**Abstract**

This chapter attempts to explore protective role of chaperone proteins in the neurodegenerative diseases caused by amyloidosis. These chaperones prevent amyloid pathology either directly, through chemical interactions with amyloidogenic species to mediate their refolding, solubilization and degradation, or indirectly, by scavenging reactive oxygen species produced as by-products of amyloid aggregation. Here we focus on structural and morphological changes during aggregation of amyloids which have been identified using Nuclear magnetic resonance spectroscopy, X-ray crystallography, Electron microscopy, Atomic force microscopy and other biophysical techniques as well as interactions between chaperone proteins and amyloid moieties. Non-proteolytic chaperones mediate amyloid clearance and metabolism through conformational changes due to proximity binding. In this chapter, we delineate these interactions as well as the molecular mechanism of chaperones used to sequester ROS products of amyloidosis with focus on amyloid-β peptides associated with the Alzheimer's disease.

**Keywords:** amyloid-β, structural biology, aggregation, chaperone, neuroprotection, Alzheimer's disease

#### **1. Introduction**

Abnormal deposition of amyloids or "Amyloidosis" is hallmark of several chronic cerebrovascular diseases including neurodegeneration culminating into dementia. Efforts to develop targeted drugs against amyloids have been hindered since there is no universal mechanism that leads to protein misfolding or aggregation, and the aggregates usually do not correspond directly to clinical symptoms of the diseases. A clearer understanding of molecular interactions of amyloids can drive the ongoing therapeutic efforts to prevent aggregation of nascent amyloids into pathological species and to design timely interventions. In addition to aging, precursor mutations in genes and proteins, gene multiplication, expansion of amyloidogenic sequences, and xenobiotics such as air pollutants are risk factors usually associated with amyloidosis disorders [1]. There are different amyloidogenic species causing a variety of neuropathic diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Poly-glutamine disorders like Huntington disease (HD), Prion diseases including Creutzfeldt-Jakob disease, Lewy body disease, Amyotrophic Lateral Sclerosis (ALS) as well as metabolic diseases such as type II diabetes (T2D) and corneal dystrophy to name a few [2]. AD is a pandemic form of dementia caused due to improper aggregation of amyloidogenic proteins-amyloid-β (Aβ), which is a cleavage product of amyloid precursor protein (APP) and tau, stabilizes microtubules in neurons [3]. Prognosis is also closely associated with aggregation of α-Synuclein (αS) protein into Lewy bodies usually concentrated in presynaptic terminals [4]. Human islet amyloid polypeptide (IAPP), also known as amylin, is secreted along with insulin from pancreatic β-islet cells. IAPP rich amyloid plaques, facilitated by insulin resistance, are hallmarks of T2D [5]. β-sheeted infectious isoform of cellular prion protein (PrP) causes transmissible spongiform encephalopathy (TSE), broadly known as prion disease [2].

In this chapter, we review various structures and conformations attained by Aβ peptides during the process of aggregation. We begin with introducing different morphologies and conformations attained by amyloids during this process. We outline mechanisms of amyloid pathology, either directly mediated by aggregates or indirectly through generation of oxidative stress. We have briefly alluded to chaperone functions of Heat shock protein (Hsp) family and their interactions to different amyloid structures as well as intracellular protease mechanisms. It is important to note that such intracellular proteases are almost entirely inefficient in dealing with large insoluble plaques. Here we emphasize on additional endogenous proteins which show potential as chaperones, albeit through different mechanisms. Towards the end, we discuss the role of oxidative stress in accelerating AD pathology and the effect of Aβ interactions with metal species. Mechanisms to alleviate oxidative stress and their possible protective role in AD have been discussed.
