International Journal of Molecular Sciences

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15 pages, 2916 KiB

Open AccessArticle

7,8-Dihydroxy Efavirenz Is Not as Effective in CYP46A1 Activation In Vivo as Efavirenz or Its 8,14-Dihydroxy Metabolite

by Natalia Mast, Yong Li and Irina A. Pikuleva

Int. J. Mol. Sci. 2024, 25(4), 2242; https://doi.org/10.3390/ijms25042242 - 13 Feb 2024

Viewed by 1229

Abstract

High dose (S)-efavirenz (EFV) inhibits the HIV reverse transcriptase enzyme and is used to lower HIV load. Low-dose EFV allosterically activates CYP46A1, the key enzyme for cholesterol elimination from the brain, and is investigated as a potential treatment for Alzheimer’s disease. Simultaneously, [...] Read more.

High dose (S)-efavirenz (EFV) inhibits the HIV reverse transcriptase enzyme and is used to lower HIV load. Low-dose EFV allosterically activates CYP46A1, the key enzyme for cholesterol elimination from the brain, and is investigated as a potential treatment for Alzheimer’s disease. Simultaneously, we evaluate EFV dihydroxymetabolites for in vivo brain effects to compare with those of (S)-EFV. We have already tested (rac)-8,14dihydroxy EFV on 5XFAD mice, a model of Alzheimer’s disease. Herein, we treated 5XFAD mice with (rac)-7,8dihydroxy EFV. In both sexes, the treatment modestly activated CYP46A1 in the brain and increased brain content of acetyl-CoA and acetylcholine. Male mice also showed a decrease in the brain levels of insoluble amyloid β₄₀ peptides. However, the treatment had no effect on animal performance in different memory tasks. Thus, the overall brain effects of (rac)-7,8dihydroxy EFV were weaker than those of EFV and (rac)-8,14dihydroxy EFV and did not lead to cognitive improvements as were seen in treatments with EFV and (rac)-8,14dihydroxy EFV. An in vitro study assessing CYP46A1 activation in co-incubations with EFV and (rac)-7,8dihydroxy EFV or (rac)-8,14dihydroxy EFV was carried out and provided insight into the compound doses and ratios that could be used for in vivo co-treatments with EFV and its dihydroxymetabolite. Full article

(This article belongs to the Special Issue New Targets and Approaches for the Treatment of Alzheimer's Disease and Related Disorders)

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17 pages, 3635 KiB

Open AccessArticle

Molecular Mechanism of Zinc-Dependent Oligomerization of Alzheimer’s Amyloid-β with Taiwan (D7H) Mutation

by Olga I. Kechko, Alexei A. Adzhubei, Anna P. Tolstova, Maria I. Indeykina, Igor A. Popov, Sergey S. Zhokhov, Nikolay V. Gnuchev, Vladimir A. Mitkevich, Alexander A. Makarov and Sergey A. Kozin

Int. J. Mol. Sci. 2023, 24(14), 11241; https://doi.org/10.3390/ijms241411241 - 8 Jul 2023

Cited by 4 | Viewed by 1577

Abstract

Amyloid-β (Aβ) is a peptide formed by 39–43 amino acids, heterogenous by the length of its C-terminus. Aβ constitutes a subnanomolar monomeric component of human biological fluids; however, in sporadic variants of Alzheimer’s disease (AD), it forms soluble neurotoxic oligomers and accumulates as [...] Read more.

