two proteins can bind to each other. Four possible peptides APP1 (390–412), APP2 (713–730), Tau1 (19–34) and Tau2 (331–348), were predicted to be involved in this interaction, with actual binding confirmed for APP1 and Tau1. In vivo studies were performed in an Alzheimer Disease animal model—APP double transgenic (Tg) 5xFAD—as well as in 5xFAD crossed with Tau transgenic 5xFADXTau (FT), which exhibit declined cognitive reduction at four months of age. Nasal administration of APP1 and Tau1 mixture, three times a week for four or five months, reduced amyloid plaque burden as well as the level of soluble Aβ 1–42 in the brain. The treatment prevented the deterioration of cognitive functions when initiated at the age of three months, before cognitive deficiency was evident, and also at the age of six months, when such deficiencies are already observed, leading to a full regain of cognitive function. Full article

(This article belongs to the Special Issue Alzheimer’s Disease and Other Dementias-Novel Therapeutic Approaches)

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15 pages, 2943 KiB

Open AccessArticle

Tetragonia tetragonioides Protected against Memory Dysfunction by Elevating Hippocampal Amyloid-β Deposition through Potentiating Insulin Signaling and Altering Gut Microbiome Composition

by Da Sol Kim, Byoung-Seob Ko, Jin Ah Ryuk and Sunmin Park

Int. J. Mol. Sci. 2020, 21(8), 2900; https://doi.org/10.3390/ijms21082900 - 21 Apr 2020

Cited by 18 | Viewed by 3010

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disease. Herbal medicine may provide efficacious treatments for its prevention and/or cure. This study investigated whether a 70% ethanol extract of Tetragonia tetragonioides Kuntze (TTK; New Zealand spinach) improved the memory deficit by reducing hippocampal amyloid-β [...] Read more.

Alzheimer’s disease (AD) is a progressive neurodegenerative disease. Herbal medicine may provide efficacious treatments for its prevention and/or cure. This study investigated whether a 70% ethanol extract of Tetragonia tetragonioides Kuntze (TTK; New Zealand spinach) improved the memory deficit by reducing hippocampal amyloid-β deposition and modulating the gut microbiota in rats with amyloid-β(25–35) infused into the hippocampus (AD rats) in an AD animal model. The AD rats had cellulose (AD-CON) or TTK (300 mg/kg bw; AD-TTK) in their high-fat diets for seven weeks. Rats with amyloid-β(35–25) infused into the hippocampus fed an AD-Con diet did not have memory loss (Normal-Con). AD-TTK protected against amyloid-β deposition compared to AD-Con, but it was higher than Normal-Con. AD-TTK protected against short-term and special memory loss measured by passive avoidance, Y maze, and water maze, compared to AD-Con. Compared to the Normal-Con, AD-Con attenuated hippocampal pCREB → pAkt → pGSK-3β, which was prevented in the AD-TTK group. Brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNTF) mRNA expression decreased in the AD-CON group, and their expression was prevented in the AD-TTK group. Hippocampal TNF-α and IL-1β mRNA expressions were higher in the AD-Con group than in the Normal-Con, and AD-TTK groups protected against the increase in their expression. The AD-CON group showed an increase in insulin resistance compared to the Normal-Con group and the AD-TTK group showed improvement. AD-Con separated the gut microbiome community compared to the Normal-Con group and AD-TTK overlapped with the normal-Con. The AD-Con group had more Clostridiales, Erysipelotrichales, and Desulfovibrionales than the AD-TKK and Normal-Con group but fewer Lactobacilales and Bacteroidales. In conclusion, the 70% ethanol extract of TTK enhanced the memory function and potentiated hippocampal insulin signaling, reduced insulin resistance, and improved gut microbiota in amyloid-β-infused rats. Full article

(This article belongs to the Special Issue Alzheimer’s Disease and Other Dementias-Novel Therapeutic Approaches)

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17 pages, 1505 KiB

Open AccessCommunication

Neuroprotective Properties of Resveratrol and Its Derivatives—Influence on Potential Mechanisms Leading to the Development of Alzheimer’s Disease

by Michał Wiciński, Anna Domanowska, Eryk Wódkiewicz and Bartosz Malinowski

Int. J. Mol. Sci. 2020, 21(8), 2749; https://doi.org/10.3390/ijms21082749 - 15 Apr 2020

Cited by 20 | Viewed by 3376

Abstract

The lack of effective Alzheimer’s disease treatment is becoming a challenge for researchers and prompts numerous attempts to search for and develop better therapeutic solutions. Compounds that affect several routes of the neurodegeneration cascade leading to the development of disease are of particular [...] Read more.

