Biomedicines

Editorial

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4 pages, 181 KiB

Open AccessEditorial

Animal and Cellular Models of Alzheimer’s Disease

by David Baglietto-Vargas, Kristine K. Freude and Juan Antonio Garcia-Leon

Biomedicines 2024, 12(6), 1308; https://doi.org/10.3390/biomedicines12061308 - 13 Jun 2024

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Abstract

Animal and cellular models have been essential tools over the years to understand many pathogenic mechanisms underlying different neurodegenerative disorders (NDDs), including Alzheimer’s disease (AD) [...] Full article

(This article belongs to the Special Issue Animal and Cellular Models of Alzheimer’s Disease)

Research

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14 pages, 5225 KiB

Open AccessArticle

Trem2 Enhances Demyelination in the Csf1r^+/− Mouse Model of Leukoencephalopathy

by Fabrizio Biundo, Violeta Chitu, Şölen Gökhan, Edward Chen, Jude Oppong-Asare and E. Richard Stanley

Biomedicines 2023, 11(8), 2094; https://doi.org/10.3390/biomedicines11082094 - 25 Jul 2023

Cited by 4 | Viewed by 1585

Abstract

Colony-stimulating factor-1 receptor (CSF-1R)-related leukoencephalopathy (CRL) is a neurodegenerative disease that triggers early demyelination, leading to an adult-onset dementia. Triggering receptor expressed on myeloid cells-2 (TREM2) is a microglial receptor that promotes the activation of microglia and phagocytic clearance of apoptotic neurons and [...] Read more.

Colony-stimulating factor-1 receptor (CSF-1R)-related leukoencephalopathy (CRL) is a neurodegenerative disease that triggers early demyelination, leading to an adult-onset dementia. Triggering receptor expressed on myeloid cells-2 (TREM2) is a microglial receptor that promotes the activation of microglia and phagocytic clearance of apoptotic neurons and myelin debris. We investigated the role of Trem2 in the demyelination observed in the Csf1r^+/− mouse model of CRL. We show that elevation of Trem2 expression and callosal demyelination occur in 4–5-month-old Csf1r^+/− mice, prior to the development of symptoms. Absence of Trem2 in the Csf1r^+/− mouse attenuated myelin pathology and normalized microglial densities and morphology in the corpus callosum. Trem2 absence also prevented axonal degeneration and the loss of cortical layer V neurons observed in Csf1r^+/− mice. Furthermore, the absence of Trem2 prevented the accumulation of myelin-derived lipids in Csf1r^+/− macrophages and reduced the production of TNF-α after myelin engulfment. These data suggest that TREM2 contributes to microglial dyshomeostasis in CRL. Full article

(This article belongs to the Special Issue Animal and Cellular Models of Alzheimer’s Disease)

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19 pages, 1878 KiB

Open AccessArticle

Unexpected Classes of Aquaporin Channels Detected by Transcriptomic Analysis in Human Brain Are Associated with Both Patient Age and Alzheimer’s Disease Status

by Zein Amro, Matthew Ryan, Lyndsey E. Collins-Praino and Andrea J. Yool

Biomedicines 2023, 11(3), 770; https://doi.org/10.3390/biomedicines11030770 - 3 Mar 2023

Cited by 5 | Viewed by 2110

Abstract

The altered expression of known brain Aquaporin (AQP) channels 1, 4 and 9 has been correlated with neuropathological AD progression, but possible roles of other AQP classes in neurological disease remain understudied. The levels of transcripts of all thirteen human AQP subtypes were [...] Read more.

The altered expression of known brain Aquaporin (AQP) channels 1, 4 and 9 has been correlated with neuropathological AD progression, but possible roles of other AQP classes in neurological disease remain understudied. The levels of transcripts of all thirteen human AQP subtypes were compared in healthy and Alzheimer’s disease (AD) brains by statistical analyses of microarray RNAseq expression data from the Allen Brain Atlas database. Previously unreported, AQPs 0, 6 and 10, are present in human brains at the transcript level. Three AD-affected brain regions, hippocampus (HIP), parietal cortex (PCx) and temporal cortex (TCx), were assessed in three subgroups: young controls (n = 6, aged 24–57); aged controls (n = 26, aged 78–99); and an AD cohort (n = 12, aged 79–99). A significant positive correlation (p < 10⁻¹⁰) was seen for AQP transcript levels as a function of the subject’s age in years. Differential expressions correlated with brain region, age, and AD diagnosis, particularly between the HIP and cortical regions. Interestingly, three classes of AQPs (0, 6 and 8) upregulated in AD compared to young controls are permeable to H₂O₂. Of these, AQPs 0 and 8 were increased in TCx and AQP6 in HIP, suggesting a role of AQPs in AD-related oxidative stress. The outcomes here are the first to demonstrate that the expression profile of AQP channels in the human brain is more diverse than previously thought, and transcript levels are influenced by both age and AD status. Associations between reactive oxygen stress and neurodegenerative disease risk highlight AQPs 0, 6, 8 and 10 as potential therapeutic targets. Full article

