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25 pages, 7729 KiB

Open AccessArticle

Tetradecyl 2,3-Dihydroxybenzoate Improves Cognitive Function in AD Mice by Modulating Autophagy and Inflammation Through IPA and Hsc70 Targeting

by Opeyemi B. Fasina, Lanjie Li, Danni Chen, Meijuan Yi, Lan Xiang and Jianhua Qi

Int. J. Mol. Sci. 2024, 25(21), 11719; https://doi.org/10.3390/ijms252111719 - 31 Oct 2024

Viewed by 865

Abstract

Drug development for Alzheimer’s disease (AD) treatment is challenging due to its complex pathogenesis. Tetradecyl 2,3-dihydroxybenzoate (ABG-001), a leading compound identified in our prior research, has shown promising NGF-mimicking activity and anti-aging properties. In the present study, both high-fat diet (HFD)-induced AD mice [...] Read more.

Drug development for Alzheimer’s disease (AD) treatment is challenging due to its complex pathogenesis. Tetradecyl 2,3-dihydroxybenzoate (ABG-001), a leading compound identified in our prior research, has shown promising NGF-mimicking activity and anti-aging properties. In the present study, both high-fat diet (HFD)-induced AD mice and naturally aging AD mice were used to evaluate anti-AD effects. Meanwhile, RNA-sequences, Western blotting, immunofluorescence staining, enzyme-linked immunosorbent assay (ELISA), cellular thermal shift assay (CETSA), drug affinity-responsive target stability (DARTS) assay, construction of expression plasmid and protein purification, surface plasmon resonance (SPR) analysis, and 16S rRNA sequence analysis were used to identify the target protein of ABG-001 and clarify the mechanism of action for this molecule. ABG-001 effectively mitigates the memory dysfunction in both HFD-induced AD mice and naturally aging AD mice. The therapeutic effect of ABG-001 is attributed to its ability to promote neurogenesis, activate chaperone-mediated autophagy (CMA), and reduce neuronal inflammation. Additionally, ABG-001 positively influenced the gut microbiota, enhancing the production of indole-3-propionic acid (IPA), which is capable of crossing the blood–brain barrier (BBB) and contributes to neuronal regeneration. Furthermore, our research revealed that IPA, linked to the anti-AD properties of ABG-001, targets the heat shock cognate 70 kDa protein (Hsc70) and regulates the Hsc70/PKM2/HK2/LC3 and FOXO3a/SIRT1 signaling pathways. ABG-001 improves the memory dysfunction of AD mice by modulating autophagy and inflammation through IPA and Hsc70 targeting. These findings offer a novel approach for treating neurodegenerative diseases, focusing on the modification of the gut microbiota and metabolites coupled with anti-aging strategies. Full article

(This article belongs to the Special Issue Advances in Aging and Alzheimer’s Disease Research: From Molecular Mechanisms to Therapeutics)

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15 pages, 2950 KiB

Open AccessArticle

Reduced Expression of CLEC4G in Neurons Is Associated with Alzheimer’s Disease

by Xinwei Feng, Fangfang Qi, Yuying Huang, Ge Zhang and Wenbin Deng

Int. J. Mol. Sci. 2024, 25(9), 4621; https://doi.org/10.3390/ijms25094621 - 24 Apr 2024

Viewed by 1361

Abstract

CLEC4G, a glycan-binding receptor, has previously been demonstrated to inhibit Aβ generation, yet its brain localization and functions in Alzheimer’s disease (AD) are not clear. We explored the localization, function, and regulatory network of CLEC4G via experiments and analysis of RNA-seq databases. CLEC4G [...] Read more.

CLEC4G, a glycan-binding receptor, has previously been demonstrated to inhibit Aβ generation, yet its brain localization and functions in Alzheimer’s disease (AD) are not clear. We explored the localization, function, and regulatory network of CLEC4G via experiments and analysis of RNA-seq databases. CLEC4G transcripts and proteins were identified in brain tissues, with the highest expression observed in neurons. Notably, AD was associated with reduced levels of CLEC4G transcripts. Bioinformatic analyses revealed interactions between CLEC4G and relevant genes such as BACE1, NPC1, PILRA, TYROBP, MGAT1, and MGAT3, all displaying a negative correlation trend. We further identified the upstream transcriptional regulators NR2F6 and XRCC4 for CLEC4G and confirmed a decrease in CLEC4G expression in APP/PS1 transgenic mice. This study highlights the role of CLEC4G in protecting against AD progression and the significance of CLEC4G for AD research and management. Full article

