Friend, Foe or Both? Immune Activity in Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is marked by the presence of amyloid beta (Aβ) plaques, neurofibrillary tangles (NFT), neuronal death and synaptic loss, and inflammation in the brain. AD research has, in large part, been dedicated to the understanding of Aβ and NFT deposition as well as to the pharmacological reduction of these hallmarks. However, recent GWAS data indicates neuroinflammation plays a critical role in AD development, thereby redirecting research efforts toward unveiling the complexities of AD-associated neuroinflammation. It is clear that the innate immune system is intimately associated with AD progression, however, the specific roles of glia and neuroinflammation in AD pathology remain to be described. Moreover, inflammatory processes have largely been painted as detrimental to AD pathology, when in fact, many immune mechanisms such as phagocytosis aid in the reduction of AD pathologies. In this review, we aim to outline the delicate balance between the beneficial and detrimental aspects of immune activation in AD as a more thorough understanding of these processes is critical to development of effective therapeutics for AD.

Keywords: amyloid; cytokine; glia; neuroinflammation and neurodegeneration; tau.

FIGURE 1

Alzheimer’s disease risk-loci are involved in a variety of immune functions including phagocytosis and lysocytic activity, cytokine signaling and adaptive immunity. Neuronal production of Aβ and tau aggregates may be the initial trigger for this immune activity in AD.

FIGURE 2

There is a delicate balance between beneficial and harmful immune activity in Alzheimer’s disease. While some aspects of inflammation are protective, such as the phagocytosis of toxic protein species, other processes, such as sustained pro-inflammatory cytokine release are neurotoxic.