The roles of innate and adaptive immunity in Alzheimer’s disease development and progression

In a recent study published in Immunity, researchers reviewed research advancements showing the significant role both innate and adaptive immune systems play in the pathological course of Alzheimer’s disease (AD).

Study: Emerging roles of innate and adaptive immunity in Alzheimer’s disease. Image Credit: Juan Gaertner/Shutterstock

Background

Studies have pointed out that the 'immune-privileged' state of the homeostatic brain parenchyma is conditional and exhibits regional variability. Non-resident immune cells can access, in particular, the border regions of the central nervous system (CNS) and form a potential connection with cell populations within the parenchyma. The brain detects and responds to these disturbances while maintaining neuronal function via immunological protection. In neurodegenerative diseases, such as AD, complex changes occur in innate and adaptive immunity.

AD, discovered in 1907, was pathologically characterized by regional brain atrophy with corresponding neuronal and synaptic loss, which likely account for cognitive changes. AD is also a disorder of protein aggregation, mainly the Amyloid-β (Aβ) and microtubule-associated protein tau. Aβ and tau aggregation subsequently damages synapses, neuronal processes, and the blood-brain barrier (BBB), which, in turn, allows the infiltration of peripheral immune cells into the brain. While AD is not an autoimmune disorder, alterations in the immune-privileged milieu, i.e., stark changes in the infrastructure of the innate and adaptive immune system, occur within the brain parenchyma in AD.

The core mechanisms governing the clinically symptomatic phase of AD are still incomprehensible. Several key regulators of innate immune pathways are genetic risk factors for AD. Data from in vivo studies points to the role of microglia; additionally, there is emerging evidence that the adaptive immunity plays a crucial role in AD pathogenesis.

Thus, it is crucial to map the disease-state-specific interlink between innate and adaptive immune systems, especially microglia and T cells. Understanding how these cells communicate, present antigens, and their pathophysiological responses could help find unique therapeutic interventions to prevent, treat, or reverse neurodegeneration in both the pre-clinical and clinically symptomatic phases of AD.

The link between AD genetic risk factors and innate and adaptive immunity

The monitoring of microglial state transitions,  including disease-associated microglia (DAM),  activated response microglia (ARM), and injury responsive microglia (IRM), could help develop specific compounds targeting microglia-mediated neurotoxicity and inflammatory pathways and might serve as a way for staging AD and developing strategies to slowdown or cease AD progression. Notably, microglia directly secrete cytokines and likely mediate synapse destruction through innate immune-related signaling pathways.

In vivo imaging in mice with Ly6C/G fluorescently labeled antibody have shown neutrophils infiltrating into brain parenchyma and migrating to amyloid plaques. They migrate into the parenchyma mediated by leukocyte function associated antigen-1 (LFA-1) integrin-dependent adhesion. However, it remains unclear whether infiltrating monocytes or monocyte-derived macrophages are beneficial or detrimental to Aβ – or tau-related pathologies. In addition, despite accumulating genetic and functional evidence, it also remains unclear whether the beneficial and detrimental roles of adaptive immunity in AD pathogenesis are direct or indirect.

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Apolipoprotein E (ApoE) is a lipoprotein whose expression is significantly enriched in immune cells, especially microglia and macrophages, especially under disease conditions. Numerous studies have revealed that ApoE is the strongest genetic risk factor for late-onset Alzheimer's disease (LOAD). A recent case report showed that an individual with two copies of the ApoE3 R136S mutation was relatively resistant to cognitive decline due to autosomal dominant AD.

The mechanism underlying this effect, however, is not clear. Transgenic animal studies have also recapitulated clinical observations and confirmed that ApoE strongly affects Aβ deposition, tau-mediated neurodegeneration, and other phenotypes, such as BBB dysfunction, antigen presentation, and T cell activation. In sporadic tauopathies, individuals bearing an ApoE4 allele had more neurodegeneration in the presence of similar amounts of tau pathology.