(This article belongs to the Special Issue Animal and Cellular Models of Alzheimer’s Disease)

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0 pages, 5131 KiB

Open AccessArticle

Analysis of Cerebral Small Vessel Changes in AD Model Mice

by Abu Zaffar Shibly, Abdullah Md. Sheikh, Makoto Michikawa, Shatera Tabassum, Abul Kalam Azad, Xiaojing Zhou, Yuchi Zhang, Shozo Yano and Atsushi Nagai

Biomedicines 2023, 11(1), 50; https://doi.org/10.3390/biomedicines11010050 - 25 Dec 2022

Cited by 7 | Viewed by 2788 | Correction

Abstract

Amyloid β (Aβ) peptide is deposited in the brains of sporadic Alzheimer’s disease (AD) due to impaired vessel-dependent clearance. To understand the mechanisms, we investigated time-dependent cerebrovascular changes in AD model mice. Cerebrovascular and other pathological changes were analyzed in AD model mice [...] Read more.

Amyloid β (Aβ) peptide is deposited in the brains of sporadic Alzheimer’s disease (AD) due to impaired vessel-dependent clearance. To understand the mechanisms, we investigated time-dependent cerebrovascular changes in AD model mice. Cerebrovascular and other pathological changes were analyzed in AD model mice (J20 strain) aging from 2 to 9 months by immunostaining. At 2 months, Aβ was only intraneuronal, whereas vessels were positive from 3 months in J20 mice. Compared to wild-type (WT), vessel density was increased at 2 months but decreased at 9 months in J20 mice, claudin-5 levels were decreased, and vascular endothelial growth factor (VEGF) levels were increased in the cortex and hippocampus of J20 mice brain at all time points. Albumin extravasation was evident from 3 months in J20 brains. Collagen 4 was increased at 2 and 3 months. Aquaporin 4 was spread beyond the vessels starting from 3 months in J20, which was restricted around the vessel in wild-type mice. In conclusion, the study showed that an early decrease in claudin-5 was associated with VEGF expression, indicating dysfunction of the blood–brain barrier. Decreased claudin-5 might cause the leakage of blood constituents into the parenchyma that alters astrocyte polarity and its functions. Full article

(This article belongs to the Special Issue Animal and Cellular Models of Alzheimer’s Disease)

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Review

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36 pages, 2114 KiB

Open AccessReview

Microbiome Alterations and Alzheimer’s Disease: Modeling Strategies with Transgenic Mice

by Juan Antonio López-Villodres, Alejandro Escamilla, Silvia Mercado-Sáenz, Carmen Alba-Tercedor, Luis Manuel Rodriguez-Perez, Isabel Arranz-Salas, Raquel Sanchez-Varo and Diego Bermúdez

Biomedicines 2023, 11(7), 1846; https://doi.org/10.3390/biomedicines11071846 - 27 Jun 2023

Cited by 2 | Viewed by 3121

Abstract

In the last decade, the role of the microbiota–gut–brain axis has been gaining momentum in the context of many neurodegenerative and metabolic disorders, including Alzheimer’s disease (AD) and diabetes, respectively. Notably, a balanced gut microbiota contributes to the epithelial intestinal barrier maintenance, modulates [...] Read more.