Amyloid-β (Aβ) is a peptide formed by 39–43 amino acids, heterogenous by the length of its C-terminus. Aβ constitutes a subnanomolar monomeric component of human biological fluids; however, in sporadic variants of Alzheimer’s disease (AD), it forms soluble neurotoxic oligomers and accumulates as insoluble extracellular polymeric aggregates (amyloid plaques) in the brain tissues. The plaque formation is controlled by zinc ions; therefore, abnormal interactions between the ions and Aβ seem to take part in the triggering of sporadic AD. The amyloid plaques contain various Aβ isoforms, among which the most common is Aβ with an isoaspartate in position 7 (isoD7). The spontaneous conversion of D7 to isoD7 is associated with Aβ aging. Aβ molecules with isoD7 (isoD7-Aβ) easily undergo zinc-dependent oligomerization, and upon administration to transgenic animals (mice, nematodes) used for AD modeling, act as zinc-dependent seeds of the pathological aggregation of Aβ. The formation of zinc-bound homo- and hetero-oligomers with the participation of isoD7-Aβ is based on the rigidly structured segment 11-EVHH-14, located in the Aβ metal binding domain (Aβ₁₆). Some hereditary variants of AD are associated with familial mutations within the domain. Among these, the most susceptible to zinc-dependent oligomerization is Aβ with Taiwan (D7H) mutation (D7H-Aβ). In this study, the D7H-Aβ metal binding domain (D7H-Aβ₁₆) has been used as a model to establish the molecular mechanism of zinc-induced D7H-Aβ oligomerization through turbidimetry, dynamic light scattering, isothermal titration calorimetry, mass spectrometry, and computer modelling. Additionally, the modeling data showed that a molecule of D7H-Aβ, as well as isoD7-Aβ in combination with two Aβ molecules, renders a stable zinc-induced heterotrimer. The trimers are held together by intermolecular interfaces via zinc ions, with the primary interfaces formed by 11-EVHH-14 sites of the interacting trimer subunits. In summary, the obtained results confirm the role of the 11-EVHH-14 region as a structure and function determinant for the zinc-dependent oligomerization of all known Aβ species (including various chemically modified isoforms and AD-associated mutants) and point at this region as a potent target for drugs aimed to stop amyloid plaque formation in both sporadic and hereditary variants of AD. Full article

(This article belongs to the Special Issue New Targets and Approaches for the Treatment of Alzheimer's Disease and Related Disorders)

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24 pages, 9857 KiB

Open AccessArticle

Mitochondria-Targeted Delivery Strategy of Dual-Loaded Liposomes for Alzheimer’s Disease Therapy

by Leysan Vasileva, Gulnara Gaynanova, Farida Valeeva, Grigory Belyaev, Irina Zueva, Kseniya Bushmeleva, Guzel Sibgatullina, Dmitry Samigullin, Alexandra Vyshtakalyuk, Konstantin Petrov, Lucia Zakharova and Oleg Sinyashin

Int. J. Mol. Sci. 2023, 24(13), 10494; https://doi.org/10.3390/ijms241310494 - 22 Jun 2023

Cited by 13 | Viewed by 2285

Abstract

Liposomes modified with tetradecyltriphenylphosphonium bromide with dual loading of α-tocopherol and donepezil hydrochloride were successfully designed for intranasal administration. Physicochemical characteristics of cationic liposomes such as the hydrodynamic diameter, zeta potential, and polydispersity index were within the range from 105 to 115 nm, [...] Read more.

Liposomes modified with tetradecyltriphenylphosphonium bromide with dual loading of α-tocopherol and donepezil hydrochloride were successfully designed for intranasal administration. Physicochemical characteristics of cationic liposomes such as the hydrodynamic diameter, zeta potential, and polydispersity index were within the range from 105 to 115 nm, from +10 to +23 mV, and from 0.1 to 0.2, respectively. In vitro release curves of donepezil hydrochloride were analyzed using the Korsmeyer–Peppas, Higuchi, First-Order, and Zero-Order kinetic models. Nanocontainers modified with cationic surfactant statistically better penetrate into the mitochondria of rat motoneurons. Imaging of rat brain slices revealed the penetration of nanocarriers into the brain. Experiments on transgenic mice with an Alzheimer’s disease model (APP/PS1) demonstrated that the intranasal administration of liposomes within 21 days resulted in enhanced learning abilities and a reduction in the formation rate of Aβ plaques in the entorhinal cortex and hippocampus of the brain. Full article