Similar to ApoE, triggering receptor expressed On myeloid cells 2 (Trem2) shows potential dual roles for DAM and disease progression in the context of amyloid plaque formation and tau pathology-mediated brain atrophy. This protein is a member of the immunoglobulin superfamily of receptors expressed in macrophages and microglia, emphasizing its potential role in immune modulation. Single amino acid differences at specific sites, such as R47H in humans, are associated with a two- to four-fold increased risk for AD. These mutations are further linked with decreased TREM2 function.

Complement pathways and their clearance functions elevate AD. For instance, in the Aβ-depositing mouse model J20, C1q, the initiating protein of the classical complement cascade, was increased and associated with synapses before overt plaque deposition, which appeared to contribute to synaptic loss. Since overtly activated complement pathways are a hallmark and driver of Aβ- and tau-mediated AD neurodegeneration, attenuating them could limit the same.

The interplay between innate and adaptive immunity in Alzheimer’s

Adaptive immunity is an important component in Aβ pathogenesis. In addition to their direct effects on neuronal viability, adaptive immunity also affects pathology and interacts with innate immunity, which, in turn, can influence neurodegeneration.

Several studies have found an increase of T cells in the CSF, leptomeninges, and hippocampus in AD patient post-mortem tissue and both Aβ and tau mouse models. A predominance of CD8+ rather than CD4+ T cells was noted. A greater number of T cells were located in the hippocampus and other limbic structures with more severe pathology in AD patients, indicating a tight link between neuronal damage and T cell accumulation.

Under homeostatic conditions, T regulatory cells and effector T cells interact with microglia, together with their secreted anti- or pro-inflammatory cytokines, including interferon-gamma (IFN-γ). In AD, microglia produce cytokines, neurotoxic reactive oxygen species (ROS), and inducible nitric oxide synthase (iNOS), leading to a neuroinflammatory cascade in the brain parenchyma that can lead to T cell invasion and activated T cells secrete neurotoxic mediators that accelerate brain atrophy.

Whether IFN-γ signaling could serve as a potential therapeutic target by either neutralization of IFN-γ or genetic or manipulation of its receptor in specific cell types, such as microglia and neurons, require further studies. Hence, the role of adaptive immunity with tauopathy and neurodegeneration together with the immune microenvironment in the brain parenchyma require investigation. In APP/PS1 mice, transgenic mice expressing a chimeric mouse/human amyloid precursor protein, aging, diabetes, circadian rhythm, sleep dysfunction, and gut microbiota, all emerged as AD risk factors.

Conclusion

Concerted activities of both innate and adaptive immune effectors are crucial for shaping an appropriate immune response in the entirely new immune milieu observed in AD patients. The interplay of these two immunity arms contributes to AD development and progression. Thus, innate and adaptive immune responses in the brain parenchyma and its periphery could be a key nexus to set up therapeutic targets for treating both the pre-symptomatic and the symptomatic stages of AD.

Journal reference:
  • "Emerging roles of innate and adaptive immunity in Alzheimer’s disease", Immunity. doi: 10.1016/j.immuni.2022.10.016. https://www.sciencedirect.com/science/article/abs/pii/S107476132200557X

Posted in: Medical Science News | Medical Research News | Disease/Infection News

Tags: Aging, Allele, Alzheimer's Disease, Amino Acid, Amyloid Plaque, Antibody, Antigen, Apolipoprotein, Autosomal, Blood, Brain, CD4, Cell, Central Nervous System, Circadian Rhythm, Cytokines, Diabetes, Genetic, Hippocampus, Imaging, Immune Response, Immune System, immunity, Immunoglobulin, in vivo, Interferon, Interferon-gamma, Leukocyte, Lipoprotein, Microglia, Monocyte, Mouse Model, Mutation, Nervous System, Neurodegeneration, Neurodegenerative Diseases, Neurons, Neutrophils, Nitric Oxide, Oxygen, Pathology, Protein, Protein Aggregation, Receptor, Research, Sleep, Synapse, Transgenic

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Written by

Neha Mathur

Neha is a digital marketing professional based in Gurugram, India. She has a Master’s degree from the University of Rajasthan with a specialization in Biotechnology in 2008. She has experience in pre-clinical research as part of her research project in The Department of Toxicology at the prestigious Central Drug Research Institute (CDRI), Lucknow, India. She also holds a certification in C++ programming.

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