Microglia heterogeneity and neurodegeneration: The emerging paradigm of the role of immunity in Alzheimer's disease

Hashemiaghdam, Arsalan; Mroczek, Magdalena

doi:10.1016/j.jneuroim.2020.577185

Cited by 68 publications

(54 citation statements)

References 86 publications

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“…In brain, TREM2 is a gene that is almost exclusively expressed in microglia. Microglia involvement in AD is being extensively investigated, although its role in the disease is still unclear, both protective and deleterious roles have been attributed to it (54). Thus, we inquired whether any of the circTREM2 described above were expressed in microglia.…”

Section: Circtrem2 In Human Microglia Cellsmentioning

confidence: 99%

A TREM2-derived circRNA is upregulated in the entorhinal cortex of Alzheimer’s disease patients

Urdánoz‐Casado

Gordoa

Robles

et al. 2021

Preprint

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Circular RNAs (circRNAs) are a novel class of noncoding RNAs characterized by a covalent and stable closed loop structure. circRNAs are enriched in neural tissues, particularly at synapses, where they are involved in synaptic plasticity. Alzheimer's disease (AD) is considered a synaptopathy since neurodegeneration causes loss or dysfunction of synapses. Microglia participate in synaptic pruning and also play a crucial role in developing AD. For instance, genetic variants in TREM2, a microglia-related gene, are risk factors for AD. Alterations in circRNAs expression have been described in different neurological diseases, including AD. However, no TREM2-derived circRNAs have been described so far. TREM2 has 3 linear RNA variants due to alternative splicing. We hypothesized that alternative splicing of exon 4 might be favoring circRNAs originating from TREM2 (circTREM2s), which in turn might be involved in AD pathogenesis. First, divergent primers (overlapping exons 3-4 and 4-5) were designed to amplify circRNAs by RT-PCR, which were confirmed by Sanger sequencing. Three candidate TREM2-derived circRNAs were identified on control human entorhinal samples. Then, additional primer sets were used to confirm back-splicing junctions. One of the circRNAs, circTREM2_1, was consistently amplified with all primer sets. In addition, circTREM2_1 was also present in AD entorhinal cortex samples and in HMC3 cells. We observed that circTREM2_1 is up-regulated in AD entorhinal cortex samples compared to controls, particularly at early stages of the disease, when we performed RT-qPCR. In conclusion, we have identified a novel circRNA derived from the TREM2 gene that could play a role in AD pathogenesis.

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Section: Circtrem2 In Human Microglia Cellsmentioning

confidence: 99%

A TREM2-derived circRNA is upregulated in the entorhinal cortex of Alzheimer’s disease patients

Urdánoz‐Casado

Gordoa

Robles

et al. 2021

Preprint

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“…Abnormalities of Aβ and tau cause activation of microglia and astrocytes, and trigger the innate immune system by releasing proinflammatory mediators (for reviews [ 119 , 120 ]). Recent studies have revealed different types of pathological microglia associated with AD and key regulators of the microglia pathogenicity, such as the triggering receptor expressed on myeloid cells 2 [ 121 , 122 ]. Therefore, glial activation with associated inflammatory mediators and regulators are important targets for therapeutic approaches in AD research.…”

Section: Protective Effects Of Neuroactive Steroids On Ad-like Neumentioning

confidence: 99%

Steroids and Alzheimer’s Disease: Changes Associated with Pathology and Therapeutic Potential

Akwa

2020

IJMS

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Alzheimer’s disease (AD) is a multifactorial age-related neurodegenerative disease that today has no effective treatment to prevent or slow its progression. Neuroactive steroids, including neurosteroids and sex steroids, have attracted attention as potential suitable candidates to alleviate AD pathology. Accumulating evidence shows that they exhibit pleiotropic neuroprotective properties that are relevant for AD. This review focuses on the relationship between selected neuroactive steroids and the main aspects of AD disease, pointing out contributions and gaps with reference to sex differences. We take into account the regulation of brain steroid concentrations associated with human AD pathology. Consideration is given to preclinical studies in AD models providing current knowledge on the neuroprotection offered by neuroactive (neuro)steroids on major AD pathogenic factors, such as amyloid-β (Aβ) and tau pathology, mitochondrial impairment, neuroinflammation, neurogenesis and memory loss. Stimulating endogenous steroid production opens a new steroid-based strategy to potentially overcome AD pathology. This article is part of a Special Issue entitled Steroids and the Nervous System.

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“…Microglia have been suggested to be a major contributor to neural development, neuroinflammation, and degeneration. Dysregulated immunoactivity in Alzheimer's disease has been broadly studied, and the latest research on animal models has identified a new cluster of microglia (disease-associated microglia) alongside previously detected glial populations (e.g., plaque-associated microglia and dark microglia) [133].…”

Section: Autophagy Regulationmentioning

confidence: 99%

Lysosomotropic Features and Autophagy Modulators among Medical Drugs: Evaluation of Their Role in Pathologies

2020

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The concept of lysosomotropic agents significantly changed numerous aspects of cellular biochemistry, biochemical pharmacology, and clinical medicine. In the present review, we focused on numerous low-molecular and high-molecular lipophilic basic compounds and on the role of lipophagy and autophagy in experimental and clinical medicine. Attention was primarily focused on the most promising agents acting as autophagy inducers, which offer a new window for treatment and/or prophylaxis of various diseases, including type 2 diabetes mellitus, Parkinson’s disease, and atherosclerosis. The present review summarizes current knowledge on the lysosomotropic features of medical drugs, as well as autophagy inducers, and their role in pathological processes.

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Microglia heterogeneity and neurodegeneration: The emerging paradigm of the role of immunity in Alzheimer's disease

Cited by 68 publications

References 86 publications

A TREM2-derived circRNA is upregulated in the entorhinal cortex of Alzheimer’s disease patients

A TREM2-derived circRNA is upregulated in the entorhinal cortex of Alzheimer’s disease patients

Steroids and Alzheimer’s Disease: Changes Associated with Pathology and Therapeutic Potential

Lysosomotropic Features and Autophagy Modulators among Medical Drugs: Evaluation of Their Role in Pathologies

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