Emerging roles of innate and adaptive immunity in Alzheimer's disease

Abstract

Alzheimer's disease (AD) is the most common neurodegenerative disease, with characteristic extracellular amyloid-β (Aβ) deposition and intracellular accumulation of hyperphosphorylated, aggregated tau. Several key regulators of innate immune pathways are genetic risk factors for AD. While these genetic risk factors as well as in vivo data point to key roles for microglia, emerging evidence also points to a role of the adaptive immune response in disease pathogenesis. We review the roles of innate and adaptive immunity, their niches, their communication, and their contributions to AD development and progression. We also summarize the cellular compositions and physiological functions of immune cells in the parenchyma, together with those in the brain border structures that form a dynamic disease-related immune niche. We propose that both innate and adaptive immune responses in brain parenchyma and border structures could serve as important therapeutic targets for treating both the pre-symptomatic and the symptomatic stages of AD.

Keywords: Alzheimer’s disease; adaptive immunity; immune niche; innate immunity.

Figure 1.. Interplay between innate and adaptive immunity in the homoeostatic and AD brain

(a) Under homeostatic conditions, the BBB, CSF/ISF fluid flow, and the lymphatic system work together to maintain a relatively immune privileged brain with surveilling microglia in the parenchyma with intact adaptive and innate immune system components at the border zone, which is believed to have an essential role to safeguard the brain including normal synapse and circuit functions. (b) In AD, sequential Aβ deposition and hyperphosphorylated tau accumulation induce parenchymal innate immune activation. These pathological changes affect the integrity of BBB, CSF/ISF flow and lymphatic drainage that subsequently lead to an evolving detrimental immune niche both in the brain parenchyma and border zone, including expansion of IFN responsive and antigen presenting microglia, increased inflammatory cytokine and antigen accumulation and T cell parenchymal infiltration, activation and TCR clonal expansion. These changes in the innate and adaptive immune system and their responses would therefore serve as a foundation for therapeutic development for AD.

Fig. 2. Microglial states and a model for a functional shift related to AD

Microglia are brain resident innate immune cells, which have major physiological functions in immune surveillance, phagocytosis and shaping neuronal functions under homeostatic conditions. In the setting of amyloid deposition, homeostatic microglia are transformed into disease associated microglia by downregulation of genes such as Cx3cr1, Tmem119 and P2ry12, and upregulation of genes such as Trem2, ApoE and Itgax. With amyloid deposition and accumulation, disease associated microglia mainly exert “protective” effects by limiting amyloid associated pathology. In the setting of tau accumulation, self-antigens and debris generated by demyelination or neuronal death trigger microglial phagocytosis and the disease associated microglia have a greater response to IFN and express MHC-I/MHC-II molecules. The IFN responsive and antigen presenting microglia could then potentially communicate with the adaptive immune system, and the detrimental immune microenvironment composed of both innate and adaptive immune cells could lead to a state with accelerated machinery driving neurodegeneration and brain atrophy.