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Immune Activation in Alzheimer Disease.
Literature Information
| DOI | 10.1146/annurev-immunol-101921-035222 |
|---|---|
| PMID | 38424470 |
| Journal | Annual review of immunology |
| Impact Factor | 33.3 |
| JCR Quartile | Q1 |
| Publication Year | 2024 |
| Times Cited | 25 |
| Keywords | Alzheimer disease, inflammasome, microglia, microglia receptors, neuroinflammation |
| Literature Type | Journal Article, Review |
| ISSN | 0732-0582 |
| Pages | 585-613 |
| Issue | 42(1) |
| Authors | Arnaud Mary, Renzo Mancuso, Michael T Heneka |
TL;DR
This review highlights the significant role of chronic immune activation, particularly through brain-resident macrophages known as microglia, in the pathogenesis of Alzheimer’s disease (AD), alongside traditional features like amyloid β plaques and tau tangles. By examining recent advances in understanding microglial activation and its transcriptional changes, the study underscores the need to consider peripheral signals and various immune cell types in developing new therapeutic strategies for AD amidst its rising medical and socio-economic burdens.
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Alzheimer disease · inflammasome · microglia · microglia receptors · neuroinflammation
Abstract
Alzheimer disease (AD) is the most common neurodegenerative disease, and with no efficient curative treatment available, its medical, social, and economic burdens are expected to dramatically increase. AD is historically characterized by amyloid β (Aβ) plaques and tau neurofibrillary tangles, but over the last 25 years chronic immune activation has been identified as an important factor contributing to AD pathogenesis. In this article, we review recent and important advances in our understanding of the significance of immune activation in the development of AD. We describe how brain-resident macrophages, the microglia, are able to detect Aβ species and be activated, as well as the consequences of activated microglia in AD pathogenesis. We discuss transcriptional changes of microglia in AD, their unique heterogeneity in humans, and emerging strategies to study human microglia. Finally, we expose, beyond Aβ and microglia, the role of peripheral signals and different cell types in immune activation.
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Primary Questions Addressed
- How does chronic immune activation influence the progression of Alzheimer's disease beyond amyloid β and tau pathology?
- What specific transcriptional changes occur in microglia during the progression of Alzheimer's disease?
- In what ways do peripheral immune signals interact with brain-resident macrophages in the context of Alzheimer's disease?
- What emerging strategies are being developed to study human microglia and their role in Alzheimer's disease?
- How does the heterogeneity of microglia in humans impact their function and response in Alzheimer's disease pathology?
Key Findings
Key Insights
Research Background and Purpose: Alzheimer disease (AD) represents the most prevalent form of neurodegeneration, with a steadily rising prevalence due to an aging population and the absence of effective curative treatments. Historically, the focus in AD research has been on the pathological hallmarks such as amyloid β (Aβ) plaques and tau neurofibrillary tangles. However, over the past 25 years, there has been a significant shift towards understanding the role of chronic immune activation in the disease's pathogenesis. The purpose of this review is to synthesize recent advancements in this area, particularly focusing on the immune system's involvement in AD and how it may contribute to disease progression.
Main Methods and Findings: The article reviews various studies that examine the activation of microglia, the brain's resident macrophages, in response to Aβ species. It highlights how these cells detect Aβ deposits and become activated, leading to both protective and detrimental effects on neuronal health. The authors discuss the transcriptional changes that microglia undergo in the context of AD and their heterogeneity, emphasizing that the immune response in humans may differ significantly from that observed in animal models. Additionally, the review explores the influence of peripheral immune signals and the involvement of various immune cell types beyond microglia in the context of AD.
Core Conclusions: The review concludes that immune activation plays a critical role in the pathogenesis of Alzheimer's disease, affecting both the progression and potential therapeutic strategies for the disease. It suggests that while microglial activation can serve a protective role against Aβ accumulation, excessive or chronic activation may lead to neuroinflammation and neuronal damage. Furthermore, the complexity of the immune response, including the interactions between central and peripheral immune systems, suggests that AD pathology is more intricate than previously understood, necessitating a broader focus in future research.
Research Significance and Impact: This article underscores the need for a paradigm shift in Alzheimer's research from merely addressing amyloid and tau pathology to incorporating immune mechanisms into the understanding and treatment of the disease. The findings may influence the development of novel therapeutic approaches that target immune activation pathways, potentially leading to more effective treatments. By highlighting the importance of microglial function and the immune response in AD, this research opens new avenues for investigating disease-modifying strategies, ultimately aiming to reduce the medical, social, and economic burdens associated with Alzheimer's disease. The insights gained could lead to improved patient outcomes and a deeper understanding of neurodegenerative diseases as a whole.
Literatures Citing This Work
- Epigenetic Changes in Alzheimer's Disease: DNA Methylation and Histone Modification. - Laura Maria De Plano;Alessandra Saitta;Salvatore Oddo;Antonella Caccamo - Cells (2024)
- The role of macrophage plasticity in neurodegenerative diseases. - Hongyue Ma;Mingxia Zhu;Mengjie Chen;Xiuli Li;Xinhong Feng - Biomarker research (2024)
- Association of MME gene polymorphisms with susceptibility to Alzheimer's disease in an Iranian population. - Fereshteh Khalili-Moghadam;Javad Hosseini Nejad;Taleb Badri;Morteza Sadeghi;Javad Gharechahi - Heliyon (2024)
- Immune system activation and cognitive impairment in arterial hypertension. - Stefanie Schreiber;Philipp Arndt;Lorena Morton;Alejandra P Garza;Patrick Müller;Katja Neumann;Hendrik Mattern;Marc Dörner;Jose Bernal;Stefan Vielhaber;Sven G Meuth;Ildiko R Dunay;Alexander Dityatev;Solveig Henneicke - American journal of physiology. Cell physiology (2024)
- Neurovascular unit, neuroinflammation and neurodegeneration markers in brain disorders. - Duraisamy Kempuraj;Kirk D Dourvetakis;Jessica Cohen;Daniel Seth Valladares;Rhitik Samir Joshi;Sai Puneeth Kothuru;Tristin Anderson;Baskaran Chinnappan;Amanpreet K Cheema;Nancy G Klimas;Theoharis C Theoharides - Frontiers in cellular neuroscience (2024)
- Penetratin and Mannose-Functionalized Cannabidiol Lipid Nanoparticles Encapsulating the BDNF Gene Reduce Amyloid-Induced Inflammation. - Bivek Chaulagain;Jagdish Singh - Molecular pharmaceutics (2025)
- The immunology of stroke and dementia. - Costantino Iadecola;Josef Anrather - Immunity (2025)
- Peripheral proteinopathy in neurodegenerative diseases. - Bin Xu;Xia Lei;Ying Yang;Jiayi Yu;Jun Chen;Zhi Xu;Keqiang Ye;Jing Zhang - Translational neurodegeneration (2025)
- Roles of central nervous system resident and recruited macrophages in the brain barrier system. - Ze Liu;Teng Cheng;Hongtian Dong;Dingya Sun;Yan Wang;Jiayan Li;Zhongwang Yu;Li Cao - Neural regeneration research (2026)
- Identification of therapeutic targets for Alzheimer's Disease Treatment using bioinformatics and machine learning. - ZhanQiang Xie;YongLi Situ;Li Deng;Meng Liang;Hang Ding;Zhen Guo;QinYing Xu;Zhu Liang;Zheng Shao - Scientific reports (2025)
... (15 more literatures)
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