The lack of effective Alzheimer’s disease treatment is becoming a challenge for researchers and prompts numerous attempts to search for and develop better therapeutic solutions. Compounds that affect several routes of the neurodegeneration cascade leading to the development of disease are of particular interest. An example of such substances is resveratrol and its synthetic and natural derivatives, which have gained popularity in recent years and show promise as a possible new therapeutic option in the approach to Alzheimer’s disease treatment. In this article, the state of the art evidence on the role of resveratrol (RSV) in neuroprotection is presented; research results are summarized and the importance of resveratrol and its derivatives in the treatment of Alzheimer’s disease are underlined. It also focuses on various modifications of the resveratrol molecule that should be taken into account in the design of future research on drugs against Alzheimer’s disease. Full article

(This article belongs to the Special Issue Alzheimer’s Disease and Other Dementias-Novel Therapeutic Approaches)

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23 pages, 2172 KiB

Open AccessArticle

Central and Peripheral Mechanisms in ApoE4-Driven Diabetic Pathology

by Amit Koren-Iton, Shiran Salomon-Zimri, Alex Smolar, Efrat Shavit-Stein, Amir Dori, Joab Chapman and Daniel M. Michaelson

Int. J. Mol. Sci. 2020, 21(4), 1289; https://doi.org/10.3390/ijms21041289 - 14 Feb 2020

Cited by 16 | Viewed by 4548

Abstract

Apolipoprotein E (APOE) ε4 gene allele and type 2 diabetes mellitus (T2DM) are prime risk factors for Alzheimer’s disease (AD). Despite evidence linking T2DM and apoE4, the mechanism underlying their interaction is yet to be determined. In the present study, we [...] Read more.

Apolipoprotein E (APOE) ε4 gene allele and type 2 diabetes mellitus (T2DM) are prime risk factors for Alzheimer’s disease (AD). Despite evidence linking T2DM and apoE4, the mechanism underlying their interaction is yet to be determined. In the present study, we employed a model of APOE-targeted replacement mice and high-fat diet (HFD)-induced insulin resistance to investigate diabetic mechanisms associated with apoE4 pathology and the extent to which they are driven by peripheral and central processes. Results obtained revealed an intriguing pattern, in which under basal conditions, apoE4 mice display impaired glucose and insulin tolerance and decreased insulin secretion, as well as cognitive and sensorimotor characteristics relative to apoE3 mice, while the HFD impairs apoE3 mice without significantly affecting apoE4 mice. Measurements of weight and fasting blood glucose levels increased in a time-dependent manner following the HFD, though no effect of genotype was observed. Interestingly, sciatic electrophysiological and skin intra-epidermal nerve fiber density (IENFD) peripheral measurements were not affected by the APOE genotype or HFD, suggesting that the observed sensorimotor and cognitive phenotypes are related to central nervous system processes. Indeed, measurements of hippocampal insulin receptor and glycogen synthase kinase-3β (GSK-3β) activation revealed a pattern similar to that obtained in the behavioral measurements while Akt activation presented a dominant effect of diet. HFD manipulation induced genotype-independent hyperlipidation of apoE, and reduced levels of brain apoE in apoE3 mice, rendering them similar to apoE4 mice, whose brain apoE levels were not affected by the diet. No such effect was observed in the peripheral plasma levels of apoE, suggesting that the pathological effects of apoE4 under the control diet and apoE3 under HFD conditions are related to the decreased levels of brain apoE. Taken together, our data suggests that diabetic mechanisms play an important role in mediating the pathological effects of apoE4 and that consequently, diabetic-related therapy may be useful in treating apoE4 pathology in AD. Full article

