The immunology of neurodegeneration

Abstract

While immune responses in neurodegeneration were regarded as little more than a curiosity a decade ago, they are now increasingly moving toward center stage. Factors driving this movement include the recognition that most of the relevant immune molecules are produced within the brain, that microglia are proficient immune cells shaping neuronal circuitry and fate, and that systemic immune responses affect brain function. We will review this complex field from the perspective of neurons, extra-neuronal brain cells, and the systemic environment and highlight the possibility that cell intrinsic innate immune molecules in neurons may function in neurodegenerative processes.

Figure 2. Innate immune receptors as sensors of intraneuronal distress.

Neurons express innate immune receptors that serve as sensors of danger signals. TLRs may recognize endogenous molecules and protein aggregates such as Aβ assemblies, ssRNA, or dsRNA aside from molecules associated with pathogens. While TLR4 and its co-receptor CD14 are present at the cell surface, TLR3, -7, -8, and -9 are located in the ER and endosomal compartments. Activation of TLRs can lead to initiation of autophagy via TRIF/RIP1 and possibly induce the clearance of defective organelles or protein aggregates. Activation of NOD1 or NOD2 may result in NF-κB–mediated transcription of pro-inflammatory genes or initiation of autophagy via Atg16L. The adaptor protein p62 can detect viral proteins in neurons and initiate clearance of viral particles via autophagy involving Atg5 and Atg7. It may also assist in the clearance of abnormal protein aggregates. Atg, autophagy-related protein; NOD, nucleotide binding oligomerization domain-like; p62, nucleoporin 62; TRIF, TIR domain–containing adapter-inducing IFN-β; RIP1, receptor interacting protein-1.

Figure 1. Immune-mediated interactions in neurodegeneration at the cellular, tissue, and systemic level.

Immune interactions in neurodegeneration can occur within neurons, in the brain tissue, or in the systemic environment through cytokines, neurotransmitters, cell-cell interactions, and peripheral nerves. Abnormalities at any of these levels of organization may modulate neurodegenerative processes in the CNS and may also serve as targets for therapeutic interventions. Some of the factors discussed in more detail in the text are listed in the figure.