(This article belongs to the Special Issue New Targets and Approaches for the Treatment of Alzheimer's Disease and Related Disorders)

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23 pages, 4295 KiB

Open AccessArticle

Distinct Effects of Beta-Amyloid, Its Isomerized and Phosphorylated Forms on the Redox Status and Mitochondrial Functioning of the Blood–Brain Barrier Endothelium

by Aleksandra V. Petrovskaya, Artem M. Tverskoi, Evgeny P. Barykin, Kseniya B. Varshavskaya, Alexandra A. Dalina, Vladimir A. Mitkevich, Alexander A. Makarov and Irina Yu. Petrushanko

Int. J. Mol. Sci. 2023, 24(1), 183; https://doi.org/10.3390/ijms24010183 - 22 Dec 2022

Cited by 9 | Viewed by 2049

Abstract

The Alzheimer’s disease (AD)-associated breakdown of the blood–brain barrier (BBB) promotes the accumulation of beta-amyloid peptide (Aβ) in the brain as the BBB cells provide Aβ transport from the brain parenchyma to the blood, and vice versa. The breakdown of the BBB during [...] Read more.

The Alzheimer’s disease (AD)-associated breakdown of the blood–brain barrier (BBB) promotes the accumulation of beta-amyloid peptide (Aβ) in the brain as the BBB cells provide Aβ transport from the brain parenchyma to the blood, and vice versa. The breakdown of the BBB during AD may be caused by the emergence of blood-borne Aβ pathogenic forms, such as structurally and chemically modified Aβ species; their effect on the BBB cells has not yet been studied. Here, we report that the effects of Aβ₄₂, Aβ₄₂, containing isomerized Asp7 residue (iso-Aβ₄₂) or phosphorylated Ser8 residue (p-Aβ₄₂) on the mitochondrial potential and respiration are closely related to the redox status changes in the mouse brain endothelial cells bEnd.3. Aβ₄₂ and iso-Aβ₄₂ cause a significant increase in nitric oxide, reactive oxygen species, glutathione, cytosolic calcium and the mitochondrial potential after 4 h of incubation. P-Aβ₄₂ either does not affect or its effect develops after 24 h of incubation. Aβ₄₂ and iso-Aβ₄₂ activate mitochondrial respiration compared to p-Aβ₄₂. The isomerized form promotes a greater cytotoxicity and mitochondrial dysfunction, causing maximum oxidative stress. Thus, Aβ₄₂, p-Aβ₄₂ and iso-Aβ₄₂ isoforms differently affect the BBBs’ cell redox parameters, significantly modulating the functioning of the mitochondria. The changes in the level of modified Aβ forms can contribute to the BBBs’ breakdown during AD. Full article

(This article belongs to the Special Issue New Targets and Approaches for the Treatment of Alzheimer's Disease and Related Disorders)

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Review

Jump to: Research

14 pages, 1733 KiB

Open AccessReview

Cannabinoid and Orexigenic Systems Interplay as a New Focus of Research in Alzheimer’s Disease

by Joan Biel Rebassa, Toni Capó, Jaume Lillo, Iu Raïch, Irene Reyes-Resina and Gemma Navarro

Int. J. Mol. Sci. 2024, 25(10), 5378; https://doi.org/10.3390/ijms25105378 - 15 May 2024

Viewed by 1288

Abstract

Alzheimer’s disease (AD) remains a significant health challenge, with an increasing prevalence globally. Recent research has aimed to deepen the understanding of the disease pathophysiology and to find potential therapeutic interventions. In this regard, G protein-coupled receptors (GPCRs) have emerged as novel potential [...] Read more.