(This article belongs to the Special Issue Alzheimer’s Disease and Other Dementias-Novel Therapeutic Approaches)

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18 pages, 3359 KiB

Open AccessArticle

Caspase-6 Knockout in the 5xFAD Model of Alzheimer’s Disease Reveals Favorable Outcome on Memory and Neurological Hallmarks

by Ariel Angel, Rotem Volkman, Tabitha Grace Royal and Daniel Offen

Int. J. Mol. Sci. 2020, 21(3), 1144; https://doi.org/10.3390/ijms21031144 - 09 Feb 2020

Cited by 19 | Viewed by 5536

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and is the most common form of dementia in the elderly. Caspases, a family of cysteine proteases, are major mediators of apoptosis and inflammation. Caspase-6 is considered to be an up-stream modulator of AD pathogenesis [...] Read more.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and is the most common form of dementia in the elderly. Caspases, a family of cysteine proteases, are major mediators of apoptosis and inflammation. Caspase-6 is considered to be an up-stream modulator of AD pathogenesis as active caspase-6 is abundant in neuropil threads, neuritic plaques, and neurofibrillary tangles of AD brains. In order to further elucidate the role of caspase-6 activity in the pathogenesis of AD, we produced a double transgenic mouse model, combining the 5xFAD mouse model of AD with caspase-6 knock out (C6-KO) mice. Behavioral examinations of 5xFAD/C6-KO double transgenic mice showed improved performance in spatial learning, memory, and anxiety/risk assessment behavior, as compared to 5xFAD mice. Hippocampal mRNA expression analyses showed significantly reduced levels of inflammatory mediator TNF-α, while the anti-inflammatory cytokine IL-10 was increased in 5xFAD/C6-KO mice. A significant reduction in amyloid-β plaques could be observed and immunohistochemistry analyses showed reduced levels of activated microglia and astrocytes in 5xFAD/C6-KO, compared to 5xFAD mice. Together, these results indicate a substantial role for caspase-6 in the pathology of the 5xFAD model of AD and suggest further validation of caspase-6 as a potential therapeutic target for AD. Full article

(This article belongs to the Special Issue Alzheimer’s Disease and Other Dementias-Novel Therapeutic Approaches)

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15 pages, 6835 KiB

Open AccessArticle

The Clustering of mApoE Anti-Amyloidogenic Peptide on Nanoparticle Surface Does Not Alter Its Performance in Controlling Beta-Amyloid Aggregation

by Roberta Corti, Alysia Cox, Valeria Cassina, Luca Nardo, Domenico Salerno, Claudia Adriana Marrano, Natalia Missana, Patrizia Andreozzi, Paulo Jacob Silva, Francesco Stellacci, Roberta Dal Magro, Francesca Re and Francesco Mantegazza

Int. J. Mol. Sci. 2020, 21(3), 1066; https://doi.org/10.3390/ijms21031066 - 05 Feb 2020

Cited by 8 | Viewed by 3527

Abstract

The deposition of amyloid-β (Aβ) plaques in the brain is a significant pathological signature of Alzheimer’s disease, correlating with synaptic dysfunction and neurodegeneration. Several compounds, peptides, or drugs have been designed to redirect or stop Aβ aggregation. Among them, the trideca-peptide CWG-LRKLRKRLLR (mApoE), [...] Read more.