(This article belongs to the Special Issue Advances in Aging and Alzheimer’s Disease Research: From Molecular Mechanisms to Therapeutics)

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17 pages, 3584 KiB

Open AccessArticle

A Stable Micellar Formulation of RAD001 for Intracerebroventricular Delivery and the Treatment of Alzheimer’s Disease and Other Neurological Disorders

by Laura Gianessi, Alessandro Magini, Roberto Dominici, Stefano Giovagnoli and Diego Dolcetta

Int. J. Mol. Sci. 2023, 24(24), 17478; https://doi.org/10.3390/ijms242417478 - 14 Dec 2023

Cited by 1 | Viewed by 1333

Abstract

A large body of evidence, replicated in many mouse models of Alzheimer’s disease (AD), supports the therapeutic efficacy of the oral mammalian target of rapamycin inhibitors (mTOR-Is). Our preliminary data show that intracerebroventricular (ICV) administration of everolimus (RAD001) soon after clinical onset greatly [...] Read more.

A large body of evidence, replicated in many mouse models of Alzheimer’s disease (AD), supports the therapeutic efficacy of the oral mammalian target of rapamycin inhibitors (mTOR-Is). Our preliminary data show that intracerebroventricular (ICV) administration of everolimus (RAD001) soon after clinical onset greatly diminished cognitive impairment and the intracellular beta amyloid and neurofibrillary tangle load. However, RAD001 shows >90% degradation after 7 days in solution at body temperature, thus hampering the development of proper therapeutic regimens for patients. To overcome such a drawback, we developed a stable, liquid formulation of mTOR-Is by loading RAD001 into distearoylphosphatidylethanolamine–polyethylene glycol 2000 (DSPE-PEG2000) micelles using the thin layer evaporation method. The formulation showed efficient encapsulation of RAD001 and a homogeneous colloidal size and stabilised RAD001, with over 95% of activity preserved after 14 days at 37 °C with a total decay only occurring after 98 days. RAD001-loaded DSPE-PEG2000 micelles were unchanged when stored at 4 and 25 °C over the time period investigated. The obtained formulation may represent a suitable platform for expedited clinical translation and effective therapeutic regimens in AD and other neurological diseases. Full article

(This article belongs to the Special Issue Advances in Aging and Alzheimer’s Disease Research: From Molecular Mechanisms to Therapeutics)

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18 pages, 29578 KiB

Open AccessArticle

Second Wave, Late-Stage Neuroinflammation in Cleared Brains of Aged 5xFAD Alzheimer’s Mice Detected by Macrolaser Light Sheet Microscopy Imaging

by Suk Hyun Lee and Hye Joo Son

Int. J. Mol. Sci. 2023, 24(23), 17058; https://doi.org/10.3390/ijms242317058 - 2 Dec 2023

Cited by 1 | Viewed by 1516

Abstract

This study leverages the innovative imaging capabilities of macrolaser light-sheet microscopy to elucidate the 3D spatial visualization of AD-associated neuropathologic networks in the transparent brains of 44-week-old 5xFAD mice. Brain samples from ten AD and seven control mice were prepared through a hydrophilic [...] Read more.

This study leverages the innovative imaging capabilities of macrolaser light-sheet microscopy to elucidate the 3D spatial visualization of AD-associated neuropathologic networks in the transparent brains of 44-week-old 5xFAD mice. Brain samples from ten AD and seven control mice were prepared through a hydrophilic tissue-clearing pipeline and immunostained with thioflavin S (β-amyloid), anti-CD11b antibody (microglia), and anti-ACSA-2 antibody (astrocytes). The 5xFAD group exhibited significantly higher average total surface volumes of β-amyloid accumulation than the control group (AD, 898,634,368 µm³ [383,355,488–1,324,986,752]; control, 33,320,178 µm³ [11,156,785–65,390,988], p = 0.0006). Within the AD group, there was significant interindividual and interindividual variability concerning the number and surface volume of individual amyloid particles throughout the entire brain. In the context of neuroinflammation, the 5xFAD group showed significantly higher average total surface volumes of anti-ACSA-2-labeled astrocytes (AD, 59,064,360 µm³ [27,815,500–222,619,280]; control, 20,272,722 µm³ [9,317,288–27,223,352], p = 0.0047) and anti-CD11b labeled microglia (AD, 51,210,100 µm³ [15,309,118–135,532,144]; control, 23,461,593 µm³ [14,499,170–27,924,110], p = 0.0162) than the control group. Contrary to the long-standing finding that early-stage neuroinflammation precedes the subsequent later-stage of neurodegeneration, our data reveal that the second wave, late-stage active neuroinflammation persists in the aged AD brains, even as they continue to show signs of ongoing neurodegeneration and significant amyloid accumulation. Full article