In the last decade, the role of the microbiota–gut–brain axis has been gaining momentum in the context of many neurodegenerative and metabolic disorders, including Alzheimer’s disease (AD) and diabetes, respectively. Notably, a balanced gut microbiota contributes to the epithelial intestinal barrier maintenance, modulates the host immune system, and releases neurotransmitters and/or neuroprotective short-chain fatty acids. However, dysbiosis may provoke immune dysregulation, impacting neuroinflammation through peripheral–central immune communication. Moreover, lipopolysaccharide or detrimental microbial end-products can cross the blood–brain barrier and induce or at least potentiate the neuropathological progression of AD. Thus, after repeated failure to find a cure for this dementia, a necessary paradigmatic shift towards considering AD as a systemic disorder has occurred. Here, we present an overview of the use of germ-free and/or transgenic animal models as valid tools to unravel the connection between dysbiosis, metabolic diseases, and AD, and to investigate novel therapeutical targets. Given the high impact of dietary habits, not only on the microbiota but also on other well-established AD risk factors such as diabetes or obesity, consistent changes of lifestyle along with microbiome-based therapies should be considered as complementary approaches. Full article

(This article belongs to the Special Issue Animal and Cellular Models of Alzheimer’s Disease)

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29 pages, 18308 KiB

Open AccessReview

Complexity of Sex Differences and Their Impact on Alzheimer’s Disease

by Marion Kadlecova, Kristine Freude and Henriette Haukedal

Biomedicines 2023, 11(5), 1261; https://doi.org/10.3390/biomedicines11051261 - 24 Apr 2023

Cited by 9 | Viewed by 7595

Abstract

Sex differences are present in brain morphology, sex hormones, aging processes and immune responses. These differences need to be considered for proper modelling of neurological diseases with clear sex differences. This is the case for Alzheimer’s disease (AD), a fatal neurodegenerative disorder with [...] Read more.

Sex differences are present in brain morphology, sex hormones, aging processes and immune responses. These differences need to be considered for proper modelling of neurological diseases with clear sex differences. This is the case for Alzheimer’s disease (AD), a fatal neurodegenerative disorder with two-thirds of cases diagnosed in women. It is becoming clear that there is a complex interplay between the immune system, sex hormones and AD. Microglia are major players in the neuroinflammatory process occurring in AD and have been shown to be directly affected by sex hormones. However, many unanswered questions remain as the importance of including both sexes in research studies has only recently started receiving attention. In this review, we provide a summary of sex differences and their implications in AD, with a focus on microglia action. Furthermore, we discuss current available study models, including emerging complex microfluidic and 3D cellular models and their usefulness for studying hormonal effects in this disease. Full article

(This article belongs to the Special Issue Animal and Cellular Models of Alzheimer’s Disease)

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19 pages, 680 KiB

Open AccessReview

Fats, Friends or Foes: Investigating the Role of Short- and Medium-Chain Fatty Acids in Alzheimer’s Disease

by Aishat O. Ameen, Kristine Freude and Blanca I. Aldana

Biomedicines 2022, 10(11), 2778; https://doi.org/10.3390/biomedicines10112778 - 1 Nov 2022

Cited by 7 | Viewed by 3325

Abstract

Characterising Alzheimer’s disease (AD) as a metabolic disorder of the brain is gaining acceptance based on the pathophysiological commonalities between AD and major metabolic disorders. Therefore, metabolic interventions have been explored as a strategy for brain energetic rescue. Amongst these, medium-chain fatty acid [...] Read more.

Characterising Alzheimer’s disease (AD) as a metabolic disorder of the brain is gaining acceptance based on the pathophysiological commonalities between AD and major metabolic disorders. Therefore, metabolic interventions have been explored as a strategy for brain energetic rescue. Amongst these, medium-chain fatty acid (MCFA) supplementations have been reported to rescue the energetic failure in brain cells as well as the cognitive decline in patients. Short-chain fatty acids (SCFA) have also been implicated in AD pathology. Due to the increasing therapeutic interest in metabolic interventions and brain energetic rescue in neurodegenerative disorders, in this review, we first summarise the role of SCFAs and MCFAs in AD. We provide a comparison of the main findings regarding these lipid species in established AD animal models and recently developed human cell-based models of this devastating disorder. Full article

(This article belongs to the Special Issue Animal and Cellular Models of Alzheimer’s Disease)

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Other

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2 pages, 855 KiB

Open AccessCorrection

Correction: Shibly et al. Analysis of Cerebral Small Vessel Changes in AD Model Mice. Biomedicines 2023, 11, 50

by Abu Zaffar Shibly, Abdullah Md. Sheikh, Makoto Michikawa, Shatera Tabassum, Abul Kalam Azad, Xiaojing Zhou, Yuchi Zhang, Shozo Yano and Atsushi Nagai

Biomedicines 2024, 12(1), 104; https://doi.org/10.3390/biomedicines12010104 - 4 Jan 2024

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Abstract

In the original publication [...] Full article

(This article belongs to the Special Issue Animal and Cellular Models of Alzheimer’s Disease)

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