The deposition of amyloid-β (Aβ) plaques in the brain is a significant pathological signature of Alzheimer’s disease, correlating with synaptic dysfunction and neurodegeneration. Several compounds, peptides, or drugs have been designed to redirect or stop Aβ aggregation. Among them, the trideca-peptide CWG-LRKLRKRLLR (mApoE), which is derived from the receptor binding sequence of apolipoprotein E, is effectively able to inhibit Aβ aggregation and to promote fibril disaggregation. Taking advantage of Atomic Force Microscopy (AFM) imaging and fluorescence techniques, we investigate if the clustering of mApoE on gold nanoparticles (AuNP) surface may affect its performance in controlling Aβ aggregation/disaggregation processes. The results showed that the ability of free mApoE to destroy preformed Aβ fibrils or to hinder the Aβ aggregation process is preserved after its clustering on AuNP. This allows the possibility to design multifunctional drug delivery systems with clustering of anti-amyloidogenic molecules on any NP surface without affecting their performance in controlling Aβ aggregation processes. Full article

(This article belongs to the Special Issue Alzheimer’s Disease and Other Dementias-Novel Therapeutic Approaches)

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Review

Jump to: Research

17 pages, 257 KiB

Open AccessReview

Is There Justification to Treat Neurodegenerative Disorders by Repurposing Drugs? The Case of Alzheimer’s Disease, Lithium, and Autophagy

by Odeya Damri, Nofar Shemesh and Galila Agam

Int. J. Mol. Sci. 2021, 22(1), 189; https://doi.org/10.3390/ijms22010189 - 27 Dec 2020

Cited by 23 | Viewed by 4274

Abstract

Lithium is the prototype mood-stabilizer used for acute and long-term treatment of bipolar disorder. Cumulated translational research of lithium indicated the drug’s neuroprotective characteristics and, thereby, has raised the option of repurposing it as a drug for neurodegenerative diseases. Lithium’s neuroprotective properties rely [...] Read more.

Lithium is the prototype mood-stabilizer used for acute and long-term treatment of bipolar disorder. Cumulated translational research of lithium indicated the drug’s neuroprotective characteristics and, thereby, has raised the option of repurposing it as a drug for neurodegenerative diseases. Lithium’s neuroprotective properties rely on its modulation of homeostatic mechanisms such as inflammation, mitochondrial function, oxidative stress, autophagy, and apoptosis. This myriad of intracellular responses are, possibly, consequences of the drug’s inhibition of the enzymes inositol-monophosphatase (IMPase) and glycogen-synthase-kinase (GSK)-3. Here we review lithium’s neurobiological properties as evidenced by its neurotrophic and neuroprotective properties, as well as translational studies in cells in culture, in animal models of Alzheimer’s disease (AD) and in patients, discussing the rationale for the drug’s use in the treatment of AD. Full article

(This article belongs to the Special Issue Alzheimer’s Disease and Other Dementias-Novel Therapeutic Approaches)

34 pages, 916 KiB

Open AccessReview

Therapeutic Targeting Strategies for Early- to Late-Staged Alzheimer’s Disease

by You Jung Kang, Yen N. Diep, Minh Tran and Hansang Cho

Int. J. Mol. Sci. 2020, 21(24), 9591; https://doi.org/10.3390/ijms21249591 - 16 Dec 2020

Cited by 21 | Viewed by 4345

Abstract

Alzheimer’s disease (AD) is the most common cause of dementia, typically showing progressive neurodegeneration in aging brains. The key signatures of the AD progression are the deposition of amyloid-beta (Aβ) peptides, the formation of tau tangles, and the induction of detrimental neuroinflammation leading [...] Read more.

Alzheimer’s disease (AD) is the most common cause of dementia, typically showing progressive neurodegeneration in aging brains. The key signatures of the AD progression are the deposition of amyloid-beta (Aβ) peptides, the formation of tau tangles, and the induction of detrimental neuroinflammation leading to neuronal loss. However, conventional pharmacotherapeutic options are merely relying on the alleviation of symptoms that are limited to mild to moderate AD patients. Moreover, some of these medicines discontinued to use due to either the insignificant effectiveness in improving the cognitive impairment or the adverse side effects worsening essential bodily functions. One of the reasons for the failure is the lack of knowledge on the underlying mechanisms that can accurately explain the major causes of the AD progression correlating to the severity of AD. Therefore, there is an urgent need for the better understanding of AD pathogenesis and the development of the disease-modifying treatments, particularly for severe and late-onset AD, which have not been covered thoroughly. Here, we review the underlying mechanisms of AD progression, which have been employed for the currently established therapeutic strategies. We believe this will further spur the discovery of a novel disease-modifying treatment for mild to severe, as well as early- to late-onset, AD. Full article

