**Abstract**

Amyloid diseases are characterized by the abnormal accumulation of proteinaceous aggregates (amyloid fibrils or plaques) in tissues and organs. This class of diseases is also characterized by the presence of inflammation. Amyloid fibrils arise from the partial denaturing and unfolding of native proteins. The accumulation of amyloid fibrils causes tissue damage and elicits local and nonlocal immune cell infiltration into tissue and proinflammatory cytokine production. Moreover, these conditions fuel a vicious cycle that can increase amyloid production and create an environment of chronic inflammation. A chronically inflamed tissue rapidly deteriorates and loses its function. In this chapter, we will discuss important data gathered over the years describing the role of inflammation in amyloid diseases. We will describe how inflammation begins and how it affects disease progression for major amyloid diseases, such as Alzheimer's disease (AD) and hereditary TTR amyloidosis (hATTR). Lastly, we will discuss the recent advancements in treatments for amyloid diseases and how they address inflammation in affected patients.

**Keywords:** amyloid diseases, neutrophils, proteases, fibrils, inflammation

### **1. Introduction**

In 1849, the term "amyloid" was first introduced by Matthias Schleiden to describe a starch-like material identified by an iodine-sulfuric acid staining of plant tissues [1]. Later in 1854, Rudolph Virchow observed similar deposits in human nervous tissue that reacted in an analogous manner as the deposits in plants after the addition of Schleiden's iodine-sulfuric acid stain [1]. With the advance in technological power and the advent of microscopy, researchers found that the starch-like deposits found in the diseased tissues of humans were made of proteinaceous structures that were organized as fibrils (termed "amyloid fibrils") and coated with carbohydrates, hence the reaction to iodine-sulfuric acid stains [1]. More than 40 pathologies are part of the family of diseases characterized as "Amyloid Diseases" [2]. The criteria that allow such characterization rely on the fact that these pathologies contain a very specific hallmark: the accumulation of amyloid fibrils in cells, tissues and/or organs. Fibrils are formed after native proteins partly unfold and aggregate into oligomers or amorphous aggregates that later organize themselves into mature, β-sheet-rich fibrillar structures [2]. On a molecular level, amyloid fibrils extracted from different patients can be indistinguishable from each other [2]. These structures can be formed outside the cell or inside the cell [2], and when they accumulate, they cause cellular damage or mechanical damage (if accumulating in between or on top of tissues).

For decades, scientists believed that amyloid fibrils were stable and inert, and the end result of a nontoxic natural pathway that serves to scavenge and store highly reactive and toxic oligomeric intermediates formed during the process of protein folding [3–5]. The reactive hydrophobic residues found exposed in oligomeric intermediates are hidden in mature amyloid fibrils, thus unable to react with important cellular components [6]. Although the latter is true about amyloid fibrils, research in the last two decades shows that these structures are neither inert nor nontoxic [5, 7]. When extracellular, amyloid fibrils are readily identified by the host immune system, mainly by macrophages or neutrophils [8–10]. These immune cells have receptors that recognize and bind to the amyloid fibrils and intermediates, activating a signaling cascade that results in the production of proinflammatory molecules [8–10]. In this chapter, we will review the inflammatory component of some clinically important amyloid diseases, such as Alzheimer's disease (AD) and familial amyloid pathologies, such as hereditary TTR amyloidosis (hATTR or familial amyloid polyneuropathy—FAP). We will also discuss how inflammatory cells contribute to disease progression by causing bystander damage to tissues or by enhancing protein aggregation, in the case of AA amyloidosis. Finally, we will provide the recent therapeutic approaches based on immune regulatory strategies for these diseases.