Alzheimer’s disease (AD) remains a significant health challenge, with an increasing prevalence globally. Recent research has aimed to deepen the understanding of the disease pathophysiology and to find potential therapeutic interventions. In this regard, G protein-coupled receptors (GPCRs) have emerged as novel potential therapeutic targets to palliate the progression of neurodegenerative diseases such as AD. Orexin and cannabinoid receptors are GPCRs capable of forming heteromeric complexes with a relevant role in the development of this disease. On the one hand, the hyperactivation of the orexins system has been associated with sleep–wake cycle disruption and Aβ peptide accumulation. On the other hand, cannabinoid receptor overexpression takes place in a neuroinflammatory environment, favoring neuroprotective effects. Considering the high number of interactions between cannabinoid and orexin systems that have been described, regulation of this interplay emerges as a new focus of research. In fact, in microglial primary cultures of APPSw/Ind mice model of AD there is an important increase in CB₂R–OX₁R complex expression, while OX₁R antagonism potentiates the neuroprotective effects of CB₂R. Specifically, pretreatment with the OX₁R antagonist has been shown to strongly potentiate CB₂R signaling in the cAMP pathway. Furthermore, the blockade of OX₁R can also abolish the detrimental effects of OX₁R overactivation in AD. In this sense, CB₂R–OX₁R becomes a new potential therapeutic target to combat AD. Full article

(This article belongs to the Special Issue New Targets and Approaches for the Treatment of Alzheimer's Disease and Related Disorders)

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18 pages, 3471 KiB

Open AccessReview

Mechanisms of 3-Hydroxyl 3-Methylglutaryl CoA Reductase in Alzheimer’s Disease

by Xun Zhou, Xiaolang Wu, Rui Wang, Lu Han, Huilin Li and Wei Zhao

Int. J. Mol. Sci. 2024, 25(1), 170; https://doi.org/10.3390/ijms25010170 - 22 Dec 2023

Cited by 4 | Viewed by 1936

Abstract

Alzheimer’s disease (AD) is the most common neurodegenerative disease worldwide and has a high incidence in the elderly. Unfortunately, there is no effective therapy for AD owing to its complicated pathogenesis. However, the development of lipid-lowering anti-inflammatory drugs has heralded a new era [...] Read more.

Alzheimer’s disease (AD) is the most common neurodegenerative disease worldwide and has a high incidence in the elderly. Unfortunately, there is no effective therapy for AD owing to its complicated pathogenesis. However, the development of lipid-lowering anti-inflammatory drugs has heralded a new era in the treatment of Alzheimer’s disease. Several studies in recent years have shown that lipid metabolic dysregulation and neuroinflammation are associated with the pathogenesis of AD. 3-Hydroxyl 3-methylglutaryl CoA reductase (HMGCR) is a rate-limiting enzyme in cholesterol synthesis that plays a key role in cholesterol metabolism. HMGCR inhibitors, known as statins, have changed from being solely lipid-lowering agents to neuroprotective compounds because of their effects on lipid levels and inflammation. In this review, we first summarize the main regulatory mechanism of HMGCR affecting cholesterol biosynthesis. We also discuss the pathogenesis of AD induced by HMGCR, including disordered lipid metabolism, oxidative stress, inflammation, microglial proliferation, and amyloid-β (Aβ) deposition. Subsequently, we explain the possibility of HMGCR as a potential target for AD treatment. Statins-based AD treatment is an ascent field and currently quite controversial; therefore, we also elaborate on the current application prospects and limitations of statins in AD treatment. Full article

(This article belongs to the Special Issue New Targets and Approaches for the Treatment of Alzheimer's Disease and Related Disorders)

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26 pages, 1788 KiB

Open AccessReview

Repositioning of Anti-Diabetic Drugs against Dementia: Insight from Molecular Perspectives to Clinical Trials

by Keren Esther Kristina Mantik, Sujin Kim, Bonsang Gu, Sohee Moon, Hyo-Bum Kwak, Dong-Ho Park and Ju-Hee Kang

Int. J. Mol. Sci. 2023, 24(14), 11450; https://doi.org/10.3390/ijms241411450 - 14 Jul 2023

Cited by 13 | Viewed by 3333

Abstract

Insulin resistance as a hallmark of type 2 DM (T2DM) plays a role in dementia by promoting pathological lesions or enhancing the vulnerability of the brain. Numerous studies related to insulin/insulin-like growth factor 1 (IGF-1) signaling are linked with various types of dementia. [...] Read more.