(This article belongs to the Special Issue Alzheimer’s Disease and Other Dementias-Novel Therapeutic Approaches)

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37 pages, 1346 KiB

Open AccessReview

Modulation of Brain Hyperexcitability: Potential New Therapeutic Approaches in Alzheimer’s Disease

by Sofia Toniolo, Arjune Sen and Masud Husain

Int. J. Mol. Sci. 2020, 21(23), 9318; https://doi.org/10.3390/ijms21239318 - 07 Dec 2020

Cited by 46 | Viewed by 8351

Abstract

People with Alzheimer’s disease (AD) have significantly higher rates of subclinical and overt epileptiform activity. In animal models, oligomeric Aβ amyloid is able to induce neuronal hyperexcitability even in the early phases of the disease. Such aberrant activity subsequently leads to downstream accumulation [...] Read more.

People with Alzheimer’s disease (AD) have significantly higher rates of subclinical and overt epileptiform activity. In animal models, oligomeric Aβ amyloid is able to induce neuronal hyperexcitability even in the early phases of the disease. Such aberrant activity subsequently leads to downstream accumulation of toxic proteins, and ultimately to further neurodegeneration and neuronal silencing mediated by concomitant tau accumulation. Several neurotransmitters participate in the initial hyperexcitable state, with increased synaptic glutamatergic tone and decreased GABAergic inhibition. These changes appear to activate excitotoxic pathways and, ultimately, cause reduced long-term potentiation, increased long-term depression, and increased GABAergic inhibitory remodelling at the network level. Brain hyperexcitability has therefore been identified as a potential target for therapeutic interventions aimed at enhancing cognition, and, possibly, disease modification in the longer term. Clinical trials are ongoing to evaluate the potential efficacy in targeting hyperexcitability in AD, with levetiracetam showing some encouraging effects. Newer compounds and techniques, such as gene editing via viral vectors or brain stimulation, also show promise. Diagnostic challenges include identifying best biomarkers for measuring sub-clinical epileptiform discharges. Determining the timing of any intervention is critical and future trials will need to carefully stratify participants with respect to the phase of disease pathology. Full article

(This article belongs to the Special Issue Alzheimer’s Disease and Other Dementias-Novel Therapeutic Approaches)

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17 pages, 1031 KiB

Open AccessReview

Clinical Utility of the Pathogenesis-Related Proteins in Alzheimer’s Disease

by Bin Zhou and Masanori Fukushima

Int. J. Mol. Sci. 2020, 21(22), 8661; https://doi.org/10.3390/ijms21228661 - 17 Nov 2020

Cited by 6 | Viewed by 2424

Abstract

Research on the Aβ cascade and alternations of biomarkers in neuro-inflammation, synaptic dysfunction, and neuronal injury followed by Aβ have progressed. But the question is how to use the biomarkers. Here, we examine the evidence and pathogenic implications of protein interactions and the [...] Read more.

Research on the Aβ cascade and alternations of biomarkers in neuro-inflammation, synaptic dysfunction, and neuronal injury followed by Aβ have progressed. But the question is how to use the biomarkers. Here, we examine the evidence and pathogenic implications of protein interactions and the time order of alternation. After the deposition of Aβ, the change of tau, neurofilament light chain (NFL), and neurogranin (Ng) is the main alternation and connection to others. Neuro-inflammation, synaptic dysfunction, and neuronal injury function is exhibited prior to the structural and metabolic changes in the brain following Aβ deposition. The time order of such biomarkers compared to the tau protein is not clear. Despite the close relationship between biomarkers and plaque Aβ deposition, several factors favor one or the other. There is an interaction between some proteins that can predict the brain amyloid burden. The Aβ cascade hypothesis could be the pathway, but not all subjects suffer from Alzheimer’s disease (AD) within a long follow-up, even with very elevated Aβ. The interaction of biomarkers and the time order of change require further research to identify the right subjects and right molecular target for precision medicine therapies. Full article

