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Alzheimer’s Disease: From Pathogenesis to Treatment

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: 30 May 2024 | Viewed by 7882

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Dr. Xavier Morató

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Guest Editor

Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya (UIC), 08028 Barcelona, Spain
Interests: dementia; Alzheimer’s disease; disease-modifying treatment; symptomatic treatment; personalized treatment; blood biomarkers

Special Issue Information

Dear Colleagues,

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the presence of insoluble amyloid plaques, hyperphosphorylation of tau with formation of intracellular neurofibrillary tangles. Furthermore, neuronal loss in different transmitter systems lead to neurochemical deficits that contribute to cognitive and behavioral symptoms. The field has gradually moved away from the simple assumption proposed by the amyloid hypothesis to new theories of pathogenesis, including neuroinflammation, changes in insulin resistance, calcium modulation, mitochondrial alterations and infections, between others.

Currently approved treatments for AD are “symptomatic” agents that aim to improve cognitive and behavioral symptoms without altering the underlying course of the disease and recently, two monoclonal antibodies targeting amyloid plaques have been approved.

With this Special Issue, we would like to focus on the mechanism of action (MoA) of pharmacological symptomatic and disease-modifying treatments for AD and describe novel non-pharmacological interventions used to manage both cognitive and behavioral symptoms.

Dr. Xavier Morató
Guest Editor

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Keywords

Alzheimer’s disease
neurodegeneration
neurotransmitter
Aβ
Tau
neuroinflammation
behavioral symptoms
symptomatic treatment
DMT

Published Papers (6 papers)

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Research

Jump to: Review

14 pages, 4003 KiB

Open AccessArticle

Astrocytes Excessively Engulf Synapses in a Mouse Model of Alzheimer’s Disease

by Lingjie Li, Shuai Lu, Jie Zhu, Xiaolin Yu, Shengjie Hou, Yaru Huang, Xiaoyun Niu, Xiaoyu Du and Ruitian Liu

Int. J. Mol. Sci. 2024, 25(2), 1160; https://doi.org/10.3390/ijms25021160 - 18 Jan 2024

Viewed by 955

Abstract

Synapse loss is one of the most critical features in Alzheimer’s disease (AD) and correlates with cognitive decline. Astrocytes mediate synapse elimination through multiple EGF-like domains 10 (MEGF10) pathways in the developing and adult brain to build the precise neural connectivity. However, whether and how astrocytes mediate synapse loss in AD remains unknown. We here find that the phagocytic receptor MEGF10 of astrocytes is significantly increased in vivo and in vitro, which results in excessive engulfment of synapses by astrocytes in APP/PS1 mice. We also observe that the astrocytic lysosomal-associated membrane protein 1 (LAMP1) is significantly elevated, colocalized with the engulfed synaptic puncta in APP/PS1 mice, and astrocytic lysosomes contain more engulfed synaptic puncta in APP/PS1 mice relative to wild type mice. Together, our data provide evidence that astrocytes excessively engulf synapses in APP/PS1 mice, which is mediated by increased MEGF10 and activated lysosomes. The approach targeting synapse engulfment pathway in astrocytes would be a potent therapy for AD. Full article

(This article belongs to the Special Issue Alzheimer’s Disease: From Pathogenesis to Treatment)

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17 pages, 3094 KiB

Open AccessArticle

Phenylacetyl-/Trolox- Amides: Synthesis, Sigma-1, HDAC-6, and Antioxidant Activities

by Rafael Flores, Shoaib Iqbal and Donald Sikazwe

Int. J. Mol. Sci. 2023, 24(20), 15295; https://doi.org/10.3390/ijms242015295 - 18 Oct 2023

Viewed by 1133

Abstract

In search of novel multi-mechanistic approaches for treating Alzheimer’s disease (AD), we have embarked on synthesizing single small molecules for probing contributory roles of the following combined disease targets: sigma-1 (σ-1), class IIb histone deacetylase-6 (HDAC-6), and oxidative stress (OS). Herein, we report the synthesis and partial evaluation of 20 amides (i.e., phenylacetic and Trolox or 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid derivatives). Target compounds were conveniently synthesized via amidation by either directly reacting acyl chlorides with amines or condensing acids with amines in the presence of coupling agents 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo [4,5-b] pyridinium 3-oxide hexafluorophosphate (HATU) or 1,1′-carbonyldiimidazole (CDI). Overall, this project afforded compound 8 as a promising lead with σ-1 affinity (Ki = 2.1 μM), HDAC-6 (IC₅₀ = 17 nM), and antioxidant (1.92 Trolox antioxidant equivalents or TEs) activities for optimization in ensuing structure–activity relationship (SAR) studies. Full article