(This article belongs to the Special Issue Advances in Aging and Alzheimer’s Disease Research: From Molecular Mechanisms to Therapeutics)

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Review

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34 pages, 2934 KiB

Open AccessReview

From Plaques to Pathways in Alzheimer’s Disease: The Mitochondrial-Neurovascular-Metabolic Hypothesis

by Sarah Kazemeini, Ahmed Nadeem-Tariq, Ryan Shih, John Rafanan, Nabih Ghani and Thomas A. Vida

Int. J. Mol. Sci. 2024, 25(21), 11720; https://doi.org/10.3390/ijms252111720 - 31 Oct 2024

Viewed by 2057

Abstract

Alzheimer’s disease (AD) presents a public health challenge due to its progressive neurodegeneration, cognitive decline, and memory loss. The amyloid cascade hypothesis, which postulates that the accumulation of amyloid-beta (Aβ) peptides initiates a cascade leading to AD, has dominated research and therapeutic strategies. [...] Read more.

Alzheimer’s disease (AD) presents a public health challenge due to its progressive neurodegeneration, cognitive decline, and memory loss. The amyloid cascade hypothesis, which postulates that the accumulation of amyloid-beta (Aβ) peptides initiates a cascade leading to AD, has dominated research and therapeutic strategies. The failure of recent Aβ-targeted therapies to yield conclusive benefits necessitates further exploration of AD pathology. This review proposes the Mitochondrial–Neurovascular–Metabolic (MNM) hypothesis, which integrates mitochondrial dysfunction, impaired neurovascular regulation, and systemic metabolic disturbances as interrelated contributors to AD pathogenesis. Mitochondrial dysfunction, a hallmark of AD, leads to oxidative stress and bioenergetic failure. Concurrently, the breakdown of the blood–brain barrier (BBB) and impaired cerebral blood flow, which characterize neurovascular dysregulation, accelerate neurodegeneration. Metabolic disturbances such as glucose hypometabolism and insulin resistance further impair neuronal function and survival. This hypothesis highlights the interconnectedness of these pathways and suggests that therapeutic strategies targeting mitochondrial health, neurovascular integrity, and metabolic regulation may offer more effective interventions. The MNM hypothesis addresses these multifaceted aspects of AD, providing a comprehensive framework for understanding disease progression and developing novel therapeutic approaches. This approach paves the way for developing innovative therapeutic strategies that could significantly improve outcomes for millions affected worldwide. Full article

(This article belongs to the Special Issue Advances in Aging and Alzheimer’s Disease Research: From Molecular Mechanisms to Therapeutics)

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28 pages, 1739 KiB

Open AccessReview

Comprehensive Overview of Alzheimer’s Disease: Etiological Insights and Degradation Strategies

by Manish Kumar Singh, Yoonhwa Shin, Songhyun Ju, Sunhee Han, Sung Soo Kim and Insug Kang

Int. J. Mol. Sci. 2024, 25(13), 6901; https://doi.org/10.3390/ijms25136901 - 24 Jun 2024

Cited by 1 | Viewed by 2746

Abstract

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder and affects millions of individuals globally. AD is associated with cognitive decline and memory loss that worsens with aging. A statistical report using U.S. data on AD estimates that approximately 6.9 million individuals suffer [...] Read more.