(This article belongs to the Special Issue Alzheimer’s Disease and Other Dementias-Novel Therapeutic Approaches)

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18 pages, 1241 KiB

Open AccessReview

Positron Emission Tomography (PET) and Neuroimaging in the Personalized Approach to Neurodegenerative Causes of Dementia

by Maria Ricci, Andrea Cimini, Agostino Chiaravalloti, Luca Filippi and Orazio Schillaci

Int. J. Mol. Sci. 2020, 21(20), 7481; https://doi.org/10.3390/ijms21207481 - 11 Oct 2020

Cited by 16 | Viewed by 5250

Abstract

Generally, dementia should be considered an acquired syndrome, with multiple possible causes, rather than a specific disease in itself. The leading causes of dementia are neurodegenerative and non-neurodegenerative alterations. Nevertheless, the neurodegenerative group of diseases that lead to cognitive impairment and dementia includes [...] Read more.

Generally, dementia should be considered an acquired syndrome, with multiple possible causes, rather than a specific disease in itself. The leading causes of dementia are neurodegenerative and non-neurodegenerative alterations. Nevertheless, the neurodegenerative group of diseases that lead to cognitive impairment and dementia includes multiple possibilities or mixed pathologies with personalized treatment management for each cause, even if Alzheimer’s disease is the most common pathology. Therefore, an accurate differential diagnosis is mandatory in order to select the most appropriate therapy approach. The role of personalized assessment in the treatment of dementia is rapidly growing. Neuroimaging is an essential tool for differential diagnosis of multiple causes of dementia and allows a personalized diagnostic and therapeutic protocol based on risk factors that may improve treatment management, especially in early diagnosis during the prodromal stage. The utility of structural and functional imaging could be increased by standardization of acquisition and analysis methods and by the development of algorithms for automated assessment. The aim of this review is to focus on the most commonly used tracers for differential diagnosis in the dementia field. Particularly, we aim to explore ¹⁸F Fluorodeoxyglucose (FDG) and amyloid positron emission tomography (PET) imaging in Alzheimer’s disease and in other neurodegenerative causes of dementia. Full article

(This article belongs to the Special Issue Alzheimer’s Disease and Other Dementias-Novel Therapeutic Approaches)

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14 pages, 541 KiB

Open AccessReview

Alzheimer’s Disease and Specialized Pro-Resolving Lipid Mediators: Do MaR1, RvD1, and NPD1 Show Promise for Prevention and Treatment?

by Keishi Miyazawa, Hisanori Fukunaga, Yasuko Tatewaki, Yumi Takano, Shuzo Yamamoto, Tatsushi Mutoh and Yasuyuki Taki

Int. J. Mol. Sci. 2020, 21(16), 5783; https://doi.org/10.3390/ijms21165783 - 12 Aug 2020

Cited by 17 | Viewed by 3293

Abstract

Alzheimer’s disease (AD) is a common neurodegenerative disease and a major contributor to progressive cognitive impairment in an aging society. As the pathophysiology of AD involves chronic neuroinflammation, the resolution of inflammation and the group of lipid mediators that actively regulate it—i.e., specialized [...] Read more.

Alzheimer’s disease (AD) is a common neurodegenerative disease and a major contributor to progressive cognitive impairment in an aging society. As the pathophysiology of AD involves chronic neuroinflammation, the resolution of inflammation and the group of lipid mediators that actively regulate it—i.e., specialized pro-resolving lipid mediators (SPMs)—attracted attention in recent years as therapeutic targets. This review focuses on the following three specific SPMs and summarizes their relationships to AD, as they were shown to effectively address and reduce the risk of AD-related neuroinflammation: maresin 1 (MaR1), resolvin D1 (RvD1), and neuroprotectin D1 (NPD1). These three SPMs are metabolites of docosahexaenoic acid (DHA), which is contained in fish oils and is thus easily available to the public. They are expected to become incorporated into promising avenues for preventing and treating AD in the future. Full article

(This article belongs to the Special Issue Alzheimer’s Disease and Other Dementias-Novel Therapeutic Approaches)

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