(This article belongs to the Special Issue Alzheimer’s Disease: From Pathogenesis to Treatment)

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17 pages, 7254 KiB

Open AccessArticle

GABA-Positive Astrogliosis in Sleep-Promoting Areas Associated with Sleep Disturbance in 5XFAD Mice

by Victor James Drew, Mincheol Park and Tae Kim

Int. J. Mol. Sci. 2023, 24(11), 9695; https://doi.org/10.3390/ijms24119695 - 02 Jun 2023

Viewed by 1588

Abstract

Sleep disturbances, a debilitating symptom of Alzheimer’s disease (AD), are associated with neuropathological changes. However, the relationship between these disturbances and regional neuron and astrocyte pathologies remains unclear. This study examined whether sleep disturbances in AD result from pathological changes in sleep-promoting brain areas. Male 5XFAD mice underwent electroencephalography (EEG) recordings at 3, 6, and 10 months, followed by an immunohistochemical analysis of three brain regions associated with sleep promotion. The findings showed that 5XFAD mice demonstrated reduced duration and bout counts of nonrapid eye movement (NREM) sleep by 6 months and reduced duration and bout counts of rapid eye movement (REM) sleep by 10 months. Additionally, peak theta EEG power frequency during REM sleep decreased by 10 months. Sleep disturbances correlated with the total number of GFAP-positive astrocytes and the ratio of GFAP- and GABA-positive astrocytes across all three sleep-associated regions corresponding to their roles in sleep promotion. The presence of GABRD in sleep-promoting neurons indicated their susceptibility to inhibition by extrasynaptic GABA. This study reveals that neurotoxic reactive astrogliosis in NREM and REM sleep-promoting areas is linked to sleep disturbances in 5XFAD mice, which suggests a potential target for the treatment of sleep disorders in AD. Full article

(This article belongs to the Special Issue Alzheimer’s Disease: From Pathogenesis to Treatment)

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25 pages, 13497 KiB

Open AccessArticle

PSEN1 E280A Cholinergic-like Neurons and Cerebral Spheroids Derived from Mesenchymal Stromal Cells and from Induced Pluripotent Stem Cells Are Neuropathologically Equivalent

by Miguel Mendivil-Perez, Carlos Velez-Pardo, Francisco Lopera, Kenneth S. Kosik and Marlene Jimenez-Del-Rio

Int. J. Mol. Sci. 2023, 24(10), 8957; https://doi.org/10.3390/ijms24108957 - 18 May 2023

Viewed by 1198

Abstract

Alzheimer’s disease (AD) is a chronic neurological condition characterized by the severe loss of cholinergic neurons. Currently, the incomplete understanding of the loss of neurons has prevented curative treatments for familial AD (FAD). Therefore, modeling FAD in vitro is essential for studying cholinergic vulnerability. Moreover, to expedite the discovery of disease-modifying therapies that delay the onset and slow the progression of AD, we depend on trustworthy disease models. Although highly informative, induced pluripotent stem cell (iPSCs)-derived cholinergic neurons (ChNs) are time-consuming, not cost-effective, and labor-intensive. Other sources for AD modeling are urgently needed. Wild-type and presenilin (PSEN)1 p.E280A fibroblast-derived iPSCs, menstrual blood-derived menstrual stromal cells (MenSCs), and umbilical cord-derived Wharton Jelly’s mesenchymal stromal cells (WJ-MSCs) were cultured in Cholinergic-N-Run and Fast-N-Spheres V2 medium to obtain WT and PSEN 1 E280A cholinergic-like neurons (ChLNs, 2D) and cerebroid spheroids (CSs, 3D), respectively, and to evaluate whether ChLNs/CSs can reproduce FAD pathology. We found that irrespective of tissue source, ChLNs/CSs successfully recapitulated the AD phenotype. PSEN 1 E280A ChLNs/CSs show accumulation of iAPPβ fragments, produce eAβ42, present TAU phosphorylation, display OS markers (e.g., oxDJ-1, p-JUN), show loss of ΔΨ_m, exhibit cell death markers (e.g., TP53, PUMA, CASP3), and demonstrate dysfunctional Ca²⁺ influx response to ACh stimuli. However, PSEN 1 E280A 2D and 3D cells derived from MenSCs and WJ-MSCs can reproduce FAD neuropathology more efficiently and faster (11 days) than ChLNs derived from mutant iPSCs (35 days). Mechanistically, MenSCs and WJ-MSCs are equivalent cell types to iPSCs for reproducing FAD in vitro. Full article