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder and affects millions of individuals globally. AD is associated with cognitive decline and memory loss that worsens with aging. A statistical report using U.S. data on AD estimates that approximately 6.9 million individuals suffer from AD, a number projected to surge to 13.8 million by 2060. Thus, there is a critical imperative to pinpoint and address AD and its hallmark tau protein aggregation early to prevent and manage its debilitating effects. Amyloid-β and tau proteins are primarily associated with the formation of plaques and neurofibril tangles in the brain. Current research efforts focus on degrading amyloid-β and tau or inhibiting their synthesis, particularly targeting APP processing and tau hyperphosphorylation, aiming to develop effective clinical interventions. However, navigating this intricate landscape requires ongoing studies and clinical trials to develop treatments that truly make a difference. Genome-wide association studies (GWASs) across various cohorts identified 40 loci and over 300 genes associated with AD. Despite this wealth of genetic data, much remains to be understood about the functions of these genes and their role in the disease process, prompting continued investigation. By delving deeper into these genetic associations, novel targets such as kinases, proteases, cytokines, and degradation pathways, offer new directions for drug discovery and therapeutic intervention in AD. This review delves into the intricate biological pathways disrupted in AD and identifies how genetic variations within these pathways could serve as potential targets for drug discovery and treatment strategies. Through a comprehensive understanding of the molecular underpinnings of AD, researchers aim to pave the way for more effective therapies that can alleviate the burden of this devastating disease. Full article

(This article belongs to the Special Issue Advances in Aging and Alzheimer’s Disease Research: From Molecular Mechanisms to Therapeutics)

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14 pages, 1624 KiB

Open AccessReview

Astrocyte–Neuron Interaction via the Glutamate–Glutamine Cycle and Its Dysfunction in Tau-Dependent Neurodegeneration

by Marta Sidoryk-Węgrzynowicz, Kamil Adamiak and Lidia Strużyńska

Int. J. Mol. Sci. 2024, 25(5), 3050; https://doi.org/10.3390/ijms25053050 - 6 Mar 2024

Cited by 5 | Viewed by 2531

Abstract

Astroglia constitute the largest group of glial cells and are involved in numerous actions that are critical to neuronal development and functioning, such as maintaining the blood–brain barrier, forming synapses, supporting neurons with nutrients and trophic factors, and protecting them from injury. These [...] Read more.

Astroglia constitute the largest group of glial cells and are involved in numerous actions that are critical to neuronal development and functioning, such as maintaining the blood–brain barrier, forming synapses, supporting neurons with nutrients and trophic factors, and protecting them from injury. These properties are deeply affected in the course of many neurodegenerative diseases, including tauopathies, often before the onset of the disease. In this respect, the transfer of essential amino acids such as glutamate and glutamine between neurons and astrocytes in the glutamate–glutamine cycle (GGC) is one example. In this review, we focus on the GGC and the disruption of this cycle in tau-dependent neurodegeneration. A profound understanding of the complex functions of the GGC and, in the broader context, searching for dysfunctions in communication pathways between astrocytes and neurons via GGC in health and disease, is of critical significance for the development of novel mechanism-based therapies for neurodegenerative disorders. Full article

(This article belongs to the Special Issue Advances in Aging and Alzheimer’s Disease Research: From Molecular Mechanisms to Therapeutics)

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16 pages, 343 KiB

Open AccessReview

Recent Aspects of Periodontitis and Alzheimer’s Disease—A Narrative Review

by Dominika Cichońska, Magda Mazuś and Aida Kusiak

Int. J. Mol. Sci. 2024, 25(5), 2612; https://doi.org/10.3390/ijms25052612 - 23 Feb 2024

Cited by 3 | Viewed by 3836

Abstract

Periodontitis is an inflammatory condition affecting the supporting structures of the teeth. Periodontal conditions may increase the susceptibility of individuals to various systemic illnesses, including Alzheimer’s disease. Alzheimer’s disease is a neurodegenerative condition characterized by a gradual onset and progressive deterioration, making it [...] Read more.

Periodontitis is an inflammatory condition affecting the supporting structures of the teeth. Periodontal conditions may increase the susceptibility of individuals to various systemic illnesses, including Alzheimer’s disease. Alzheimer’s disease is a neurodegenerative condition characterized by a gradual onset and progressive deterioration, making it the primary cause of dementia, although the exact cause of the disease remains elusive. Both Alzheimer’s disease and periodontitis share risk factors and clinical studies comparing the associations and occurrence of periodontitis among individuals with Alzheimer’s disease have suggested a potential correlation between these conditions. Brains of individuals with Alzheimer’s disease have substantiated the existence of microorganisms related to periodontitis, especially Porphyromonas gingivalis, which produces neurotoxic gingipains and may present the capability to breach the blood–brain barrier. Treponema denticola may induce tau hyperphosphorylation and lead to neuronal apoptosis. Lipopolysaccharides—components of bacterial cell membranes and mediators of inflammation—also have an impact on brain function. Further research could unveil therapeutic approaches targeting periodontal pathogens to potentially alleviate AD progression. Full article