Insulin resistance as a hallmark of type 2 DM (T2DM) plays a role in dementia by promoting pathological lesions or enhancing the vulnerability of the brain. Numerous studies related to insulin/insulin-like growth factor 1 (IGF-1) signaling are linked with various types of dementia. Brain insulin resistance in dementia is linked to disturbances in Aβ production and clearance, Tau hyperphosphorylation, microglial activation causing increased neuroinflammation, and the breakdown of tight junctions in the blood–brain barrier (BBB). These mechanisms have been studied primarily in Alzheimer’s disease (AD), but research on other forms of dementia like vascular dementia (VaD), Lewy body dementia (LBD), and frontotemporal dementia (FTD) has also explored overlapping mechanisms. Researchers are currently trying to repurpose anti-diabetic drugs to treat dementia, which are dominated by insulin sensitizers and insulin substrates. Although it seems promising and feasible, none of the trials have succeeded in ameliorating cognitive decline in late-onset dementia. We highlight the possibility of repositioning anti-diabetic drugs as a strategy for dementia therapy by reflecting on current and previous clinical trials. We also describe the molecular perspectives of various types of dementia through the insulin/IGF-1 signaling pathway. Full article

(This article belongs to the Special Issue New Targets and Approaches for the Treatment of Alzheimer's Disease and Related Disorders)

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19 pages, 1587 KiB

Open AccessReview

Synthetic, Cell-Derived, Brain-Derived, and Recombinant β-Amyloid: Modelling Alzheimer’s Disease for Research and Drug Development

by Kseniya B. Varshavskaya, Vladimir A. Mitkevich, Alexander A. Makarov and Evgeny P. Barykin

Int. J. Mol. Sci. 2022, 23(23), 15036; https://doi.org/10.3390/ijms232315036 - 30 Nov 2022

Cited by 7 | Viewed by 3277

Abstract

Alzheimer’s disease (AD) is the most common cause of dementia in the elderly, characterised by the accumulation of senile plaques and tau tangles, neurodegeneration, and neuroinflammation in the brain. The development of AD is a pathological cascade starting according to the amyloid hypothesis [...] Read more.

Alzheimer’s disease (AD) is the most common cause of dementia in the elderly, characterised by the accumulation of senile plaques and tau tangles, neurodegeneration, and neuroinflammation in the brain. The development of AD is a pathological cascade starting according to the amyloid hypothesis with the accumulation and aggregation of the β-amyloid peptide (Aβ), which induces hyperphosphorylation of tau and promotes the pro-inflammatory activation of microglia leading to synaptic loss and, ultimately, neuronal death. Modelling AD-related processes is important for both studying the molecular basis of the disease and the development of novel therapeutics. The replication of these processes is often achieved with the use of a purified Aβ peptide. However, Aβ preparations obtained from different sources can have strikingly different properties. This review aims to compare the structure and biological effects of Aβ oligomers and aggregates of a higher order: synthetic, recombinant, purified from cell culture, or extracted from brain tissue. The authors summarise the applicability of Aβ preparations for modelling Aβ aggregation, neurotoxicity, cytoskeleton damage, receptor toxicity in vitro and cerebral amyloidosis, synaptic plasticity disruption, and cognitive impairment in vivo and ex vivo. Further, the paper discusses the causes of the reported differences in the effect of Aβ obtained from the sources mentioned above. This review points to the importance of the source of Aβ for AD modelling and could help researchers to choose the optimal way to model the Aβ-induced abnormalities. Full article

(This article belongs to the Special Issue New Targets and Approaches for the Treatment of Alzheimer's Disease and Related Disorders)

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