(This article belongs to the Special Issue Alzheimer’s Disease: From Pathogenesis to Treatment)

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Review

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19 pages, 3736 KiB

Open AccessReview

Iron and Targeted Iron Therapy in Alzheimer’s Disease

by Jian Wang, Jiaying Fu, Yuanxin Zhao, Qingqing Liu, Xiaoyu Yan and Jing Su

Int. J. Mol. Sci. 2023, 24(22), 16353; https://doi.org/10.3390/ijms242216353 - 15 Nov 2023

Viewed by 1455

Abstract

Alzheimer’s disease (AD) is the most common neurodegenerative disease worldwide. β-amyloid plaque (Aβ) deposition and hyperphosphorylated tau, as well as dysregulated energy metabolism in the brain, are key factors in the progression of AD. Many studies have observed abnormal iron accumulation in different regions of the AD brain, which is closely correlated with the clinical symptoms of AD; therefore, understanding the role of brain iron accumulation in the major pathological aspects of AD is critical for its treatment. This review discusses the main mechanisms and recent advances in the involvement of iron in the above pathological processes, including in iron-induced oxidative stress-dependent and non-dependent directions, summarizes the hypothesis that the iron-induced dysregulation of energy metabolism may be an initiating factor for AD, based on the available evidence, and further discusses the therapeutic perspectives of targeting iron. Full article

(This article belongs to the Special Issue Alzheimer’s Disease: From Pathogenesis to Treatment)

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14 pages, 554 KiB

Open AccessReview

Calcium Dyshomeostasis Drives Pathophysiology and Neuronal Demise in Age-Related Neurodegenerative Diseases

by Gerard Griffioen

Int. J. Mol. Sci. 2023, 24(17), 13243; https://doi.org/10.3390/ijms241713243 - 26 Aug 2023

Cited by 2 | Viewed by 977

Abstract

This review postulates that age-related neurodegeneration entails inappropriate activation of intrinsic pathways to enable brain plasticity through deregulated calcium (Ca²⁺) signalling. Ca²⁺ in the cytosol comprises a versatile signal controlling neuronal cell physiology to accommodate adaptive structural and functional changes of neuronal networks (neuronal plasticity) and, as such, is essential for brain function. Although disease risk factors selectively affect different neuronal cell types across age-related neurodegenerative diseases (NDDs), these appear to have in common the ability to impair the specificity of the Ca²⁺ signal. As a result, non-specific Ca²⁺ signalling facilitates the development of intraneuronal pathophysiology shared by age-related NDDs, including mitochondrial dysfunction, elevated reactive oxygen species (ROS) levels, impaired proteostasis, and decreased axonal transport, leading to even more Ca²⁺ dyshomeostasis. These core pathophysiological processes and elevated cytosolic Ca²⁺ levels comprise a self-enforcing feedforward cycle inevitably spiralling toward high levels of cytosolic Ca²⁺. The resultant elevated cytosolic Ca²⁺ levels ultimately gear otherwise physiological effector pathways underlying plasticity toward neuronal demise. Ageing impacts mitochondrial function indiscriminately of the neuronal cell type and, therefore, contributes to the feedforward cycle of pathophysiology development seen in all age-related NDDs. From this perspective, therapeutic interventions to safely restore Ca²⁺ homeostasis would mitigate the excessive activation of neuronal destruction pathways and, therefore, are expected to have promising neuroprotective potential. Full article

(This article belongs to the Special Issue Alzheimer’s Disease: From Pathogenesis to Treatment)

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