(This article belongs to the Special Issue Advances in Aging and Alzheimer’s Disease Research: From Molecular Mechanisms to Therapeutics)

27 pages, 820 KiB

Open AccessReview

Multi-Omic Blood Biomarkers as Dynamic Risk Predictors in Late-Onset Alzheimer’s Disease

by Oneil G. Bhalala, Rosie Watson and Nawaf Yassi

Int. J. Mol. Sci. 2024, 25(2), 1231; https://doi.org/10.3390/ijms25021231 - 19 Jan 2024

Cited by 3 | Viewed by 2786

Abstract

Late-onset Alzheimer’s disease is the leading cause of dementia worldwide, accounting for a growing burden of morbidity and mortality. Diagnosing Alzheimer’s disease before symptoms are established is clinically challenging, but would provide therapeutic windows for disease-modifying interventions. Blood biomarkers, including genetics, proteins and [...] Read more.

Late-onset Alzheimer’s disease is the leading cause of dementia worldwide, accounting for a growing burden of morbidity and mortality. Diagnosing Alzheimer’s disease before symptoms are established is clinically challenging, but would provide therapeutic windows for disease-modifying interventions. Blood biomarkers, including genetics, proteins and metabolites, are emerging as powerful predictors of Alzheimer’s disease at various timepoints within the disease course, including at the preclinical stage. In this review, we discuss recent advances in such blood biomarkers for determining disease risk. We highlight how leveraging polygenic risk scores, based on genome-wide association studies, can help stratify individuals along their risk profile. We summarize studies analyzing protein biomarkers, as well as report on recent proteomic- and metabolomic-based prediction models. Finally, we discuss how a combination of multi-omic blood biomarkers can potentially be used in memory clinics for diagnosis and to assess the dynamic risk an individual has for developing Alzheimer’s disease dementia. Full article

(This article belongs to the Special Issue Advances in Aging and Alzheimer’s Disease Research: From Molecular Mechanisms to Therapeutics)

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13 pages, 2403 KiB

Open AccessReview

Advances in Alzheimer’s Disease-Associated Aβ Therapy Based on Peptide

by Cunli Wang, Shuai Shao, Na Li, Zhengyao Zhang, Hangyu Zhang and Bo Liu

Int. J. Mol. Sci. 2023, 24(17), 13110; https://doi.org/10.3390/ijms241713110 - 23 Aug 2023

Cited by 4 | Viewed by 2503

Abstract

Alzheimer’s disease (AD) urgently needs innovative treatments due to the increasing aging population and lack of effective drugs and therapies. The amyloid fibrosis of AD-associated β-amyloid (Aβ) that could induce a series of cascades, such as oxidative stress and inflammation, is a critical [...] Read more.

Alzheimer’s disease (AD) urgently needs innovative treatments due to the increasing aging population and lack of effective drugs and therapies. The amyloid fibrosis of AD-associated β-amyloid (Aβ) that could induce a series of cascades, such as oxidative stress and inflammation, is a critical factor in the progression of AD. Recently, peptide-based therapies for AD are expected to be great potential strategies for the high specificity to the targets, low toxicity, fast blood clearance, rapid cell and tissue permeability, and superior biochemical characteristics. Specifically, various chiral amino acids or peptide-modified interfaces draw much attention as effective manners to inhibit Aβ fibrillation. On the other hand, peptide-based inhibitors could be obtained through affinity screening such as phage display or by rational design based on the core sequence of Aβ fibrosis or by computer aided drug design based on the structure of Aβ. These peptide-based therapies can inhibit Aβ fibrillation and reduce cytotoxicity induced by Aβ aggregation and some have been shown to relieve cognition in AD model mice and reduce Aβ plaques in mice brains. This review summarizes the design method and characteristics of peptide inhibitors and their effect on the amyloid fibrosis of Aβ. We further describe some analysis methods for evaluating the inhibitory effect and point out the challenges in these areas, and possible directions for the design of AD drugs based on peptides, which lay the foundation for the development of new effective drugs in the future. Full article

(This article belongs to the Special Issue Advances in Aging and Alzheimer’s Disease Research: From Molecular Mechanisms to Therapeutics)

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